Lec 5 Heme/Onc
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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
What is myelosuppression?
the decrease in cells responsible for providing immunity (WBC), carrying oxygen (RBC) and those responsible for normal blood clotting (platelets)
What is the most common dose-limiting toxicity of chemotherapy?
What is the risk of low RBC?
- losing oxygen carrying capacity (fatigue)
- not circulating enough hemoglobin (heart has to work harder --> ischemia, HF, exacerbation)
What risk is associated with low WBC?
- < 0.5
- neutropenia --> infections
What risk is associated with low platelet count?
When does myelosuppression hit its nadir (lowest point)?
typically 10-14 days after receiving chemo
What is the recovery time for myelosuppression?
- 3-4 weeks
- this is why chemo is dosed every 3-4 weeks
What are the factors affecting myelosuppression?
- previous chemotherapy or radiation therapy
- tumor bone marrow involvement
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
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)
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)
Define mild, moderate and severe anemia.
- mild = Hgb 1-11 g/dL
- moderate = 8-10 g/dL
- severe = < 8 g/dL
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
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
What is the pharmocology of ESAs?
bind to erythropoietin receptors on bone marrow cells and stimulate proliferation of erythroid colony-forming units
How long does it take to increase Hgb?
approximately 2-6 weeks
How often do the ESA drugs get administered?
- Epoetin alfa (Epoetin) = 3x/wk, weekly, q2wk, q3wk regimens
- Darbepoetin (Aranesp) = weekly, q2wk, q3wk regimens
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
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
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)
What is REMS?
risk evaluation and mitigation strategies
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
What is the ESA patient counseling?
- pt must sign acknowledgement form regarding risks
- "tumor may grow faster and you may die sooner"
What are the toxicities associated with cancer-related neutropenia colony stimulating factors (CSF)?
- injection site reactions
- BONE PAIN
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
When is cancer-related thrombocytopenia typically seen?
nadir = approximately 7 days after chemo
What happens if a patient is due for chemo but is currently experiencing thrombocytopenia?
may have chemo delay or receive lower dose
What is the patient counseling for thrombocytopenia?
- unexpected bruising or bleeding
- bad headaches, weakness
What is the treatment for cancer-related thrombocytopenia?
transfusion or oprelvekin
When can a patient receive platelet transfusions?
- usually only when platelet < 10-20K
- life span of transfused platelets = 2-6 days
How does oprelvekin work?
- stimulates megakaryocytopoiesis
- peak platelet in 14-21 days
- use limited by adverse effects (edema 70%, arrhythmias), delayed effect, and cost
What chemo drugs are arthralgias/myalgias associated with?
taxanes, aromatase inhibitors, CSFs
How does arthralgias/myalgias present?
- musculoskeletal symptoms
- flu-like symmptoms (paclitaxel)
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.)
What drugs cause cardiovascular toxicity?
- trastuzumab (cardiomyopathy)
- bevacizumab (hypertension)
- cyclophosphamide (cardiomyopathy)
- other agents (fluorouracil, taxanes)
What is the nature of toxicity of anthracyclines?
- associated with cumulative doses
- acute: abnormal EKG, may involve arrhythmias
- chronic: (many years later) cardiomyopathy/HF
What is the mechanism of toxicity of anthracyclines?
- acute: catecholamine release
- chronic: damage to mitochondrial DNA, free radical production
What is the diagnosis/monitoring for anthracyclines?
need ejection fraction at baseline and continue to monitor through course of therapy
What are the risk factors of anthracycline cardiovascular toxicity?
- age >70
- combination therapy
- cardiac disease
- liver disease
- previous/current radiation
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
What is the lifetime dose of doxorubicin?
What is the potential antidote for drugs that cause cardiovascular toxicity?
What is the MOA of dexrazoxane?
- chelates iron
- interferes with Topoisomerase II
When is dexrazoxane use OPTIONAL?
- women receiving doxorubicin for metastatic breast cancer
- directly competes with doxorubicin --> great for toxicity, but takes away from efficacy
When is dexrazoxane given in regards to doxorubicin?
15-30 minutes prior
What is another marketed use of doxrazoxane (Totect)?
What is the major adverse event associated with doxrazoxane?
Discuss the drug toxicity associated with trastuzumab.
- does not appear to be dose-related
- higher incidence when combined with anthracyclines, cyclophosphamide, or paclitaxel
- black box warning
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)
Discuss the drug toxicity associated with cyclophosphamide.
- cardiomyopathy (2-10%)
- higher risk with higher dose regimens
Which drugs cause nephrotoxicity?
- cyclophosphamide (renotubular problems)
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
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
What are the risk factors for nephrotoxicity due to cisplatin?
- increased dose (large single doses and cumulative doses)
- previous cisplatin therapy
- concomitant nephrotoxins
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
Which drugs can cause bladder toxicity --> hemorrhagic cystitis?
How do drugs cuase hemorrhagic cystitis?
- cyclophosphamide and ifosfamide get metabolized to acroelin which sticks to bladder
- **acroelin metabolite**
What is the strategy for treatment/prevention of hemorrhagic cystitis?
- Mesna (give w/ ifosfamide, high-dose cyclphosphamide)
What is Mesna?
- metabolized to free thiol compound which detoxfies acrolein
- available in IV and PO
- dosing is based on ifosfamide or cyclphosphamide dose
What are the 4 dermatologic toxicities associated with chemotherapy agents?
- 1. alopecia
- 2. hand-foot syndrome
- 3. EGFR inhibitor skin reactions
- 4. nail changes
- 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
Which drugs are associated with hand-foot syndrome?
What are the symptoms of mild-moderate hand-foot syndrome?
- palm and sole redness
What are the symptoms of severe hand-foot syndrome?
- cracked skin
- severe pain
- difficulty using feet & hands
What is the management for hand-foot syndrome?
- alter chemo schedule
- oral or topical corticosteroids
- vitamin B6
What causes hand-foot syndrome?
leakage of chemo out of vessel into feet and hands that causes tissue damage --> antimetabolites
What are the common EGFR inhibitor skin reactions?
- rash in 50% of patients
- xerosis (dry, itchy skin), nail changes, changes in hair texture
What patient counseling can be given for EGFR inhibitor skin reactions?
- avoid sun exposure
- skin care
- nail care
What is the management of EGFR inhibitor skin reactions?
topical or systemic antibiotics and corticosteroids based on severity
What chemo drug causes nail changes?
What is the nature and metchanism of pulmonary toxicity?
- reduction in carbon dioxide diffusing capacity
- fibrosis (stiffening or scarring - may become irreversible)
- pulmonary edema
What are the s/sx of developing pulmonary toxicity?
- infiltrates (CXR)
What is the treatment for pulmonary toxicity?
- discontinuation of agent
- supportive care
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
What is the potential nature/mechanism of pulmonary toxicity of interleukin-2?
capillary leak/pulmonary edema
What is the potential nature/mechanism of pulmonary toxicity of cetuximab?
fibrotic lung disease
What is the potential nature/mechanism of pulmonary toxicity of methotrexate?
What is the potential nature/mechanism of pulmonary toxicity of radiation therapy?
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)
What are the risk factors of neurological toxicity?
- other patient co-morbidities (diabetic --> diabetic neuropathy)
- avoid oxaliplatin if toher options are available
What is the treatment/prevention for central nervous system toxicity, cerebellar, and encephalopathy?
What is the treatment/prevention for peripheral, motor and sensory neuropathy toxicity?
What are the 2 types of haptotoxicity?
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
What is the strategy for treatment/prevention of hepatotoxicity?
- withhold therapy until LFTs in normal range
- dose adjustments
- non-hepatotoxic alternative
What are the common agents that cuase hypersensitivity?
- platinum agents
What is the clinical presentation of hypersensitivy reactions?
- rash or drug fever
Which agents should get pre-medication to prophylax for hypersensitivity?
What are the prophylaxis and treatment strategies for hypersensitivity?
- premedicate (paclitaxel, docetaxel, rituximab)
- slow infusion rate (rituximab)
- desensitization protocols (carboplatin)
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
What is the antidote for 5-FU?
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
What are possible etiologies for secondary malignancies?
- autologous stem cell transplantation
- environmental factors (smoking, chemicals)
- genetic predisposition
When chemo agents are used for secondary malignancies?
- alkylating agents
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