Chapter 33 — Anti-Cancer Drugs Part I: Pharmacology — Module 6 — Miscellaneous Cytotoxics, Drug Interactions, and Supportive Pharmacology
1. A 24-year-old woman with sickle cell disease has had five vaso-occlusive crises requiring hospitalization in the past year and one prior episode of acute chest syndrome. She is not pregnant and wishes to reduce her crisis frequency. Which intervention is most appropriate, and what monitoring does it require?
A) Begin chronic opioid therapy as the primary disease-modifying strategy, with no laboratory monitoring needed
B) Begin lenalidomide to raise fetal hemoglobin, monitoring for venous thromboembolism
C) Begin asparaginase to deplete the sickle hemoglobin precursor, monitoring coagulation parameters
D) Begin hydroxyurea to raise fetal hemoglobin and reduce sickle hemoglobin polymerization, with periodic complete blood count monitoring for myelosuppression
E) Begin a CYP3A4 inducer to accelerate clearance of sickle hemoglobin, monitoring liver enzymes
ANSWER: D
Rationale:
Hydroxyurea is the established disease-modifying therapy for sickle cell disease with frequent vaso-occlusive episodes; it raises fetal hemoglobin, which does not polymerize and reduces the fraction of sickle hemoglobin available to sickle, thereby decreasing crises, acute chest syndrome, and transfusion need. Because its dose-limiting toxicity is myelosuppression, periodic complete blood count monitoring is required.
Option A: Option A is incorrect because opioids treat pain but are not disease-modifying and do not reduce crisis frequency.
Option B: Option B is incorrect because lenalidomide is not a sickle cell therapy and does not raise fetal hemoglobin; raising fetal hemoglobin is the hydroxyurea mechanism.
Option C: Option C is incorrect because asparaginase has no role in sickle cell disease and does not act on a sickle hemoglobin precursor.
Option E: Option E is incorrect because CYP3A4 induction does not affect sickle hemoglobin and is not a treatment strategy in this disease.
2. A 9-year-old boy receiving pegaspargase for T-cell acute lymphoblastic leukemia develops severe epigastric pain radiating to the back, vomiting, and a serum lipase five times the upper limit of normal. Which is the most appropriate interpretation and management step?
A) This is an expected infusion reaction; premedicate and continue pegaspargase at the same dose
B) This is asparaginase-associated pancreatitis; hold asparaginase, provide supportive care, and avoid rechallenge in clinically significant or severe cases
C) This is silent inactivation; switch to Erwinia asparaginase and continue without delay
D) This is asparaginase-induced hyperglycemia; start insulin and continue asparaginase unchanged
E) This is cerebral venous sinus thrombosis; begin anticoagulation and continue asparaginase
ANSWER: B
Rationale:
Severe epigastric pain with markedly elevated lipase during asparaginase therapy indicates asparaginase-associated pancreatitis, a recognized and potentially serious toxicity; management is to hold asparaginase and provide supportive care, and in clinically significant or severe pancreatitis the drug is generally not rechallenged.
Option A: Option A is incorrect because this presentation is pancreatitis rather than an infusion reaction, and premedication would not address it.
Option C: Option C is incorrect because silent inactivation refers to antibody-mediated loss of enzyme activity without clinical symptoms, not to acute pancreatitis, and switching preparations does not treat pancreatitis.
Option D: Option D is incorrect because, although asparaginase can cause hyperglycemia, the pain and elevated lipase define pancreatitis rather than hyperglycemia, and continuing the drug would be inappropriate.
Option E: Option E is incorrect because the clinical picture is pancreatitis rather than cerebral venous sinus thrombosis, which presents with neurologic features rather than epigastric pain and elevated lipase.
3. A 63-year-old man with newly diagnosed multiple myeloma is about to begin lenalidomide with dexamethasone. He has hypertension and prior deep vein thrombosis, placing him at higher thrombotic risk. Which step is most appropriate before starting therapy?
A) Initiate thromboprophylaxis, with low molecular weight heparin or therapeutic-intensity anticoagulation appropriate for this higher-risk patient rather than aspirin alone
B) Withhold all thromboprophylaxis, since dexamethasone offsets the clotting risk of lenalidomide
C) Begin antifungal prophylaxis as the principal preventive measure and omit anticoagulation
D) Reduce the lenalidomide dose solely to prevent neuropathy and provide no thromboprophylaxis
E) Defer lenalidomide indefinitely because it is absolutely contraindicated after any prior thrombosis
ANSWER: A
Rationale:
Lenalidomide combined with dexamethasone markedly increases venous thromboembolism risk, so thromboprophylaxis is mandatory; in a higher-risk patient with prior deep vein thrombosis, low molecular weight heparin or therapeutic-intensity anticoagulation is appropriate rather than aspirin alone, which is reserved for lower-risk patients.
Option B: Option B is incorrect because dexamethasone adds to rather than offsets the thrombotic risk.
Option C: Option C is incorrect because antifungal prophylaxis does not address the thrombotic risk that defines this scenario.
Option D: Option D is incorrect because, although lenalidomide is less neurotoxic than thalidomide, the omission of thromboprophylaxis in a high-risk patient is unsafe.
Option E: Option E is incorrect because prior thrombosis is not an absolute contraindication to lenalidomide; it raises the intensity of required prophylaxis rather than precluding therapy.
4. A 52-year-old woman taking adjuvant tamoxifen for hormone receptor-positive breast cancer develops major depression and needs an antidepressant. Which choice best preserves the efficacy of her tamoxifen?
A) Paroxetine, because it has no effect on tamoxifen metabolism
B) Fluoxetine, because it enhances conversion of tamoxifen to endoxifen
C) Bupropion, because it strongly induces CYP2D6 and increases endoxifen
D) Any antidepressant is acceptable because tamoxifen does not require metabolic activation
E) Venlafaxine or escitalopram, because their low CYP2D6 inhibition preserves conversion of tamoxifen to active endoxifen
ANSWER: E
Rationale:
Tamoxifen is a prodrug activated by CYP2D6 to endoxifen, so an antidepressant with minimal CYP2D6 inhibition such as venlafaxine or escitalopram preserves that activation and is preferred.
Option A: Option A is incorrect because paroxetine is among the most potent CYP2D6 inhibitors and substantially reduces endoxifen, the opposite of having no effect.
Option B: Option B is incorrect because fluoxetine also strongly inhibits CYP2D6 and reduces rather than enhances endoxifen formation.
Option C: Option C is incorrect because bupropion inhibits rather than induces CYP2D6 and would lower endoxifen.
Option D: Option D is incorrect because tamoxifen does require CYP2D6-mediated activation, which is precisely why the antidepressant choice matters.
5. A 30-year-old woman with acute lymphoblastic leukemia is receiving vincristine and is started on voriconazole for invasive aspergillosis. Two weeks later she develops worsening foot drop, areflexia, and severe constipation. Which action is most appropriate?
A) Increase the vincristine dose to overcome presumed underdosing
B) Continue both drugs unchanged, since the symptoms are unrelated to therapy
C) Recognize azole-potentiated vincristine neurotoxicity from CYP3A4 inhibition, hold or reduce vincristine, and substitute a less potent CYP3A4-inhibiting antifungal
D) Administer the next vincristine dose intrathecally to bypass the interaction
E) Add a second azole to enhance antifungal coverage and maintain the vincristine dose
ANSWER: C
Rationale:
Voriconazole potently inhibits CYP3A4, the enzyme that clears vincristine, so co-administration raises vincristine exposure and can precipitate severe neurotoxicity such as motor weakness, areflexia, and autonomic constipation; the correct response is to recognize the interaction, hold or reduce vincristine, and substitute a less potent CYP3A4-inhibiting antifungal.
Option A: Option A is incorrect and dangerous because the neurotoxicity reflects excess vincristine exposure, so increasing the dose would worsen it.
Option B: Option B is incorrect because the symptoms are classic vincristine neurotoxicity amplified by the interaction rather than unrelated findings.
Option D: Option D is incorrect and lethal because vincristine must never be administered intrathecally under any circumstances.
Option E: Option E is incorrect because adding another azole would further inhibit CYP3A4 and intensify vincristine toxicity.
6. A 58-year-old man receiving oxaliplatin-based therapy for colon cancer calls the day after his first infusion, alarmed that drinking ice water triggered tingling and a tight, choking sensation in his throat and that touching cold objects causes prickling in his fingertips. He has no rash, wheeze, or hypotension. Which is the most appropriate response?
A) Advise that this is anaphylaxis and instruct him to use an epinephrine autoinjector immediately
B) Reassure him that this is the expected acute cold-triggered syndrome of oxaliplatin caused by altered sodium channel kinetics, and counsel him to avoid cold food, drink, and air around each infusion
C) Tell him this represents cumulative dorsal root ganglion neuropathy requiring immediate discontinuation
D) Instruct him to stop oxaliplatin permanently because these symptoms indicate irreversible nerve death
E) Advise that this is a drug interaction and that he should stop all other medications
ANSWER: B
Rationale:
Oxaliplatin characteristically produces an acute, cold-triggered sensory syndrome within hours to days of infusion, including perioral and pharyngolaryngeal dysesthesias and fingertip prickling, attributed to cold-induced alteration of sodium channel kinetics; the absence of rash, wheeze, or hypotension distinguishes it from anaphylaxis, and management is reassurance plus counseling to avoid cold exposure around each infusion.
Option A: Option A is incorrect because the picture lacks the features of anaphylaxis and is the recognized cold syndrome rather than an allergic emergency.
Option C: Option C is incorrect because the cumulative dorsal root ganglion neuropathy develops gradually over many cycles rather than acutely after a single infusion, and it does not mandate immediate discontinuation in this acute context.
Option D: Option D is incorrect because the acute cold syndrome is transient rather than irreversible nerve death and does not require permanent cessation.
Option E: Option E is incorrect because the symptoms are the intrinsic acute oxaliplatin effect rather than a drug interaction.
7. A 70-year-old woman has lower-risk myelodysplastic syndrome with isolated deletion 5q and symptomatic, transfusion-dependent anemia. Which therapy offers the highest likelihood of transfusion independence, and why is it specifically effective in her disease?
A) Lenalidomide, because it directs cereblon to degrade casein kinase 1-alpha, to which del(5q) clones are selectively vulnerable owing to haploinsufficiency, producing transfusion independence in roughly two-thirds of such patients
B) Hydroxyurea, because ribonucleotide reductase inhibition selectively spares del(5q) clones
C) Asparaginase, because del(5q) cells are auxotrophic for asparagine
D) Thalidomide, because it is more potent than lenalidomide at degrading casein kinase 1-alpha
E) Pomalidomide, because it is renally cleared and therefore preferred in older patients
ANSWER: A
Rationale:
Lenalidomide produces a near-disease-specific response in lower-risk del(5q) myelodysplastic syndrome because it additionally directs cereblon to degrade casein kinase 1-alpha, whose gene lies in the deleted 5q region; the resulting haploinsufficiency makes del(5q) clones selectively dependent on residual casein kinase 1-alpha and vulnerable to its degradation, yielding transfusion independence in roughly two-thirds of patients.
Option B: Option B is incorrect because hydroxyurea does not selectively target del(5q) clones and is not the disease-modifying choice here.
Option C: Option C is incorrect because asparagine auxotrophy is the basis of asparaginase activity in acute lymphoblastic leukemia, not del(5q) myelodysplastic syndrome.
Option D: Option D is incorrect because thalidomide is less potent than lenalidomide and lacks the casein kinase 1-alpha degradation that drives del(5q) selectivity.
Option E: Option E is incorrect because pomalidomide is not the established del(5q) therapy, and renal clearance is not the reason for the del(5q) response.
8. A 60-year-old woman scheduled to begin paclitaxel for breast cancer is taking gemfibrozil for hypertriglyceridemia. Recognizing the relevant metabolic pathway, which management step is most appropriate before starting paclitaxel?
A) Continue gemfibrozil and increase the paclitaxel dose to overcome anticipated underexposure
B) Continue gemfibrozil, since it induces CYP2C8 and lowers paclitaxel levels harmlessly
C) Switch paclitaxel to a CYP3A4 substrate, since gemfibrozil does not affect CYP2C8
D) Discontinue gemfibrozil before paclitaxel when feasible, because gemfibrozil inhibits CYP2C8 and can roughly double paclitaxel exposure, increasing toxicity
E) Add an azole antifungal to counteract the gemfibrozil interaction
ANSWER: D
Rationale:
Paclitaxel is metabolized primarily by CYP2C8, and gemfibrozil is a potent CYP2C8 inhibitor that can increase paclitaxel exposure approximately two-fold, raising toxicity risk; the appropriate step is to discontinue gemfibrozil before paclitaxel when feasible.
Option A: Option A is incorrect because exposure rises rather than falls, so increasing the dose would compound toxicity.
Option B: Option B inverts the pharmacology because gemfibrozil inhibits rather than induces CYP2C8 and raises rather than lowers paclitaxel levels.
Option C: Option C is incorrect because gemfibrozil does inhibit CYP2C8, the primary paclitaxel pathway, so the premise is false.
Option E: Option E is incorrect because adding an azole would introduce further CYP inhibition rather than resolve the gemfibrozil interaction.
9. A 55-year-old woman treated 6 years ago with high-dose cyclophosphamide-containing therapy now presents with pancytopenia and a dysplastic, hypocellular marrow. Cytogenetics show monosomy 7. Which interpretation and prognostic statement is most accurate?
A) This is a topoisomerase II inhibitor-related leukemia with a balanced KMT2A rearrangement and favorable prognosis
B) This is an unrelated de novo myelodysplastic syndrome with normal-risk cytogenetics
C) This is alkylating agent-related treatment-related myeloid neoplasm, consistent with the long latency, antecedent myelodysplastic phase, and monosomy 7, and it carries a poor prognosis with allogeneic transplant as the main potentially curative option
D) This is a transient cytopenia that will resolve spontaneously without intervention
E) This finding reflects ribonucleotide reductase inhibition and warrants only observation
ANSWER: C
Rationale:
The long latency of about 6 years, the antecedent dysplastic and hypocellular marrow, and monosomy 7 are characteristic of alkylating agent-related treatment-related myeloid neoplasm following cyclophosphamide; the prognosis is poor, with low complete remission rates to standard induction and allogeneic hematopoietic stem cell transplantation as the main potentially curative option in eligible patients.
Option A: Option A is incorrect because the balanced KMT2A rearrangement and short latency characterize topoisomerase II inhibitor-related disease, not this alkylating agent pattern, and the prognosis is not favorable.
Option B: Option B is incorrect because the prior alkylating agent exposure, long latency, and monosomy 7 mark this as treatment-related rather than an unrelated normal-risk de novo process.
Option D: Option D is incorrect because treatment-related myeloid neoplasms do not resolve spontaneously.
Option E: Option E is incorrect because ribonucleotide reductase inhibition is the hydroxyurea mechanism and is unrelated to this entity, and observation alone is inappropriate.
10. A 64-year-old man who completed taxane chemotherapy 4 months ago has persistent painful numbness and burning in both feet that disturbs his sleep. Examination confirms a length-dependent sensory neuropathy. Which pharmacologic treatment is best supported by evidence as first-line for his established painful neuropathy?
A) Calcium and magnesium infusions, which prevent and treat established taxane neuropathy
B) Acetyl-L-carnitine, which reverses established chemotherapy-induced neuropathy
C) Vitamin E, which has high-quality evidence for treating neuropathic pain
D) Topical lidocaine as the evidence-based first-line systemic therapy
E) Duloxetine, the only agent with Level I randomized evidence for established painful chemotherapy-induced peripheral neuropathy, started at 30 mg daily and titrated to 60 mg daily
ANSWER: E
Rationale:
Duloxetine is the only agent with Level I randomized evidence for treating established painful chemotherapy-induced peripheral neuropathy and is recommended first-line, typically started at 30 mg daily and titrated to 60 mg daily.
Option A: Option A is incorrect because calcium and magnesium infusions were studied for prevention of oxaliplatin neuropathy and failed, and they are not a treatment for established taxane neuropathy.
Option B: Option B is incorrect because acetyl-L-carnitine has not shown consistent benefit and may worsen neuropathy in some data.
Option C: Option C is incorrect because vitamin E lacks high-quality evidence for treating established neuropathic pain.
Option D: Option D is incorrect because topical lidocaine has weak, inconsistent evidence and is not the evidence-based first-line therapy, nor is it a systemic agent.
11. A 28-year-old man cured of testicular cancer two years ago with a bleomycin-containing regimen is scheduled for elective surgery requiring general anesthesia. Which perioperative measure is most important to communicate to the anesthesiology team?
A) Administer the highest tolerated inspired oxygen throughout the case to maximize tissue oxygenation
B) Minimize the fraction of inspired oxygen during anesthesia, because prior bleomycin exposure predisposes to oxygen-potentiated pulmonary injury and there is no safe time threshold after exposure
C) No special precaution is needed because bleomycin pulmonary risk resolves completely within one year
D) Avoid all intravenous fluids to prevent bleomycin-related pulmonary edema
E) Give prophylactic anthracyclines perioperatively to protect the lungs
ANSWER: B
Rationale:
Prior bleomycin exposure sensitizes the lungs to oxygen-potentiated injury, so the anesthesiology team should minimize the fraction of inspired oxygen during anesthesia; importantly, there is no established safe time threshold after exposure, so the precaution persists even years later.
Option A: Option A is incorrect and hazardous because high inspired oxygen is precisely the exposure that can potentiate bleomycin pulmonary injury.
Option C: Option C is incorrect because the risk does not reliably resolve within a year and lacks a safe threshold.
Option D: Option D is incorrect because the key perioperative concern is inspired oxygen rather than fluid administration.
Option E: Option E is incorrect because anthracyclines carry their own cardiac toxicity and have no protective pulmonary role.
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