Transcript Chemotherapy: Nuts and Bolts of Acute Issues

Chemotherapy: Nuts and Bolts
Jennifer M. Pope, MD
Chemotherapy dosing
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In general, done by body surface area
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Intrathecal chemotherapy
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√Weight in kg x height in cm
3600
Dosed by age
Be very careful with infants, many drugs dosed by kg
instead of BSA if patients is < 10kg
In general, don’t bother with decimals greater than
tenths
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i.e. 2.1 mg is fine, 2.14mg should be rounded to 2.1, 2.16mg
rounded to 2.2mg
General principles
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Most chemotherapeutic agents have significant
toxicities, even those that are “targeted”
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i.e. imatinib (Gleevec) can cause myelosuppression,
transaminitis
Some toxicities are common (alopecia,
myelosuppression, nausea/vomiting, mucositis), they
occur with greater severity or frequency with certain
agents
Other toxicities are rare, but can be severe, and are
specific to certain agents
Knowledge of idiosyncracies of specific agents is
critical to safe management of patients
Nausea/Vomiting
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Experienced by 70% to 80%
of cancer patients
Types of emesis:
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Acute: begins within two
hours of chemotherapy
without prophylaxis
Delayed: begins 24 hours
after chemotherapy
complete
Anticipatory: conditioned
response to previous cycles
of highly emetic
chemotherapy
Pathophysiology
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Neuroanatomy
Five neurotransmitter receptor sites are of
primary importance in the vomiting reflex:
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M1 – muscarinic
D2 – dopamine
H1 – histamine
5-HT3 – serotonin
NK1 – substance P
Nausea/Vomiting
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Incidence and severity related to:
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Emetic risk of the chemotherapeutic agent
Dose
Schedule
Route of administration
Patient variability
Emetic risk
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High (>90%)
Moderate (30% to 90%)
Low (10% to 30%)
minimal (<10%)
Anti-emetics
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Serotonin [5-HT3] antagonists (ondansetron and granisetron)
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Corticosteroids (dexamethasone)
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inhibit chemoreceptor trigger zone of the area postrema
acute nausea
Most common side effect is headache
EKG changes may occur
Mechanism of action unknown
Best in combination with 5-HT3 antagonists
Do not give to leukemia/lymphoma patients
Side effects: mood disturbance, hyperglycemia, insomnia
Benzodiazepines (lorezepam)
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Weak antiemetics when low doses are used
Anticipatory nausea
Anti-emetics (cont)
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Antihistamines (diphenhydramine)
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Dopamine antagonists (phenergen)
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use with diphenhydramine to prevent dystonia
do not give to kids < 2 years of age
Neurokinin-1 receptors (aprepitant)
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May be used alone or in combination
Sedation is the major side effect
acute and delayed
CYP3A4 inhibitor so watch out for drug interactions
Adolescents/young adults
Scopolamine
Cannabinoids
ASCO Guidelines
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High ( 90%) emetic risk. 5-HT3 serotonin receptor
antagonist, dexamethasone, and aprepitant is
recommended before chemotherapy (includes
anthracycline/cyclophosphamide combination).
Moderate ( 30% to 90%) emetic risk. Two-drug
combination of a 5-HT3 receptor serotonin
antagonist and dexamethasone.
Low (10% to 30%) emetic risk. Dexamethasone
premedication (adult recs, we tend to use 5-HT3
receptor serotonin antagonist)
Kris MG. J Clin Oncol 24:2932-2947, 2006
Hydration
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Certain agents require hyperhydration to facilitate
excretion and/or protect from associated toxicity
Ifosfamide/cyclophosphamide, methotrexate (highdose, > 1g/m2), cisplatin/carboplatin
Patients receiving these agents will have strict I/Os
recorded, and urine dipped for specific gravity, blood,
and pH  this is a source of many questions
overnight!
In some cases, in order to maintain adequate urine
output, you may need to give NS bolus or lasix 
check the protocol and ask the attending if you are not
sure!
Allergic Reaction
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Allergic reactions range from
itching to anaphylaxis
Emergency meds include
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Epinephrine: 0.01 mg/kg (0.01
mL/kg/dose of 1:1000 solution)
not to exceed 0.5 mg
SUBCUTANEOUS
Diphenhydramine: 1 mg/kg
Intravenous
Either
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Hydrocortisone: 1 mg/kg IV
Methylprednisolone: 1mg/kg IV
Allergic Reaction
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Agents requiring bedside
emergency medications:
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Asparaginase (all forms)
Etoposide
ATG (anti-thymocyte globulin
Bleomycin
Carboplatin
Doxetaxel
Doxorubicin (liposomal form
only)
Any of the monoclonal
anitbodies (rituximab,
infliximab, gemtuzamab,
Campath, etc)
Chemotherapy Extravasation
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Irritant vs. vesicant
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Irritant causes an inflammatory reaction without tissue sloughing or necrosis.
Extravasation of a vesicant drug has potential to cause tissue necrosis
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Dactinomycin, Taxanes, Anthracyclines, Mechlorethamine, Oxaliplatin, Vinca alkaloids
Key is prevention – free-flowing IV, preferably central line with confirmed position
Treatment:
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Stop the infusion immediately. Do not flush the line, and avoid applying pressure to the
extravasated site.
Elevate the affected extremity.
Attempt to aspirate fluid from the extravasated area
Apply antidote, if available
Topical application of ice or cold packs is recommended for extravasation of all vesicant
or irritant drugs except the vinca alkaloids (vincristine, vinblastine, vinorelbine) and
epipodophyllotoxins such as etoposide. Intermittent cooling is thought to cause
vasoconstriction, thereby diminishing the spread of the drug and the extent of the local
injury. Cold compresses also reduce local inflammation and pain.
Application of ice is contraindicated for extravasations of vinca alkaloids or
epipodophyllotoxins, as cold worsens the ulceration caused by these drugs, at least in
animal models. Instead, the application of heat is generally recommended for these
agents.
Cytarabine (Ara-C)
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Synthetic analogue of the naturally occurring nucleoside cytidine
Intracellularly converted to AraCTP which is a potent inhibitor of DNA replication
by competitive inhibition of DNA polymerase; also incorporates into the DNA
strand acting as a relative chain terminator
May be intrathecal, low-dose or high-dose
Unique side effects
– Conjunctivitis: high-dose regimens include steroid eye drop prophylaxis
– Neurotoxicity: headache, malaise, confusion, seizures, fever, irritability,
cerebral and cerebellar dysfunction (somnolence, personality changes, coma,
ataxia)
– Hand-foot syndrome: palmar plantar erythrodesia
– Risk of life-threatening infection: prolonged and profound neutropenia, high
rate of viridans streptococcal sepsis and translocation of other oral mucosal
organisms  empiric vancomycin for any fever
– Ara-C syndrome: fever, myalgia, bone pain, rash, conjunctivitis, malaise
occurring 6-12 hours after administration (if severe, may require treatment
with dexamethasone) NOTE: if fever, assume infection until proven
otherwise
Hemorrhagic Cystitis
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Oxazaphosphorine alkylating agents
(Cyclophosphamide/ifosfamide)
Etiology: urinary excretion of hepatic metabolite
acrolein
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Diffuse bladder mucosal inflammation with hemorrhage
Bleeding can range from minimal (5 to 50 RBC per high
powered field), to massive, requiring transfusion
Incidence increases with higher individual doses,
larger cumulative doses, and ifosfamide >
cyclophosphamide
Hemorrhagic cystitis 2
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PREVENTION
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hyperhydration (125-200mL/m2/hr, Urine Specific Gravity < 1.010
prior to start of chemotherapy, maintain urine output >2-3mL/kg/hour)
If urine output dropping off, give NS bolus or lasix
Remember that cyclophosphamide can rarely cause SIADH, so if the
urine output dropping in spite of fluids, get serum Na, Cr, Osm
MESNA: Within minutes of intravenous administration, mesna is
oxidized to a stable inactive disulfide in the serum but is reactivated
in the kidney. In the urine, it binds to acrolein, creating an inert
thioether that is excreted
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The serum half-life of mesna is 90 minutes, while cyclophosphamide and
ifosfamide have half-lives of six and seven hours, respectively. Mesna
must be present in the bladder at the time of chemotherapy
administration in order to be effective. Usually dosed at 60% of
cyclophosphamide/ifosfamide dosing).
MESNA fun fact: makes urine positive for ketones!
What do you do if there is hematuria?
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Noted on urine dip only, send formal U/A (consider
urine culture, BK virus).
If persistent microscopic hematuria (>2 abnormal
urinalyses during a cycle of therapy) increase
hydration to 3500-4000 ml/m2/day and daily MESNA
dose to 100% of the cyclophosphamide or ifosfamide
dose.
Gross hematuria: STOP the chemo! Change fluids
and MESNA as above. Call urology as may need
continuous bladder irrigation
Ifosfamide: nephrotoxicity
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In addition to hemorrhagic cystitis, ifosfamide
is directly nephrotoxic due to direct tubular
injury (cyclophosphamide is not)
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The metabolite chloracetaldehyde is toxic to tubular
cells, rather than the parent drug or acrolein
At equivalent doses, the rate of chloracetaldehyde
generation with ifosfamide is 40 times greater than
with cyclophosphamide
Another possible mechanism of toxicity may be
energy depletion via mitochondrial damage
Ifosfamide (continued)
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Clinical manifestations (Fanconi renal syndrome – proximal
tubule damage)
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Hypophosphatemia glucosuria, aminoaciduria, tubular proteinuria (ie,
low molecular weight proteins but not albumin)
Polyuria due to nephrogenic diabetes insipidus  rare
Renal potassium wasting, which may cause severe hypokalemia
Metabolic acidosis with a normal anion gap (hyperchloremic
acidosis) due to type 1 (distal) or type 2 (proximal) renal tubular
acidosis.
May be transient infusions, and become persistent as cumulative
dose increases
Can lead to mild reduction (20-30% below baseline) in GFR
Risk factors: age < 5 years, concurrent cisplatin therapy, and
cumulative ifosfamide dose above 60 g/m2 with severe
nephrotoxicity primarily occurring at a total dose of 120 g/m2 or
more
Ifosfamide: neurotoxicity
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2-5% of children, 10-15% of adults
increased with a prior history of ifosfamide-related
encephalopathy, renal dysfunction, low serum
albumin, or prior cisplatin treatment, may be increased
with use of aprepitant
Complex mechanism
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chloroethylamine, a metabolite of ifosfamide conjugates with
cysteine forming thialysine, which is metabolized to thialysine
ketimine, which inhibits electron-binding flavoproteins and,
consequently, mitochondrial respiration. The consequence is
NADH accumulation and prevention of the inactivation of
chloracetaldehyde, a neurotoxic metabolite of ifosfamide
Translation: looks like alcohol intoxication (where the
neurotoxic substance is acetaldehyde)
Neurotoxicity (continued)
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Symptoms include somnolence, lethargy, irritability, excitement,
disorientation, confusion, weakness, asterixis, hallucinations,
seizures.
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Normally rare and transient. Rarely severe and progressive.
What to do?
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STOP the infusion. Evaluate for other causes of altered mental
status
Methylene blue: acts as an electron accepting agent, thereby
correcting derangement in mitochondrial flavoproteins. It prevents
encephalopathy by a different mechanism when used
prophylactically, namely oxidation of excessive NADH formed
during ifosfamide
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Downsides: modest efficacy, side effects include nausea, abdominal
pain, dizziness, headache, profuse sweating, confusion,
methemoglobinemia
Thiamine: not sure how it works, case reports, non-toxic.
Methotrexate
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Used in many doses and formulations in ALL, lymphoma,
osteosarcoma
Toxicities include myelosuppression, mucositis, renal toxicity,
hepatic toxicity, neurotoxicity
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acute elevation in the serum transaminases from 2-20x normal
levels, even in patients who receive leucovorin rescue. Acute
transaminitis occurs in as many as 60 to 80 percent of patients and
typically resolves spontaneously within one to two weeks.
Myelosuppression usually mild with leucovorin rescue
IT MTX is eliminated from the cerebrospinal fluid by slow passive
diffusion into the systemic circulation. Because of this, some
recommend a short course of leucovorin rescue for patients with
renal dysfunction AND patients with Down syndrome
Methotrexate: mechanism
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Dihydrofolate reductase
(DHFR) converts
dihydrofolate to
tetrahydrofolate, thus
continuously replenishing the
cell's supply of reduced
folates.
At high doses, MTX is
polyglutamated and remains
intracellular
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More active
More toxic
Methotrexate excretion
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90% renal excretion (MUST dose adjust in renal impairment)
Rapidly excreted in urine, insoluble at pH< 7.0, if accumulates
can precipitate in tubules and cause renal failure
Hydration and alkalinization to urine pH 7-8, specific gravity <
1.010 is IMPERATIVE.
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Do not start MTX until urine parameters are met! Can give NS and
bicarbonate boluses. Monitor urine parameters until MTX is excreted
below 0.1uM.
Protocols specify acceptable levels at different time points (i.e. 24,
42, 48 hour levels). If elevated, increase hydration to 200mL/m2/hr
and leucovorin rescue per protocol.
If level is unacceptably high, consider Glucarpidase
(carboxypeptidase G2) to rapidly lower serum MTX levels
Methotrexate (continued)
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Many drugs inhibit renal excretion of MTX and may increase
treatment-related toxicity. STOP these in advance of HD-MTX
infusion
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NSAIDs, phenytoin, ciprofloxacin, penicillin-type drugs,
probenecid, amiodarone, and proton pump inhibitors
Bactrim (trimethoprim/sulfamethoxazole) increases toxicity and
may interfere with efficacy
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Sulfa drugs inhibit MTX renal excretion, while trimethoprim (also an
antifolate) compete with MTX for binding sites on DHFR
Third-space fluid collections (eg, ascites, pleural effusions) can
accumulate high levels of the drug that slowly leak back into the
circulation long after the initial dose.
Leucovorin rescue
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MTX has little selectivity for tumor cells, and its effectiveness is limited by
toxicity to normal tissue, particularly the gastrointestinal (GI) epithelium
and bone marrow.
Rescue normal cells from toxicity by providing reduced folates
(leucovorin) 24-42 hours after administration of MTX
Dosing: usually 15mg/m2 q6hr starting at hour 24-42 depending on
protocol, increase to q3h or higher doses depending on levels. Continue
until MTX level < 0.1uM
Why does it work?
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folate transport is deficient in malignant cells?
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leucovorin cannot be transported into the malignant cell, but it can enter normal
cells and compete with MTX for binding sites on DHFR because they retain a
normal folate carrier protein
cellular differences in polyglutamation?
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Intracellularly, leucovorin is able to compete with free but not polyglutamated MTX
for binding to DHFR In contrast to tumor cells, comparatively little PGMTX synthesis
occurs in normal gut epithelium and bone marrow precursors under similar
conditions. It is hypothesized that because of the lower levels of intracellular
PGMTX, leucovorin can more effectively curtail DHFR inhibition in normal as
compared to malignant cells.
MTX neurotoxicity
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Leukoencephalopathy
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White matter changes on MRI
Variable incidence, common in patients on therapy, but in many cases is
transient and resolves after completion of therapy
Clinical presentations
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Most asymptomatic
Acute encephalopathy with transient focal neurologic deficits (~3-5%): strokelike (hemiparesis, aphasia), seizures, tranverse myelitis
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Evaluate for stroke (especially if recent asparaginase), infection, hypertension
Treatment: often resolves with supportive care, other options in case series include
aminophylline (antagonizes effect of increased adenosine), dextromethorphan
(NMDA antagonist)
Chronic encephalopathy
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Demyelination, calcifications
Exacerbated by cranial radiation
Neurocognitive difficulties
Platinum compounds
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Cisplatin (osteosarcoma, germ cell tumors, CNS)
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highly emetogenic
Nephrotoxicity with selective proximal tubule injury – may
be abrupt, or insidious with cumulative dosing
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Often heralded by hypomagnesemia (which can exacerbate
cisplatin toxicity), can have Fanconi renal syndrome and falling
GFR
PREVENTION with forced diuresis, replete magnesium
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High rate of fluid administration
Mannitol diuresis
Other toxicities: axonal neuropathy, dose-dependent highfrequency sensorineural hearing loss
Carboplatin
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Significantly less nephrotoxic than cisplatin
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Can see magnesium and salt-wasting
Renal clearance is critical, dosing by AUC
(area under curve) and GFR rather than
body surface area  Calvert formula
Infusion reaction/anaphylaxis: 12-30%,
increases with repeated exposure
Vincristine
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Vinca alkaloids, mechanism = microtubule disruption
Dose-limiting toxicity is axonal neuropathy involving both sensory
and motor fibers, with small sensory fibers most affected
Virtually all patients have some degree of neuropathy.
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Earliest symptoms = paresthesias in the fingertips and feet, +/- muscle
cramps.
Loss of DTRs is universal. May have bilateral foot drop, wrist drop
Occasional severe weakness should cause you to look for underlying
disorder (Charcot-Marie-Tooth)
There is no treatment
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PT/OT critical, Gabapentin to manage pain symptoms
Dose reduction ONLY if severe
Natural history is gradual improvement after cessation of therapy over months or
longer.
Vincristine (cont)
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SIADH, resulting in hyponatremia, confusion, and seizures
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Autonomic neuropathies : Colicky abdominal pain and constipation
common. All patients should have prophylactic stool softeners or
laxative. Occasional paralytic ileus. To give VCR, must be
stooling and have bowel sounds!
Focal neuropathies: most common oculomotor nerve, facial nerve
(jaw pain), recurrent laryngeal nerve (vocal cord paralysis)
Other rare CNS complications that are unrelated to SIADH include
seizures, encephalopathy, transient cortical blindness, ataxia,
athetosis (slow, writhing movements of the limbs), and
parkinsonism
VCR is fatal if administered intrathecally
Asparaginase
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Breaks down extracellular asparagine into aspartic acid and
ammonia
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Unlike normal cells, lymphoblasts lack the enzyme to synthesize asparagine and therefore rely on an
exogenous source of this amino acid to maintain cellular protein synthesis.
Pegylated E.coli-derived formulation has prolonged half-life (six
days), least immunogenic
Hyperlipidemia (TG), hyperglycemia (especially with concurrent
steroids, manage with insulin, do not change dose!),
hyperammonemia
Allergic reaction
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5-10% of patients
Indication to switch to Erwinase (Erwinia-derived, non-pegylated) if systemic anaphylaxis (33%
recurrence)
Asparaginase (cont)
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Pancreatitis
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Coagulopathy due to decreased protein synthesis of clotting factors with
reductions in plasminogen, fibrinogen, antithrombin, protein C/S, and factors IX
and X with prolonged aPTT
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2-7% of patients, increased in adolescents
Typically occurs within four weeks of first dose of asparaginase
Symptomatic pancreatitis associated with high rate of recurrence with retreatment, but
strongly consider retreatment as asparaginase is a key component of ALL therapy.
Chronic complications uncommon but can develop pseudocysts
Usually results in thrombosis (catheter-related 5% symptomatic, venous sinus
thrombosis 2.9%, DVT 5-10%)
More common in induction than later in therapy
If thrombosis, perform inherited thrombophilia evaluation (i.e. Factor V Leiden etc),
treat with lovenox, replete AT3
Hepatic toxicity
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20% transaminase elevations, 3% hyperbilirubinemia, mostly mild and transient
Etoposide
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Anaphylaxis
Hypotension with rapid IV infusion
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Must run over 30-60min
Must be diluted minimum of 0.4mg/mL
If diastolic or systolic blood pressure (BP) falls 20 mm Hg
during infusion, reduce infusion rate by 50%. Start a
simultaneous infusion of NS 10 ml/kg if BP fails to recover
or falls further.
Stop infusion if BP does not recover, continue NS. If the
patient has had any episode of hypotension, prehydrate
with 0.9% NaCl at 10 mL/kg/hr for 2 hours prior to any
subsequent infusion.
Doxorubicin
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Anthracycline antibiotic
Intercalates between DNA double helix and inhibits
topoisomerase II
Red going in, red coming out
Significant toxicities:
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Cardiovascular – acute and delayed
Nausea/vomiting
Mucositis
Radiation recall
Other drugs for another day…
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ATRA – pseudotumor cerebri
Bleomycin – pulmonary fibrosis
Mercaptopurine/thioguanine
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Myelosuppression
TPMT deficiency
Veno-occlusive disease