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How is a drug toxicity graded?
- 0 = normal, no toxicity
- 1 = mild toxicity (may even be asymptomatic)
- 2 = mild to moderate toxicity
- 3 = moderate to moderately severe
- 4 = most severe, generally requires dose-modification or discontinuation
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What is myelosuppression?
the decrease in cells responsible for providing immunity (WBC), carrying oxygen (RBC) and those responsible for normal blood clotting (platelets)
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What is the most common dose-limiting toxicity of chemotherapy?
myelosuppression
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What is the risk of low RBC?
- losing oxygen carrying capacity (fatigue)
- not circulating enough hemoglobin (heart has to work harder --> ischemia, HF, exacerbation)
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What risk is associated with low WBC?
- < 0.5
- neutropenia --> infections
- leukopenia
- granulocytopenia
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What risk is associated with low platelet count?
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When does myelosuppression hit its nadir (lowest point)?
typically 10-14 days after receiving chemo
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What is the recovery time for myelosuppression?
- 3-4 weeks
- this is why chemo is dosed every 3-4 weeks
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What are the factors affecting myelosuppression?
- previous chemotherapy or radiation therapy
- tumor bone marrow involvement
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What are the causes of cancer-related anemia?
- decreased production of RBC, erythropoietin d/t cancer invading bone marrow, relase of cytokines can decrease RBC, toxicity of chemo or radiation
- decreased body stores (nutritinal deficiencies)
- blood loss
- other causes
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What are the clinical findings/complications of cancer-related anemia?
- fatigue and decreased QOL
- may compromise efficacy and tolerabilitiy of treatment
- symptoms of severe anemia (severe fatigue)
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What are the laboratory findings of cancer-related anemia?
- low Hgb and Hct (most often normocytic MCV 80-100)
- may have low retic count if marrow involvement or recent chemotherapy
- severity (based on Hgb and patient symptoms)
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Define mild, moderate and severe anemia.
- mild = Hgb 1-11 g/dL
- moderate = 8-10 g/dL
- severe = < 8 g/dL
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What is involved in the initial workup of cancer-related anemia?
- identify correctable causes (make sure it's not just the cancer)
- identify thromboembolic risk factors
- drug exposure history
- Labs: CBC, retic count, iron panel, folate, B12, stool guaiac
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What are the treatment options for cancer-related anemia?
- address functional iron deficiency or absolute iron deficiency, if present
- transfusions and erythropoiesis-stimulating agents (ESA)
- individualized goals of treatment
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What is the pharmocology of ESAs?
bind to erythropoietin receptors on bone marrow cells and stimulate proliferation of erythroid colony-forming units
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How long does it take to increase Hgb?
approximately 2-6 weeks
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How often do the ESA drugs get administered?
- Epoetin alfa (Epoetin) = 3x/wk, weekly, q2wk, q3wk regimens
- Darbepoetin (Aranesp) = weekly, q2wk, q3wk regimens
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What are the ESA "rules"?
- use only for anemia from myelosuppressive chemo
- SHOULDN'T USE IF CANCER CURE ANTICIPATED!
- consider if concomitant chronic kidney disease, palliative treatment, etc.
- "adjust doses for patient to have lowest Hgb sufficient to avoid trasfusion"
- discontinue at 8 weeks if minimal response and transfusions still required
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What are the more common drug complications of cancer-related anemia?
- local irritation at injection site - minimized if injected at room temp
- headache, joint and muscle pain, GI stress, edema
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What are the less common ESA drug complications of cancer-related anemia?
- hypertension (d/t increase in RBC)
- thrombosis (risk multiplies b/c pt has cancer)
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What is REMS?
risk evaluation and mitigation strategies
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What are the REMS for ESA therapy?
- food and drug associated (FDA) requirement for drug companies
- ESA prescriber/dispensers must have special training
- medication guide for patients
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What is the ESA patient counseling?
- pt must sign acknowledgement form regarding risks
- "tumor may grow faster and you may die sooner"
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What are the toxicities associated with cancer-related neutropenia colony stimulating factors (CSF)?
- injection site reactions
- BONE PAIN
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When are CSFs given and why?
CSF usually given 24 hours after chemo b/c if they are given at the same time as chemo it is working against itself
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When is cancer-related thrombocytopenia typically seen?
nadir = approximately 7 days after chemo
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What happens if a patient is due for chemo but is currently experiencing thrombocytopenia?
may have chemo delay or receive lower dose
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What is the patient counseling for thrombocytopenia?
- unexpected bruising or bleeding
- bad headaches, weakness
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What is the treatment for cancer-related thrombocytopenia?
transfusion or oprelvekin
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When can a patient receive platelet transfusions?
- usually only when platelet < 10-20K
- life span of transfused platelets = 2-6 days
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How does oprelvekin work?
- stimulates megakaryocytopoiesis
- peak platelet in 14-21 days
- use limited by adverse effects (edema 70%, arrhythmias), delayed effect, and cost
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What chemo drugs are arthralgias/myalgias associated with?
taxanes, aromatase inhibitors, CSFs
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How does arthralgias/myalgias present?
- musculoskeletal symptoms
- flu-like symmptoms (paclitaxel)
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What are the treatment approaches for arthralgias/myalgias?
- patient education
- nonpharmacological approaches (exercise, weight loss - as appropriate)
- pain management (APAP, NSAIDS, etc.)
- other agents (amitriptyline, gabapentin, etc.)
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What drugs cause cardiovascular toxicity?
- anthracyclines
- trastuzumab (cardiomyopathy)
- bevacizumab (hypertension)
- cyclophosphamide (cardiomyopathy)
- other agents (fluorouracil, taxanes)
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What is the nature of toxicity of anthracyclines?
- associated with cumulative doses
- acute: abnormal EKG, may involve arrhythmias
- chronic: (many years later) cardiomyopathy/HF
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What is the mechanism of toxicity of anthracyclines?
- acute: catecholamine release
- chronic: damage to mitochondrial DNA, free radical production
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What is the diagnosis/monitoring for anthracyclines?
need ejection fraction at baseline and continue to monitor through course of therapy
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What are the risk factors of anthracycline cardiovascular toxicity?
- age >70
- combination therapy
- cardiac disease
- liver disease
- previous/current radiation
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What are the strategies for treatment/prevention of anthracycline associated cardiovascular toxicity?
- early recognition, supportive care, discontinuation of therapy
- monitor ejection fraction
- LIMIT LIFETIME DOSES liposomal anthracycliens --> much less risk
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What is the lifetime dose of doxorubicin?
450 mg/m2
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What is the potential antidote for drugs that cause cardiovascular toxicity?
dexrazoxane (zinecard)
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What is the MOA of dexrazoxane?
- chelates iron
- interferes with Topoisomerase II
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When is dexrazoxane use OPTIONAL?
- women receiving doxorubicin for metastatic breast cancer
- directly competes with doxorubicin --> great for toxicity, but takes away from efficacy
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When is dexrazoxane given in regards to doxorubicin?
15-30 minutes prior
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What is another marketed use of doxrazoxane (Totect)?
extravasation
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What is the major adverse event associated with doxrazoxane?
myelosuppression
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Discuss the drug toxicity associated with trastuzumab.
- cardiomyopathy
- does not appear to be dose-related
- higher incidence when combined with anthracyclines, cyclophosphamide, or paclitaxel
- black box warning
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What is the most common adverse event with bevacizumab?
- severe hypertension
- 11-16% with grade 3-4 hypertension
- severe HTN (>200-110) in 5-7%
- nephrotic proteinuria (2.2% of grade 3-4 proteinuria)
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Discuss the drug toxicity associated with cyclophosphamide.
- cardiomyopathy (2-10%)
- higher risk with higher dose regimens
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Which drugs cause nephrotoxicity?
- cisplatin
- bevacizumab
- methotrexate
- cyclophosphamide (renotubular problems)
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How can nephrotoxicity be prevented?
- aggressive hydration with IVF (2-3L over 8-10 hours) before, during and after to flush cisplatin out
- prophylactic magnesium
- amifostine (optional) --> antidoge involved in free radical scavenging
- electrolyte repletion is important
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What is the nature and mechanism of toxicity of cisplatin?
- tubular cell dysfunction, decreased GFR
- acute renal failure, often seen about 10 days after cisplatin administration
- often with hypomagnesemia, hypokalemia
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What are the risk factors for nephrotoxicity due to cisplatin?
- increased dose (large single doses and cumulative doses)
- previous cisplatin therapy
- concomitant nephrotoxins
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What are the strategies for treatment/prevention of cisplatin induced nephrotoxicity?
- saline-based hydration pre- and post-cisplatin
- electrolyte supplementation (prophylactic Mg)
- amifostine (free-radical scavenging) --> can cause hypotension (pt to d/c antiHTN meds 24h prior to therapy
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Which drugs can cause bladder toxicity --> hemorrhagic cystitis?
- cyclophosphamide
- ifosfamide
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How do drugs cuase hemorrhagic cystitis?
- cyclophosphamide and ifosfamide get metabolized to acroelin which sticks to bladder
- **acroelin metabolite**
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What is the strategy for treatment/prevention of hemorrhagic cystitis?
- hydration
- Mesna (give w/ ifosfamide, high-dose cyclphosphamide)
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What is Mesna?
- metabolized to free thiol compound which detoxfies acrolein
- available in IV and PO
- dosing is based on ifosfamide or cyclphosphamide dose
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What are the 4 dermatologic toxicities associated with chemotherapy agents?
- 1. alopecia
- 2. hand-foot syndrome
- 3. EGFR inhibitor skin reactions
- 4. nail changes
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Discuss alopecia.
- major psychological impact
- damage to hair follicles from chemo and/or radiation
- amount varies from person to person
- most often starts in first few weeks and increases 1-2 months into treatment
- management: patient preparation
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Which drugs are associated with hand-foot syndrome?
- capecitabine
- fluorouracil
- cytarabine
- doxorubicin
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What are the symptoms of mild-moderate hand-foot syndrome?
- palm and sole redness
- swelling
- tingling/burning
- tenderness
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What are the symptoms of severe hand-foot syndrome?
- cracked skin
- blisters
- ulcers
- severe pain
- difficulty using feet & hands
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What is the management for hand-foot syndrome?
- alter chemo schedule
- oral or topical corticosteroids
- analgesics
- vitamin B6
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What causes hand-foot syndrome?
leakage of chemo out of vessel into feet and hands that causes tissue damage --> antimetabolites
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What are the common EGFR inhibitor skin reactions?
- rash in 50% of patients
- xerosis (dry, itchy skin), nail changes, changes in hair texture
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What patient counseling can be given for EGFR inhibitor skin reactions?
- avoid sun exposure
- skin care
- nail care
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What is the management of EGFR inhibitor skin reactions?
topical or systemic antibiotics and corticosteroids based on severity
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What chemo drug causes nail changes?
docetaxel
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What is the nature and metchanism of pulmonary toxicity?
- reduction in carbon dioxide diffusing capacity
- fibrosis (stiffening or scarring - may become irreversible)
- pulmonary edema
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What are the s/sx of developing pulmonary toxicity?
- SOB
- dyspnea
- rales
- infiltrates (CXR)
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What is the treatment for pulmonary toxicity?
- discontinuation of agent
- supportive care
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What is the potential nature/mechanism of pulmonary toxicity of busulfan?
reduction in carbon dioxide diffusing capacity
-
What is the potential nature/mechanism of pulmonary toxicity of bleomycin?
injury to pulmonary capillary epithelium
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What is the potential nature/mechanism of pulmonary toxicity of interleukin-2?
capillary leak/pulmonary edema
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What is the potential nature/mechanism of pulmonary toxicity of cetuximab?
fibrotic lung disease
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What is the potential nature/mechanism of pulmonary toxicity of methotrexate?
fibrosis/pulmonary edema
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What is the potential nature/mechanism of pulmonary toxicity of radiation therapy?
decreased surfactant/fibrosis
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What is the nature/mechanism of neurological toxicity?
- CNS, cerebellar, mental status changes, disorientation, tremor
- peripheral, motor and sensory neuropathy (burning, tingling, numbness, sensitivity to temp)
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What are the risk factors of neurological toxicity?
- other patient co-morbidities (diabetic --> diabetic neuropathy)
- avoid oxaliplatin if toher options are available
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What is the treatment/prevention for central nervous system toxicity, cerebellar, and encephalopathy?
- cytarabine
- ifosfamide
- corticosteroids
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What is the treatment/prevention for peripheral, motor and sensory neuropathy toxicity?
- bortezomib
- cisplatin
- carboplatin
- oxaliplatin
- doxcetaxel
- paclitaxel
- vincas
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What are the 2 types of haptotoxicity?
- hepatocellular
- cholestatic
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What are the common causes of elevated liver function tests in cancer patients?
- tumor involvement with the liver
- infections or reactivation of infections
- parenteral nutrition
- concomitant hepatotoxi drugs or liver diseases
-
What agents cause hepatotoxicity?
asparaginase, cytarabine, methotrexate
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What is the strategy for treatment/prevention of hepatotoxicity?
- withhold therapy until LFTs in normal range
- dose adjustments
- non-hepatotoxic alternative
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What are the common agents that cuase hypersensitivity?
- asparaginase
- paclitaxel/docetaxel
- platinum agents
- rituximab
- trastuzumab
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What is the clinical presentation of hypersensitivy reactions?
- rash or drug fever
- flushing
- angioedema
- bronchospasm
- anaphylaxis
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Which agents should get pre-medication to prophylax for hypersensitivity?
- paclitaxel
- docetaxel
- rituximab
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What are the prophylaxis and treatment strategies for hypersensitivity?
- premedicate (paclitaxel, docetaxel, rituximab)
- slow infusion rate (rituximab)
- desensitization protocols (carboplatin)
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What drugs can Leucovorin be used as adjuvant therapy/antidotes?
- methotrexate (protectant)
- enhances fluorouracil activity
-
What is the MOA of Leucovorin?
- inhibits thymidylate synthase
- converted to folic acid derivative
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What is the antidote for 5-FU?
uridine triacetate
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What factors may contribute to infertility?
- type and dose of drug or radiation
- type of cancer
- patient age and gender
- past history of fertility problems
- fertility preseveration options
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What are possible etiologies for secondary malignancies?
- chemotherapy
- radiation
- autologous stem cell transplantation
- environmental factors (smoking, chemicals)
- genetic predisposition
- immunosuppression
- chance
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When chemo agents are used for secondary malignancies?
- alkylating agents
- podophyllotoxins
- anthracyclines
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