Chemotherapy Flashcards
What is the Mosteller formula for BSA?
The square root of the following:
[Height (cm) x Weight (kg)]/3600
ASPARAGINASE
In which three forms is asparaginase available?
Which forms of asparaginse are produced by E. coli?
Where does Erwinia asparaginase come from and why is it useful?
Why is IM asparaginase the current standard of care?
Forms of asparaginase:
- L-asparaginase (Elspar®)
- Polyethylene glycol (PEG)-asparaginase (Oncaspar®)
- Erwinia (Erwinase®)
Asparaginase is a naturally occurring enzyme produced by many microorganisms. In the L- and PEG-asparaginase forms, the enzyme is produced by Escherichia coli, whereas the Erwinia form is produced by Erwinia chrysanthemi. PEG-asparaginase is a modified form of L-asparaginase with a much longer half-life resulting from its covalent binding to PEG, allowing the same therapeutic effect from fewer doses. Intramuscular asparaginase is the current standard of care due to concerns about severe anaphylaxis with intravenous (IV) use; however, two current Children’s Oncology Group (COG) protocols are investigating the safety and efficacy of IV PEG-asparginase. Less frequent dosing with PEG-asparaginase is important for patient comfort and convenience until intravenous asparaginase becomes more widely accepted. Since Erwinia is produced by a different microorganism, it is immunologically distinct and can be utilized in patients that have had a hypersensitivity reaction to the E. coli forms.
Asparaginase mechanism of action?
L-asparagine is a nonessential amino acid that cannot be synthesized by malignant cells of lymphoid and myeloid origin. Asparaginase depletes L-asparagine from leukemic cells by catalyzing the conversion of L-asparagine to aspartic acid and ammonia.
Asparaginase - used in which cancers?
Acute lymphoblastic leukemia
Acute myelogenous leukemia
Non-Hodgkin lymphoma
Asparaginse SEs, monitoring and treatment. What is the most immediate SE? How long should you monitor patients after Elspar vs Oncaspar? How is allergic reaction treated? What is the commonest later side effect? Name three rare side effects?
Most immediate SE from asparaginase compounds is an allergic reaction that can range from local irritation to anaphylaxis.
Patients should be monitored closely for at least 1 hour after Elspar injection, and 2 hours following Oncaspar injection.
Based on the level of allergic symptoms, treatment can range from an antihistamine such as diphenhydramine to treatment of anaphylaxis with steroids, an antihistamine, an H2 blocker (i.e., ranitidine), and epinephrine.
A common later side effect is coagulopathy secondary to decreased synthesis of antithrombin III (ATIII), fibrinogen, and other clotting factors. Monitoring of ATIII and fibrinogen and repletion of low levels is routinely done on some protocols that use l-aspa.
Rare side effects include pancreatitis, thrombosis, and seizures.
BLEOMYCIN
Source?
MoA?
Cells in which stage of the cell cycle are targeted?
Clinical uses?
Immediate side effects? Later side effects? How would you monitor for pulmonary SEs?
Source: Bleomycin is obtained as a mixture of antibiotics isolated from Streptomyces verticillus.
MoA: Bleomycin leads to the formation of oxygen-free radicals that cause single-strand and double-strand DNA breaks. Also leads to cellular degradation of cellular RNA. Bleomycin is cell cycle specific, targeting the G2 and M phases, thus inhibiting cell growth and division, especially in rapidly dividing cells.
Utilized in germ cell tumors hodgkin lymphoma
Side Effects, Monitoring, and Treatment:
- infusional fever and chills
- mucositis
- pruritus and excoriation leading to hyperpigmentation/rash
- Raynaud’s phenomenon can also commonly occur later, especially with combination chemotherapy.
- Dysgeusia (distorted sense of taste) and anorexia.
- Due to the formation of oxygen-free radicals, patients are at risk for dose-dependent pneumonitis and rarely pulmonary fibrosis and therefore should be monitored with pulmonary function testing, especially carbon monoxide-diffusing capacity (PFT/DLCO).
- An anaphylactoid-type reaction may also rarely occur.
CISPLATIN/CARBOPLATIN
Which is more nephro/ototoxic? Which is more myelosuppressive?
MoA?
Give 6 main SEs. What are the commonest electrolyte disturbances? How would you recognise a patient developing Fanconi syndrome?
What would you monitor for patients on platinum agents?
Cisplatin was the first of the platinum-based chemotherapeutic agents. Carboplatin has less severe side effects, in particular decreased nephrotoxicity and ototoxicity. It is more myelosuppressive, however.
MoA: The platinum agents, like the alkylators, cause interstrand DNA cross-linking. In addition, they bind to replicating DNA causing single-strand breaks.
Utilized in
- Brain tumors
- Germ cell tumors
- Hepatoblastoma
- Hodgkin lymphoma
- Neuroblastoma
- Osteogenic sarcoma
- Soft tissue sarcomas
- Wilms tumor
Side Effects, Monitoring, and Treatment
- Extremely emetogenic - infusional nausea and vomiting are common
- Myelosuppression
- Electrolyte disturbance: hypokalemia, hypomagnesemia, hypocalcemia, and hyponatremia are common
- Fanconi syndrome (diminished reabsorption of solutes by the proximal tubule resulting in hypophosphatemia, metabolic acidosis, and secondary hypokalemia).
- Nephrotoxicity
- Ototoxicity (high-frequency sensorineural hearing loss) occur occasionally with carboplatin but are more common and severe with cisplatin.
Monitoring:
- Serial audiograms
- Chemistry panels including magnesium should be followed daily while receiving platinum-based therapy.
- Intake and output - should be well-matched. If it appears the patient is developing a negative fluid balance, additional fluids should be provided. If the patient develops a positive fluid balance, mannitol should be used to increase urine output.
- Renal function: a reduction in the glomerular filtration rate will necessitate a dose reduction. In general, for pediatric patients with no previous history of nephrotoxicity, serum creatinine can serve as a measure of renal function utilizing the Cockcroft-Gault equation. Decrease in the estimated creatinine clearance should lead to more formal measurements of the glomerular filtration rate and likely platinum dose reduction (contentious).
Cyclophosphamide/Ifosfamide
Cyclophosphamide (Cytoxan) and ifosfamide are alkylating agents and structural analogues. They are related to nitrogen mustard.
Mechanism of Action
Cyclophosphamide and ifosfamide require conversion by the hepatic P450 system to their active form that ultimately leads to the intracellular release of two compounds, acrolein and phosphoramide mustard. Phosphoramide mustard causes interstrand DNA cross-linking.
Utilized in
- Acute lymphoblastic leukemia
- Acute myelogenous leukemia
- Brain tumors
- Ewing sarcoma
- Germ cell tumors
- Hodgkin
- non-Hodgkin lymphoma
- Neuroblastoma
- Osteogenic sarcoma
- Soft tissue sarcomas
- Wilms tumor
Side Effects, Monitoring, and Treatment
Cyclophosphamide and ifosfamide commonly cause nausea, vomiting, and anorexia with drug infusion. Myelosuppression, immunosuppression, and alopecia are common later adverse effects. Sterility is dose dependent (greatest with cumulative doses of cyclophosphamide >7.5 g/m2) and occurs more commonly in pubertal males (though prepubertal males and females are also at risk). Due to the risk of nephrotoxicity, particularly with ifosfamide, patients should be well-hydrated prior to and after infusion. Though the syndrome of inappropriate diuretic hormone (SIADH) is rare, patients should be monitored for appropriate urine output by following their intake and output as well as urine specific gravity. Electrolytes are also routinely followed for hyponatremia. If there are signs of fluid retention, the patient should initially be given increased hydration followed by diuresis with furosemide or mannitol if hydration is ineffective. Excretion of acrolein into the urine can cause hemorrhagic cystitis. The addition of MESNA for bladder protection when the cyclophosphamide dose exceeds 1.0 g/m2/day has significantly decreased the frequency of this adverse event. MESNA specifically binds to acrolein and other toxic metabolites in the urine to detoxify them and protect the bladder wall. The urine should be monitored for the presence of occult blood during and after infusion and, if positive, should be examined microscopically. If red blood cells are noted on microscopy, hydration should be increased. Of note, MESNA can cause a false positive test for ketones on urine dipstick. Finally, metabolism of ifosfamide leads to formation of chloroacetaldehyde, a byproduct thought responsible for nephrotoxicity as well as the neurotoxicity seen occasionally with ifosfamide (somnolence, depressive psychosis, and confusion). Thiamine prophylaxis may have benefit in a patient with prior neurotoxicity.
CYTARABINE
Cytarabine (Ara-C), also known as cytosine arabinoside or Ara-C (arabinofuranosyl cytidine), is utilized in the treatment of hematologic malignancies.
Mechanism of Action
Cytarabine is an antimetabolite that inhibits DNA polymerase. In addition, it is cell cycle specific, killing cells during synthesis (S phase); it therefore specifically targets rapidly dividing cells.
Utilized in
- Acute lymphoblastic leukemia
- Acute myelogenous leukemia
- Hodgkin and non-Hodgkin lymphoma
Side Effects, Monitoring, and Treatment
Cytarabine commonly causes nausea, vomiting, and anorexia immediately after infusion. Later, myelosuppression, stomatitis, and alopecia are common. Although not common, the patient should be monitored for Ara-C syndrome that includes fever, myalgias, bone pain, malaise, conjunctivitis, maculopapular rash, and occasionally chest pain. High-dose IV cytarabine requires prophylaxis with dexamethasone eye drops to prevent conjunctivitis. A flu-like syndrome with fever, chills, and rash occurs occasionally with cytarabine; infection must still be ruled out with bacterial cultures. Streptococcus viridans sepsis and acute respiratory distress syndrome are possible after high-dose cytarabine, therefore the addition of vancomycin with fever or clinical deterioration should be strongly considered. Intrathecal (IT) cytarabine similarly can cause fever, nausea, and vomiting in addition to headache. More serious and immediate side effects including arachnoiditis, somnolence, meningismus, convulsions, and paresis are rare but should be considered as clinically indicated.
Dactinomycin (Actinomycin-D)
What sort of compound is this?
Where is it isolated from?
Which other class of chemo agent does it resemble?
What is its mechanism of action?
Dactinomycin is an antibiotic compound isolated from Streptomyces parvullus, similar to the anthracycline class.
Mechanism of Action
Dactinomycin intercalates with DNA, inhibiting RNA and DNA synthesis. In addition, dactinomycin interacts with topoisomerase, which is required for DNA replication, and leads to single-strand DNA breaks.
Utilized in
- Soft tissue sarcomas
- Wilms tumor
- AML! or should be
Side Effects, Monitoring, and Treatment
Infusional nausea and vomiting are common, followed later by alopecia and myelosuppression. Anorexia, fatigue, diarrhea, and mucositis also occur occasionally. Radiation recall can occur in patients who previously received radiation therapy.
Daunorubicin/Doxorubicin/Idarubicin
Daunorubicin and doxorubicin are both anthracycline antibiotics isolated from Streptomyces species
