Supportive Care: I Flashcards

1
Q

complications of N/V

  • most feared complication of chemo despite ___ nature
  • can result in the inability to deliver intended dose of chemo
A

limited
- dehydration
- electrolyte
- abnormalities
- fatigue
- depression

before 5-HT3 anti-emetics, it was expected to vomit 5-12 times per day

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2
Q

Types of N/V

anticipatory
- ___ response conditioned by severity and duration of previous emetic reactions from prior cycles of chemo
- non-PCOL like hypnosis helpful
- can be provoked by sight, sound, or smell

A

learned

cancer patients have hightened senses

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3
Q

Types of N/V

Acute
- emetic response correlating with the administration of chemo
- within __ hours of receiving chem

Delayed
- Related to chemotherapy occurring > ___ hours following completion of chemotherapy
– Mechanism is not fully understood, but there is ↑
evidence that substance P binding to ___ receptor may play a role

A

24
24
neurokinin 1

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4
Q

Types of N/V

Breakthrough
- occurs even if on scheduled anti-emetics ___ to chemotherapy

Refractory
- persists despite ___ anti-emetics
- Failed other therapies

A
  • prior
  • appropriate
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5
Q

Patho of CINV

  • Chemo is toxic to GI tract inducing damage to the epithelial cells
  • Enterochromaffin cells lining the GI tract contain large stores of ___ that are released in massive quantities after exposure to chemo
  • chemoreceptor trigger zone (CTZ)
    stimulates the vomiting center
  • Located in the nucleus tractus solitarii in the ___ which stimulates the emetic response
  • Input to the vomiting center from the higher cortical centers, pharynx, and GI
    tract can induce emesis
A
  • serotonin
  • medulla
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6
Q

Neurotransmitters implicated in CINV (5)

A
  • dopamine
  • histamine
  • acetylcholine
  • serotonin
  • substance P
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7
Q

highly emetogenic chemo (level 5)

single agent

A
  • Carboplatin
  • Carmustine
  • Cisplatin
  • Cyclophosphamide
  • Dacarbazine
  • Doxorubicin
  • Epirubicin
  • Fam-trastuzumab-deruxtecan
  • Ifosfamide
  • Mechlorethamine
  • Melphalan
  • Sacituzumab govitecan-hziy
  • Streptozocin
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8
Q

Combo Chemo

when considering combo chemo, need to consider emetogenicity
- level 1 or 2 agents do not contribute to the emetogenicity of the regimen
- adding level 3 or 4 ___ the emetogenicity of the combo by 1 level per agent
- add the different levels together to decide on which antiemetics to use

A

increasing

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9
Q

Oral Anticancer Agents

Moderate to high emetic risk:
(≥ 30% risk) Prophylaxis required on days of oral anticancer agent administration

A
  • Azacitidine
  • Busulfan
  • Ceritinib
  • Cyclophosphamide
  • Fedratinib
  • Lomustine
  • Midostaurin
  • Mitotane
  • Selinexor
  • Temozolomide
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10
Q

Oral Anticancer Agents

Moderate to high emetic risk:
(≥ 30% risk) As needed dosing is initially appropriate on days of oral anticancer agent administration

A
  • Adagrasib
  • Elacestrant
  • Avapritinib
  • Binimetinib
  • Bosutinib
  • Cabozantinib
  • Crizotinib
  • Dabrafenib
  • Enasidenib
  • Encorafenib
  • Estramustine
  • Etoposide
  • Imatinib
  • Lenvatinib
  • Niraparib
  • Olaparib
  • Procarbazine
  • Rucaparib
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11
Q

risk factors for CINV

  • women __ men
  • younger __ older
  • prior history of ___ and ___ sickness
  • previous CINV tend to do worse
  • anxiety/high pretreatment ___ of nausea
  • chronic ethanol can be ___
A
  • >
  • >
  • motion, morning
  • anticipation
  • protective
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12
Q

treatment guidelines

___ for acute N/V is based on the emetogenic potential of chemo
- ___ receptor antagonists may be substituted for each other
- oral efficacy = IV efficacy

A

prophylaxis
- 5HT3

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13
Q

highly emetogenic regimens

A) 4 drug
B) 3 drug
C) 3 drug

A

A) NK-1 antagonist, steroid, 5-HT3 antagonist, atypical anti-psychotic
B) atypical antipsychotic, 5HT-3 antagonist, steroid
C) NK-1 antagonist, steroid, 5-HT3 antagonist

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14
Q

These 3 agents can be added with any regimen and any emetogenicity if patients are experiencing these toxicities

A

+/- Lorazepam 0.5 mg to 2 mg PO or IV or sublingual either every 4 or 6 hours as needed
+/- H2 blocker or proton pump inhibitor

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15
Q

moderately emetogenic

A) 2 drug
B) 3 drug
C) 3 drugs

A
  • steroid, 5-HT3
  • anti-psychotic, steroid, 5-HT3
  • NK-1, steroid, 5-HT3 antagonist
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16
Q

low emetogenic regimens

only 1 needed
- steroid ( ___ )
- metoclopramide
- prochlorperazine
- 5-HT3 (3)

A
  • dexamethasone
  • dolasetron, granisetron, ondansetron
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17
Q

Breakthrough Nausea and Vomiting

give an additional agent from a different drug class as needed

A
  • haloperidol or metoclopramide
  • prochlorperazine or promethazine
  • olanzapine
  • lorazepam
  • dronabinol or nabilone
  • dolasetron, granisetron, or ondansetron
  • dexamethazone
  • scopolamine

Depending on the severity of the N/V, you can schedule these agents

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18
Q

Delayed Nausea and Vomiting

typically involves use of one of the following (3)

A
  • dexamethasone
  • NK-1 antagonist
  • olanzapine
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19
Q

Anticipatory N/V

___ - Use optimal antiemetic therapy during
every cycle of treatment
___ - 0.5 to 1 mg orally beginning the night before treatment and then again 1 to 2 hours prior to beginning of
chemotherapy

A
  • prevention
  • lorazepam
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20
Q

other prevention guidelines

Oral chemotherapy - High to moderate emetogenic risk
- Start ___ chemotherapy and continue daily
- ___ antagonists

Low to minimal emetogenic risk
- Start ___ chemotherapy and maybe given daily or prn
– ___
– ___
– ___ antagonists

A
  • before
  • 5-HT3
  • before
  • Metoclopramide
  • Prochlorperazine
  • 5-HT3
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21
Q

Other Prevention Guidelines

Radiation Induced Emesis
- Start pretreatment for each day of radiation
therapy
- ___ PO +/- dexamethasone
- ___ PO +/- dexamethasone

A

Granisetron
Ondansetron

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22
Q

Radiopharmaceuticals

  • Nausea is associated with the ___ infusion accompanying treatment
  • Antiemetics should be given ___ minutes prior to start of infusion

Recommendations for antiemetics include:
- ___ or ___ antagonists
- NOT ___ due to down regulation of somatostatin receptors

A
  • amino acid
  • 30
  • 5-HT3, NK-1
  • steroids
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23
Q

Common Toxicities Across Classes

Serotonin (5-HT3) antagonists
- Ondansetron
- Granisetron
- Dolasetron
- Palonosetron single agent or combination products (+/- netupitant
or fosnetupitant)

A
  • Headache
  • asymptomatic and transient EKG changes (max doses)
  • constipation
  • increased transaminases
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24
Q

Common Toxicities Across Classes

Corticosteroids
- Dexamethasone

A

(Short term use):
- Anxiety
- euphoria
- insomnia
- hyperglycemia
- ↑’d appetite

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25
# Common Toxicities Across Classes Substance P antagonists - Aprepitant - Aprepitant injectable emulsion - Fosaprepitant - Rolapitant - Netupitant - Fosnetupitan
- Hiccups - worry about drug interactions
26
# Common Toxicities Across Classes Dopamine antagonists - Chlorpromazine - Haloperidol - Metoclopramide
- Extrapyramidal side effects - diarrhea - sedation
27
# Common Toxicities Across Classes Atypical antipsychotic - Olanzapine
- dystonic reactions - sedation
28
# Common Toxicities Across Classes Phenothiazines - Prochlorperazine - Promethazine
- Sedation - akathesia - dystonia - IV promethazine = tissue damage
29
# Common Toxicities Across Classes Cannibanoids - Dronabinol
- Drowsiness - dizziness - euphoria - mood changes - hallucinations - ↑’d appetite
30
# Common Toxicities Across Classes Benzodiazepines - Lorazepam
- sedation - hypotension - urinary - incontinence - hallucinations
31
# Common Toxicities Across Classes Anticholinergic - Scopolamine Patch
- Anti-cholinergic side effects
32
# Important Principles for Prevention and Management - Review medical history, diagnosis, and concurrent medications – Consider any contributing causes to nausea/vomiting, and treat appropriately – ___ is a risk with phenothiazines and metoclopramide - Evaluate the emetogenic potential and pattern of the chemotherapeutic regimen to be given
EPS
33
# Important Principles for Prevention and Management - Emetogenicity is ___ - Emetogenic potential may be different on different days of treatment (stronger day 1 than 2 and 3) - acute/delayed N/V - most guidelines are tailored to chemo on day 1
additive
34
# Important Principles for Prevention and Management T or F: Anti-emetics are most effective when given as prophylaxis
T - Begin therapy at least 5 to 30 minutes prior to chemo - Administer around-the-clock until chemo is complete and provide PRN agents for breakthrough N/V - Always provide patients with additional PRN anti-emetics to take home
35
# Mucositis GI mucosa is comprised of epithelial cells and has a rapid turnover rate - Initiation -> Up-regulation with generation of messengers -> Signaling and amplification -> Ulceration -> Healing - range from mild inflammation to bleeding ulcerations - It can affect the entire length of the GI tract from top to bottom - Course parallels the neutrophil nadir and begins on day 5 to 7 after chemotherapy and improves as the neutrophil count ___
increases
36
# chemo induced mucositis Continuous infusions ___ short IV infusions
>
37
# risk factors to mucositis - Pre-existing oral lesions - Poor dental hygiene or ill-fitting dentures - Combined modality treatment ( ___ + ___ )
- chem + radiation
38
# Prevention and Treatment Diet recommendations: – Avoid rough food, spices, salt and acidic fruit – Mainly eat soft or liquid foods nonacidic fruits, soft cheeses, and eggs – Avoid ___ and alcohol Pre-treatment dental screening, especially in patients receiving ___ therapy to the oral mucosa or those receiving high-dose chemo with a ___ transplant – Baking soda rinses, soft-bristled toothbrush to minimize gingival irritation, saliva substitute for radiation-induced xerostomia
- smoking - radiation - bone marrow
39
# Pain Management - mucositis Topical anesthetics – Often provide adequate relief, but the effect tends to be short-lived – Various combinations of lidocaine, diphenhydramine, and antacids have been used with success ( ___ ___ ) - Patients should be instructed to swish and spit or swallow depending on the location of the mucositis) every few hours as needed Ice Chips - vaso ___ decreased chemo delivery to mouth - 30 min prior to ___ doses decreases incidence/severity Sucralfate - nauseating
magic mouthwash vasoconstriction 5-FU
40
# Pain Management - mucositis Oral and parenteral opioid analgesics - Often required in moderate to severe mucositis - Many oral solutions contain a high percentage of alcohol, which may burn (dont get OTC) - Opioids are best administered ___ for patients with moderate to severe mucositis - Use of ___ is common
- around the clock - PCA
41
# neutropenia White blood cells (WBC): - Normal range of 4.8-10.8 x10 3 /μL - Decreased WBC = Neutropenia (< 0.5 x 103 /μL), leukopenia, or granulocytopenia - Risk of life-threatening ___ Megakaryocytes (platelets) - Normal range of 140 - 440 x 10 3 /μL - ___ platelets = Thrombocytopenia (< 100 x 103 /μL) - Risk of ___ Red blood cells (RBC) - Normal range of 4.6 to 6.2 x1012 /L - Decreased RBC = ___ - Risks of hypoxia and __
- infection - decreased - bleeding - anemia - fatigue
42
# Neutropenia ___ suppression is the most common dose-limiting toxicity of chemo The ___ (usually described by the absolute neutrophil count or ANC) is the lowest value the blood counts fall to during a cycle of chemo - Generally, occurs ___to ___ days after chemo administration and counts usually recover by 3 to 4 weeks after - Some exceptions include mitomycin C and nitrosoureas which nadirs 4 - 6 weeks after treatment
- bone marrow - nadir - 10, 14
43
# Neutropenia ANC = WBC x % granulocytes (Segs + Bands) - To administer chemotherapy safely the patient’s counts should be as assessed prior to administration. These are typical guidelines: – WBC > __ x103 /μL OR – Absolute neutrophil count (ANC) of > ___ x103 /μL AND platelet count > ___ x103 /μL
- 3 - 1.5, 100
44
# neutropenia Severe neutropenia is defined as ANC < ___ x 103 /μL * Neutropenic patients are at an ↑’d risk of developing serious infections * ___ neutropenia (FN) is defined as: – ANC < 0.5 x 103 /μL and a single oral temperature > 101°F (> 38.3°C) or > 100.4°F (> 38.0°C) for at least an hour
- 0.5 - febrile
45
# neutropenia Other factors affecting myelosuppression:
- previous chemotherapy - previous radiation therapy - direct bone marrow involvement
46
# neutropenia T or F: The usual s/s of infection (abscess, pus, infiltrates on chest x-ray) are absent with fever being the only reliable indicator
T WBC low = no pus
47
# Colony Stimulating Factors (CSFs) Prophylactic use following chemo has demonstrated decreased: - Incidence of ___ neutropenia - Length of hospitalization - Confirmed ___ - Duration of ___
- febrile - infections - antibiotics
48
# CSF guidelines (ASCO NCCN) Primary prophylaxis If the patient is to receive a chemo regimen that is expected to cause > 20% incidence of ___ neutropenia High risk patients defined as: - Preexisting neutropenia due to disease - Extensive prior chemo - Previous irradiation to the pelvis or other areas containing large amounts of ___
- febrile - bone marrow
49
# CSF guidelines (ASCO) Secondary prophylaxis - The patient experienced a neutropenic complication from a previous cycle of chemo and now you want to prevent that again – Use a CSF ___ with next cycle of chemo
preventively
50
# Other uses for CSF’s: - Used to support patients through dose ___ chemo - Can be used alone, after chemo, or in combination with ___ to mobilize peripheral blood progenitor cells - After a __ transplant to reduce the duration of severe neutropenia - Guidelines for pediatric use are available and should be followed
- dense - plerixafor - stem cell
51
CSF agents (3)
- filgrastim - pegfilgrastim - sargramostim
52
# CSF - filgrastim - Regulates the production, maturation, and function of neutrophil cell line - Dose dependent elevation in neutrophil count, rapid drop in WBC and neutrophil count following ___ (approximately 50% decrease within 24 hours)
discontinuation
53
# CSF - pegfilgrastim - Differs from filgrastim due to a 20-kD pegylated molecule that is attached to the N-terminus of filgrastim - Stimulates production & maturation of neutrophil precursors like filgrastim - ___ pharmacokinetics & clearance ___ with increasing neutrophil count
- Non-linear - increases
54
# CSF - Sargramostim - Effects on phagocytic accessory cells which mediates its action on the neutrophil lineage - Drop in WBC & neutrophil count following ___ (approximately 50% decrease within 24 hours)
- discontinuation
55
# CSF - Biosimilars: Similar or Not? 1. Tbo-Filgrastim (Granix) 2. Filgrastim-sndz (Zarxio) 3. Filgrastim-aafi (Nivestym) 4. Filgrastim-ayow (Releuko)
Tbo-filgrastim is not considered a biosimilar and received an original biologic license through the FDA - Filgrastim-sndz was the first biosimilar approved in the US in March 2015 - Did NOT receive interchangeable status **Patient should remain on whichever agent it is started on and not switch between manufactured products**
56
# Dosing and Adverse Effects Filgrastim: 5 mcg/kg/day – Start up to 3 - 4 days ___ completion of chemotherapy and continue until post-nadir ANC recovery to ___ ish levels
- after - normal
57
# Dosing and Adverse Effects Pegfilgrastim: 6 mg SQ x 1 dose - Start at least 24 hours ___ chemo and can be given up to 3 – 4 days after chemo - At least __ days should elapse between dose and the next cycle of chemo - Same day therapy is generally not recommended - OnPro® body injector can be applied same day
after 14
58
CSF Adverse Effects
- Flu-like symptoms - bone and joint pain - DVT
59
# CSF Adverse Effects Bone or musculoskeletal pain occurs in 20-30% of patients receiving CSF’s - Attributed to rapid proliferation of the bone marrow myeloid cells - Can use acetaminophen/non-opioid analgesics - Data with use of ___ . Why? Thought is that pain is due to histamine release. Rare Adverse Effects - ___ enlargement with long term CSF use
- loratidine - splenic
60
# Thrombocytopenia Usually defined as a platelet count < ___ x 10 3 /μL, however increased risk of bleeding occurs when platelet count is < 20 x 10 3 /μL and therefore may require transfusion - Most institutions do not transfuse until patient becomes ___ - ASCO guideline recommends a threshold for platelet transfusion of ___ x 10 3 /μL
- 100 - symptomatic - 10
61
# General Causes of Anemia Decreased red blood cell production - Cancer therapy: Radiation or chemo - Tumor infiltration into the ___ Decreased erythropoietin production - ___ dysfunction - Decreased body stores of vitamin B12, iron, or folic acid - Blood loss
- bone marrow - renal
62
# Significance of Anemia in Cancer Fatigue has been reported in several surveys as more troubling to cancer patients than nausea, vomiting, or pain - Low ___ levels have been correlated with poor performance status which has been correlated with decreased survival and quality of life
hemoglobin
63
# Chemotherapy Induced Anemia Patients with a Hgb ≤ __ g/dL or ≥ __ g/dL drop from baseline should undergo a work-up:
11, 2
64
# Chemotherapy Induced Anemia If patient is symptomatic: - ___ as indicated - Consider use of ___ - Perform ___ studies:
- transfuse - ESA - iron | patients need to be counseled on the risks and benefits of therapy
65
ESA warnings
WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE | boxed warnings
66
# Considerations for Use of ESA’s ESAs are NOT recommended: – In patients receiving myelosuppressive chemotherapy with ___ intent – In patients with cancer NOT receiving chemo – In patients receiving non- ___ chemo
- curative - myelosuppressive
67
# Considerations for Use of ESA’s Consider using: – Cancer and ___ – Patient’s undergoing ___ chemotherapy – Patients without other identifiable causes
- CKD - palliative
68
# Risks and Benefits of Therapy Survival studies: - 3 meta-analyses demonstrated ___ survival when taking ESAs to correct Hgb > 12 g/dL - 2 meta-analysis did not show differences in survival when ESAs utilized - Additional ongoing trials are underway to guide optimal use
- decreased
69
# Risk and Benefits of Therapy Risks 1. Increased ___ events 2. Possible ___ survival 3. Time to tumor progression ___ Benefits 1. ___ avoidance 2. Gradual improvement in ___ related symptoms
- thrombotic - decreased - shortened - transfusion - anemia
70
# Risk and Benefits of Therapy Risks 1. Transfusion ___ 2. Transfusion related circulatory overload 3. Virus transmission (hepatitis, HIV, etc.) 4. Bacterial contamination 5. Iron overload 6. Increased ___ events 7. Possible decreased survival Benefits 1. Rapid increase of ___ and hematocrit levels 2. Rapid improvement in anemia related symptoms like ___
- reactions - thrombotic - hemoglobin - fatigue
71
# Epoetin alfa (Erythropoietin, Epoetin) Pharmacology - Glycoprotein which stimulates ___ production - Stimulates ___ and ___ of committed erythroid progenitors in the bone marrow - Produced in the ___ - Endogenous production regulated by level of tissue oxygenation
- RBC - division, differentiation - kidney
72
# Epoetin alfa (Erythropoietin, Epoetin) For chemotherapy-associated anemia - Dose should be adjusted to maintain the ___ Hgb level - If the Hgb increases > __ g/dL in a 2-week period, the dose should be decreased by __ % for epoetin alfa and __ % for darbepoetin
- lowest - 1 - 25, 40
73
# Darbepoetin (Aranesp) Stimulates erythropoiesis by binding to the ___ receptor like erythropoietin - Biochemically distinct from epoetin alfa by the addition of a sialic acid - half life 2 - 3 x ___ than epoetin Indications - Anemia in patients with non- ___ malignancies where anemia is caused by chemo Dosing - Titrate to response same as with epoetin alfa
- epoetin - longer - myeloid
74
# Iron in Anemic Cancer Patients T or F: All oncology patients who are prescribed ESA therapy should have baseline iron studies performed
T
75
# Iron in Anemic Cancer Patients Serum ferritin, iron, iron saturation - If a patient is iron deficient, a workup should be done - If no other causes for anemia is identified, **oral iron supplementation is ___** - Iron absorption will be ___ (by as much as half) if food is eaten 2 hours before or 1 hour after ingestion
- recommended - decreased
76
# Iron Dosing - Low Molecular Weight Iron Dextran (Dexferrum) - IV ___ - Iron Sucrose (Venofer) - IV ___ , ___ - Ferric Gluconate (Ferrlecit) - IV ___ , ___ Patients with an active ___ should not receive iron therapy
- infusion - infusion, injection - infusion, injection - infection
77
# Classic Chemotherapy Toxicities Toxicity: Myalgias/Arthralgias Chemo (5) Treatment (2)
- Paclitaxel, Docetaxel Anastrozole, Letrozole, Exemestane - NSAIDs, opioids
78
# Classic Chemotherapy Toxicities Toxicity: Hemorrhagic cystitis Chemo (2) Treatment (2)
- High dose cyclophosphamide, Ifosfamide - Hydration (prevention), Mesna (prevention)
79
# Classic Chemotherapy Toxicities Toxicity: Heart Failure Chemo (3) Treatment (3)
- Anthracyclines, High dose cyclophosphamide, Trastuzumab (other HER2 targeted therapies) - Monitor cumulative dose, assess for risk factors, Dexrazoxane (chemoprotectant)
80
# Classic Chemotherapy Toxicities Toxicity: Peripheral Neuropathy Chemo (3) Treatment (2)
- Taxanes, Vinca Alkaloids, Platinums - Change infusion rates (i.e., Paclitaxel), Adjunctive pain medications (ex. Gabapentin, amitriptyline)
81
# Classic Chemotherapy Toxicities Toxicity: Pulmonary Chemo: (1) Treatments (1)
- bleomycin - Corticosteroids (no good treatment once it happens)
82
# Mesna Mesna should be used with standard ifosfamide ( ___ ) doses of < 2.5 g/m2 /day to decrease risk of hemorrhagic cystitis - toxic metabolite: ___
- cyclophosphamide - acrolein
83
# Cardiac Toxicity Mechanism - Formation of iron-dependent oxygen free ___ due to stable anthracycline-iron complexes, which cause catalysis of electron transfer - Myocardium is more susceptible due to lower levels of ___ capable of detoxifying oxygen free radicals compared with other tissues
- radicals - enzymes
84
# Type I Chemotherapy Related: Cardiac Dysfunction Acute - Occurs immediately after a single dose or course of therapy with an ___ - Uncommon and transient - May involve abnormal ECG findings, including QT-interval prolongation, ST-T wave changes, and arrhythmias - Rarely, CHF and/or pericarditis are observed - Not related to cumulative dose and is uncommon
anthracycline
85
# Type I Chemotherapy Related: Cardiac Dysfunction Chronic - Onset usually within a ___ of receiving ___ therapy - Rapid onset and progression - Common and life threatening - Related to ___ dose patient received - Symptoms include tachycardia, tachypnea, exercise intolerance, pulmonary and venous congestion, ventricular dilatation, poor perfusion, and pleural effusion
- year - anthracycline - cumulative
86
# Type I Chemotherapy Related Cardiac Dysfunction Late-onset - Develops several years or even ___ after therapy - Manifests as ventricular dysfunction, CHF, conduction disturbances, and arrhythmias - Occurs more often in childhood / adolescence cancer survivors who received ___
- decades - anthracyclines
87
# Type II Chemotherapy Related Cardiac Dysfunction Trastuzumab - Does not appear to be dose related or occur in all patients - Ranges widely in severity - Has not been associated with cardiac ___ - Mechanism involves ___ pathway which normally blunts the effects of stress signaling pathways (a stunning effect) that are required to maintain cardiac function, structure, and contractility
- damage - EGFR
88
# Type II Chemotherapy Related Cardiac Dysfunction Trastuzumab - Appears to be largely ___ and short lived - Incidence is ~ 3% in non-anthracycline treated patients and increases to 5% in those who have received previous anthracyclines - If trastuzumab is given ___ with anthracycline, the incidence can increase up to ___ % cardiac toxicity (NYHA class III/IV)
- reversible - concurrently - 27%
89