Chapter 33 — Anti-Cancer Drugs Part I Pharmacology — Module 3 — Antimetabolites: Folate Antagonists, Fluoropyrimidines, Cytidine and Purine Analogs, and Hypomethylating Agents
1. A 19-year-old with osteosarcoma is receiving high-dose methotrexate with leucovorin rescue and intravenous hydration. At 48 hours the plasma methotrexate level remains elevated at 1.2 micromolar (expected to be below approximately 0.1 micromolar by this time), the serum creatinine has risen from 0.8 to 1.9 mg/dL, and the patient has oral mucositis. What is the most appropriate immediate management?
A) Stop leucovorin, because continued rescue is no longer needed once mucositis appears
B) Discontinue hydration and observe, since methotrexate will clear spontaneously
C) Recognize delayed methotrexate clearance with evolving nephrotoxicity: intensify leucovorin rescue (higher dose, more frequent), continue vigorous hydration with urinary alkalinization, and consider glucarpidase for the markedly elevated level
D) Administer allopurinol to lower the methotrexate level
E) Switch to capecitabine to bypass the renal problem
ANSWER: C
Rationale:
A methotrexate level well above the expected threshold at 48 hours together with a rising creatinine indicates delayed clearance with methotrexate-associated nephrotoxicity, a medical emergency. Management intensifies leucovorin rescue (higher and more frequent dosing guided by levels), maintains vigorous hydration with urinary alkalinization, and considers glucarpidase to rapidly degrade circulating methotrexate when the level is markedly elevated or rescue is failing.
Option C is correct because escalating rescue, supporting renal clearance, and considering glucarpidase is the established response to delayed methotrexate clearance.
Option A: Option A is incorrect because leucovorin must be intensified, not stopped, when the level remains high; mucositis signals ongoing toxicity requiring more rescue.
Option B: Option B is incorrect because the level is dangerously high with worsening renal function and will not safely clear without intervention.
Option D: Option D is incorrect because allopurinol does not lower methotrexate levels and would not address the toxicity.
Option E: Option E is incorrect because switching to capecitabine does not treat the current methotrexate toxicity and is not relevant to this emergency.
2. A 58-year-old begins capecitabine for colorectal cancer. Five days into the first cycle she develops severe mucositis, grade 4 neutropenia and thrombocytopenia, profuse diarrhea, and cerebellar-type neurotoxicity. What is the most likely explanation and the appropriate action?
A) Dihydropyrimidine dehydrogenase (DPD) deficiency causing impaired 5-fluorouracil catabolism: stop the fluoropyrimidine immediately, provide intensive supportive care, and obtain urgent DPYD genotyping or phenotypic DPD testing
B) Expected mild toxicity of capecitabine: continue at full dose and reassess next cycle
C) Tumor lysis syndrome from rapid tumor breakdown: give rasburicase and continue capecitabine
D) An allergic reaction to capecitabine: give antihistamines and rechallenge at full dose
E) Vitamin B12 deficiency: administer intramuscular B12 and continue at full dose
ANSWER: A
Rationale:
Severe, early, multi-system toxicity (profound mucositis, marrow suppression, diarrhea, and neurotoxicity) within the first week of a fluoropyrimidine is the classic presentation of dihydropyrimidine dehydrogenase (DPD) deficiency, in which 5-fluorouracil generated from capecitabine cannot be catabolized. The fluoropyrimidine must be stopped immediately, with intensive supportive care and urgent DPYD genotyping or phenotypic DPD testing to guide any future therapy.
Option A is correct because the early severe multi-system toxicity pattern indicates DPD deficiency and mandates stopping the drug and testing.
Option B: Option B is incorrect because this is severe, life-threatening toxicity, not expected mild toxicity to continue through.
Option C: Option C is incorrect because the picture is fluoropyrimidine toxicity, not tumor lysis syndrome, and continuing the drug would be dangerous.
Option D: Option D is incorrect because this is a metabolic toxicity from DPD deficiency, not an allergic reaction, and rechallenge at full dose could be fatal.
Option E: Option E is incorrect because B12 deficiency does not explain this presentation, and continuing full-dose capecitabine in DPD deficiency is hazardous.
3. A 67-year-old on chronic warfarin for atrial fibrillation (international normalized ratio [INR] previously stable at 2.4) starts capecitabine for breast cancer. Twelve days later, routine testing shows an INR of 6.8 with no bleeding. What is the best explanation and management?
A) Capecitabine induced warfarin metabolism, so the warfarin dose should be increased
B) The high INR is unrelated to capecitabine; continue both drugs unchanged
C) Capecitabine caused malabsorption of warfarin, so warfarin should be given intravenously
D) Capecitabine inhibits CYP2C9 (cytochrome P450 2C9) and reduces clearance of S-warfarin; hold warfarin, manage the elevated INR per protocol, monitor INR frequently, and resume at a substantially lower dose (or transition to a direct oral anticoagulant, which is not CYP2C9-dependent)
E) The patient should be switched to a higher warfarin dose with weekly checks
ANSWER: D
Rationale:
Capecitabine inhibits CYP2C9 (cytochrome P450 2C9), reducing clearance of the more potent S-warfarin enantiomer and raising the INR, often within one to two weeks. The supratherapeutic INR is managed per protocol; warfarin is held and resumed at a substantially lower dose with frequent monitoring, and transition to a direct oral anticoagulant (not metabolized by CYP2C9) avoids the interaction.
Option D is correct because it identifies CYP2C9 inhibition of S-warfarin and applies appropriate INR management and a lower or alternative anticoagulant.
Option A: Option A is incorrect because capecitabine inhibits rather than induces warfarin metabolism, so increasing the dose would worsen over-anticoagulation.
Option B: Option B is incorrect because the interaction is well described and the elevated INR requires action.
Option C: Option C is incorrect because the mechanism is CYP2C9 inhibition, not malabsorption, and intravenous warfarin is not the solution.
Option E: Option E is incorrect because raising the warfarin dose would further increase the INR; the dose must be reduced or the drug changed.
4. A 63-year-old receiving high-dose cytarabine (HiDAC) consolidation for acute myeloid leukemia develops, on day 4, gait ataxia, slurred speech (dysarthria), and nystagmus. Renal function has declined during admission. What is the most appropriate action?
A) Continue HiDAC at full dose and add an antiemetic, since these are expected gastrointestinal effects
B) Recognize cytarabine cerebellar neurotoxicity (a dose-dependent Purkinje cell injury, with older age and renal impairment as risk factors) and discontinue cytarabine immediately, as continued dosing risks irreversible cerebellar damage
C) Increase the cytarabine dose to overcome presumed resistance
D) Diagnose a primary cerebellar stroke and continue cytarabine unchanged
E) Attribute the findings to anxiety and proceed with the next dose
ANSWER: B
Rationale:
Ataxia, dysarthria, and nystagmus during high-dose cytarabine indicate cerebellar neurotoxicity from Purkinje cell injury, with older age and renal impairment as key risk factors. Neurologic examination is performed before each dose, and the appearance of cerebellar signs mandates immediate discontinuation because continued dosing risks irreversible cerebellar damage.
Option B is correct because the cerebellar syndrome requires immediate cessation of cytarabine.
Option A: Option A is incorrect because these are central cerebellar signs, not gastrointestinal effects, and continuing would risk permanent injury.
Option C: Option C is incorrect because increasing the dose would worsen the neurotoxicity.
Option D: Option D is incorrect because the temporal association with HiDAC and the classic triad point to drug toxicity; continuing cytarabine is unsafe.
Option E: Option E is incorrect because objective cerebellar signs cannot be dismissed as anxiety, and another dose would be dangerous.
5. A 70-year-old receiving gemcitabine for pancreatic adenocarcinoma develops progressive dyspnea and hypoxemia during the second cycle. Chest imaging shows bilateral interstitial infiltrates, and infection and cardiac failure have been reasonably excluded. What is the most likely cause and appropriate action?
A) Gemcitabine pulmonary toxicity (drug-induced interstitial lung disease): hold gemcitabine and provide supportive care, with corticosteroids in severe cases
B) Cerebellar toxicity of gemcitabine: reduce the dose and continue
C) Expected flu-like syndrome of gemcitabine: give acetaminophen and continue at full dose without further evaluation
D) Hemolytic uremic syndrome: the infiltrates indicate microangiopathy and require plasma exchange
E) Hand-foot syndrome involving the lungs: apply topical therapy and continue
ANSWER: A
Rationale:
Gemcitabine can cause a distinctive pulmonary toxicity presenting as dyspnea, hypoxemia, and interstitial infiltrates, usually within the first few cycles, after infection and cardiac causes are excluded. Management is to hold gemcitabine and provide supportive care, with corticosteroids for severe drug-induced interstitial lung disease.
Option A is correct because the presentation is classic gemcitabine pulmonary toxicity requiring drug cessation and supportive care.
Option B: Option B is incorrect because gemcitabine does not characteristically cause cerebellar toxicity (that is high-dose cytarabine), and the findings are pulmonary.
Option C: Option C is incorrect because progressive dyspnea with infiltrates is not the benign flu-like syndrome and warrants evaluation and drug cessation.
Option D: Option D is incorrect because hemolytic uremic syndrome presents with microangiopathic hemolysis, thrombocytopenia, and acute kidney injury, not isolated interstitial infiltrates.
Option E: Option E is incorrect because hand-foot syndrome is a cutaneous palmar-plantar reaction and does not produce pulmonary infiltrates.
6. A 61-year-old who has received several cycles of gemcitabine presents with new fatigue and dark urine. Labs show anemia with schistocytes on smear (microangiopathic hemolytic anemia), thrombocytopenia, an elevated lactate dehydrogenase with low haptoglobin, and a rising creatinine. Coagulation studies are near normal. What is the diagnosis and immediate action regarding the drug?
A) Disseminated intravascular coagulation: continue gemcitabine and give fresh frozen plasma
B) Cytarabine cerebellar toxicity: this is unrelated to gemcitabine and needs no drug change
C) Iron deficiency anemia: continue gemcitabine and start oral iron
D) Autoimmune hemolytic anemia from gemcitabine: continue the drug with corticosteroids
E) Gemcitabine-induced hemolytic uremic syndrome (a thrombotic microangiopathy): discontinue gemcitabine immediately and provide supportive care
ANSWER: E
Rationale:
Microangiopathic hemolytic anemia (schistocytes), thrombocytopenia, and acute kidney injury with near-normal coagulation in a patient on gemcitabine indicate gemcitabine-induced hemolytic uremic syndrome, a thrombotic microangiopathy. Although rare, it is potentially fatal, and the essential action is immediate discontinuation of gemcitabine with supportive care.
Option E is correct because the triad with preserved coagulation defines a thrombotic microangiopathy (hemolytic uremic syndrome) requiring drug cessation.
Option A: Option A is incorrect because coagulation studies are near normal, arguing against disseminated intravascular coagulation, and continuing gemcitabine would be harmful.
Option B: Option B is incorrect because cerebellar toxicity is a high-dose cytarabine effect and does not explain the hematologic-renal findings.
Option C: Option C is incorrect because schistocytes, thrombocytopenia, and acute kidney injury are not iron deficiency, which would not present this way.
Option D: Option D is incorrect because the microangiopathic picture is a thrombotic microangiopathy requiring discontinuation, not an autoimmune hemolytic anemia managed by continuing the drug.
7. A 45-year-old with Crohn disease is maintained on azathioprine (a prodrug cleaved to 6-mercaptopurine). He develops an acute gout flare, and a clinician is about to start standard-dose allopurinol. What is the most appropriate action to prevent a dangerous interaction?
A) Start standard-dose allopurinol with no change to azathioprine, as there is no meaningful interaction
B) Increase the azathioprine dose to maintain disease control while on allopurinol
C) Recognize that allopurinol inhibits xanthine oxidase, a major catabolic route for 6-mercaptopurine, and either reduce the azathioprine dose to approximately 25 to 33% with close blood-count monitoring, or treat the urate problem with an agent such as rasburicase instead of allopurinol
D) Stop azathioprine permanently because any allopurinol exposure is invariably fatal
E) Add leucovorin to neutralize the interaction and continue both at full dose
ANSWER: C
Rationale:
Azathioprine is converted to 6-mercaptopurine, which is catabolized in part by xanthine oxidase. Allopurinol inhibits xanthine oxidase, raising thiopurine levels several-fold and risking fatal myelosuppression. The safe approach is to reduce the thiopurine dose to roughly 25 to 33% with close monitoring when allopurinol is unavoidable, or to manage urate with an alternative such as rasburicase.
Option C is correct because dose reduction with monitoring (or substituting rasburicase) addresses the xanthine oxidase interaction.
Option A: Option A is incorrect because the interaction is real and potentially fatal.
Option B: Option B is incorrect because increasing the thiopurine dose would worsen toxicity given reduced catabolism.
Option D: Option D is incorrect because the combination can be managed with dose reduction; permanent discontinuation is not mandatory.
Option E: Option E is incorrect because leucovorin does not counteract this thiopurine-xanthine oxidase interaction.
8. A 6-year-old in maintenance therapy for acute lymphoblastic leukemia is started on standard-dose 6-mercaptopurine. Within two weeks she develops profound pancytopenia and severe mucositis. Pretreatment pharmacogenomic testing had not been performed. Which finding would best explain this, and what does it imply for dosing?
A) High (wild-type) TPMT activity; the dose should be increased
B) Low or absent thiopurine methyltransferase (TPMT) activity, causing marked accumulation of thioguanine nucleotides; 6-mercaptopurine must be drastically reduced (to roughly 10 to 20% of standard) or held, with TPMT-guided dosing thereafter
C) DPYD deficiency; the dose of 6-mercaptopurine is unaffected and should continue unchanged
D) UGT1A1 polymorphism; this explains the toxicity and requires no dose change
E) Normal metabolism; this degree of toxicity is expected and acceptable at standard dosing
ANSWER: B
Rationale:
Profound early myelosuppression at standard 6-mercaptopurine dosing is the hallmark of low or absent thiopurine methyltransferase (TPMT) activity, which prevents methylation and shunts drug toward toxic thioguanine nucleotide accumulation. Such patients require drastic dose reduction (commonly to roughly 10 to 20% of standard) or holding, with TPMT genotype- or phenotype-guided dosing thereafter.
Option B is correct because low TPMT activity explains the severe toxicity and mandates a large dose reduction.
Option A: Option A is incorrect because high (wild-type) activity would not cause this toxicity, and increasing the dose would be dangerous.
Option C: Option C is incorrect because DPYD deficiency governs fluoropyrimidine, not thiopurine, toxicity.
Option D: Option D is incorrect because UGT1A1 polymorphism relates to irinotecan toxicity and does not explain 6-mercaptopurine myelosuppression.
Option E: Option E is incorrect because this severe pancytopenia is not the expected, acceptable effect of standard dosing.
9. A 68-year-old with chronic lymphocytic leukemia (CLL) on fludarabine develops worsening fatigue and jaundice. Labs show a falling hemoglobin, elevated lactate dehydrogenase, low haptoglobin, spherocytes, and a positive direct antiglobulin test (DAT). What is the most appropriate action regarding the fludarabine?
A) Continue fludarabine and transfuse, since the hemolysis is unrelated to therapy
B) Increase the fludarabine dose to suppress the autoimmune process faster
C) Switch to cladribine, which does not cause this complication
D) Recognize fludarabine-associated autoimmune hemolytic anemia (AIHA) and discontinue fludarabine immediately, since continuation worsens the hemolysis; treat the AIHA (for example, corticosteroids) as indicated
E) Add allopurinol, which reverses fludarabine-associated hemolysis
ANSWER: D
Rationale:
A warm autoimmune hemolytic anemia (positive direct antiglobulin test, spherocytes, elevated lactate dehydrogenase, low haptoglobin) arising during fludarabine therapy in chronic lymphocytic leukemia is a recognized, potentially severe complication. The development of autoimmune hemolytic anemia is an indication to discontinue fludarabine immediately, because continuation worsens hemolysis; the autoimmune hemolytic anemia is then treated (for example, with corticosteroids).
Option D is correct because immediate discontinuation plus treatment of the autoimmune hemolytic anemia is the established response.
Option A: Option A is incorrect because the hemolysis is drug-associated and continuing fludarabine is harmful.
Option B: Option B is incorrect because increasing the dose would worsen the autoimmune hemolysis.
Option C: Option C is incorrect because cladribine is also a purine analog that causes profound immunosuppression and is not a safe automatic substitute here; the priority is stopping the offending drug.
Option E: Option E is incorrect because allopurinol does not reverse fludarabine-associated hemolysis.
10. Four months after completing a fludarabine-containing regimen for chronic lymphocytic leukemia, a 66-year-old presents with progressive dyspnea, dry cough, fever, and marked hypoxemia. Chest imaging shows diffuse bilateral interstitial infiltrates. He had not received infection prophylaxis. Which complication is most likely, and what does this case underscore?
A) Pneumocystis jirovecii pneumonia (PCP) due to prolonged fludarabine-induced CD4 (cluster of differentiation 4) T-lymphocyte depletion; this underscores the need for PCP prophylaxis (typically trimethoprim-sulfamethoxazole) during and for months after purine-analog therapy
B) Gemcitabine pulmonary toxicity; restart fludarabine after symptoms improve
C) Cytarabine cerebellar toxicity presenting as respiratory failure
D) Hand-foot syndrome of the lungs requiring topical therapy
Fludarabine produces prolonged depletion of CD4 (cluster of differentiation 4) T-helper lymphocytes lasting months to years, predisposing to opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP). A subacute hypoxemic pneumonia with diffuse interstitial infiltrates months after therapy in a patient who received no prophylaxis fits PCP and underscores why PCP prophylaxis (commonly trimethoprim-sulfamethoxazole) is given during and for months after purine-analog therapy.
Option A is correct because the opportunistic infection reflects sustained CD4 depletion and highlights the role of prophylaxis.
Option B: Option B is incorrect because the patient is not on gemcitabine, and restarting fludarabine in this setting is inappropriate.
Option C: Option C is incorrect because cerebellar toxicity is a high-dose cytarabine effect and does not cause this pulmonary infection.
Option D: Option D is incorrect because hand-foot syndrome is a cutaneous reaction and does not produce pulmonary infiltrates.
Option E: Option E is incorrect because the patient is not described as on warfarin and capecitabine, and that interaction does not cause this opportunistic pneumonia.
11. A 74-year-old with higher-risk myelodysplastic syndrome has completed two cycles of azacitidine with no improvement in blood counts and continued transfusion dependence. Hematologic tolerance has been acceptable. The covering team proposes stopping azacitidine for "treatment failure." What is the most appropriate recommendation?
A) Stop azacitidine now, since absence of response after two cycles proves resistance
B) Switch immediately to intensive induction chemotherapy because hypomethylating agents have failed
C) Add allopurinol to potentiate azacitidine and continue
D) Declare failure and move to best supportive care only
E) Continue azacitidine, because hypomethylating agents act through passive demethylation that accumulates over successive cell divisions; a minimum of four to six cycles is generally needed before declaring failure when tolerance permits
ANSWER: E
Rationale:
Hypomethylating agents work through passive demethylation that accumulates only across repeated cell divisions, so responses in myelodysplastic syndrome typically emerge after several cycles, often between cycles four and six. Stopping after two cycles in a patient tolerating therapy risks aborting a response that has not yet had time to develop; a minimum of four to six cycles is recommended before declaring failure.
Option E is correct because the demethylation mechanism requires four to six cycles before treatment failure can be declared.
Option A: Option A is incorrect because two cycles is too early to conclude resistance with this mechanism.
Option B: Option B is incorrect because switching to intensive induction is not warranted simply because an adequate hypomethylating-agent trial has not yet been completed.
Option C: Option C is incorrect because allopurinol does not potentiate azacitidine and carries its own interaction risks with other agents.
Option D: Option D is incorrect because moving to supportive care only is premature before an adequate four-to-six-cycle trial.
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