Chapter 33 — Anti-Cancer Drugs Part I — Module 2 — Alkylating Agents
1. A 54-year-old woman receiving high-dose cyclophosphamide as part of a stem cell mobilization regimen develops dysuria and visible blood in her urine on the second day. Urinalysis confirms hematuria without casts or infection. What is the most appropriate next step in management?
A) Discontinue cyclophosphamide permanently and switch to a platinum agent for the remainder of therapy
B) Begin aggressive intravenous hydration and administer mesna to bind urinary acrolein
C) Start broad-spectrum antibiotics for presumed hemorrhagic urinary tract infection
D) Administer intravenous methylene blue to reverse the urotoxic metabolite
E) Initiate continuous bladder irrigation alone and continue cyclophosphamide at the same dose without further measures
ANSWER: B
Rationale:
Option B is correct. The clinical picture is cyclophosphamide-induced hemorrhagic cystitis, caused by acrolein concentrated in the bladder lumen. Management combines aggressive hydration to dilute and flush urinary acrolein with mesna, whose thiol group binds acrolein to form a non-toxic conjugate. These are the directed measures against the responsible metabolite.
Option A: Option A is incorrect because hemorrhagic cystitis is managed with hydration and mesna rather than mandating permanent discontinuation and a platinum switch as the immediate step.
Option C: Option C is incorrect because the urinalysis shows no infection; antibiotics do not address acrolein-mediated urothelial injury.
Option D: Option D is incorrect because methylene blue treats ifosfamide encephalopathy, not hemorrhagic cystitis; it does not bind acrolein.
Option E: Option E is incorrect because irrigation alone, without hydration and mesna and without addressing dose, fails to target the acrolein mechanism and risks ongoing injury.
2. A 38-year-old man receiving ifosfamide for a soft tissue sarcoma becomes increasingly confused and somnolent roughly 30 hours into the infusion, with new cerebellar ataxia and visual hallucinations. Metabolic panel and head imaging are unremarkable. What is the most appropriate management?
A) Continue the ifosfamide infusion and add lorazepam for presumed delirium
B) Administer hypertonic saline for suspected infusion-related hyponatremia
C) Begin high-dose corticosteroids for presumed leptomeningeal disease
D) Stop the ifosfamide and administer intravenous methylene blue
E) Increase the mesna dose to neutralize the neurotoxic metabolite in the central nervous system
ANSWER: D
Rationale:
Option D is correct. The presentation is ifosfamide encephalopathy, caused by the neurotoxic metabolite chloroacetaldehyde, typically appearing 12 to 48 hours after infusion onset. The appropriate response is to discontinue ifosfamide and administer intravenous methylene blue, which acts as an electron acceptor that reverses the metabolic disturbance underlying the encephalopathy.
Option A: Option A is incorrect because continuing the offending drug allows the encephalopathy to progress; the cause is metabolite-mediated, not primary delirium.
Option B: Option B is incorrect because the metabolic panel is unremarkable, making hyponatremia an unlikely cause; the syndrome is chloroacetaldehyde toxicity.
Option C: Option C is incorrect because imaging is unremarkable and the temporal link to ifosfamide points to encephalopathy, not leptomeningeal disease.
Option E: Option E is incorrect because mesna acts in the urinary tract against acrolein and does not treat chloroacetaldehyde-mediated encephalopathy; the treatment is methylene blue.
3. A 61-year-old man with head and neck cancer is on his third cycle of cisplatin-based chemoradiation. Laboratory studies now show a serum magnesium of 1.2 mg/dL, potassium of 3.1 mEq/L, and a creatinine that has risen from 0.9 to 1.6 mg/dL over the treatment course. Which interpretation and management is most appropriate?
A) This is cumulative cisplatin nephrotoxicity with tubular electrolyte wasting; intensify saline hydration, replete magnesium, and consider switching to carboplatin
B) This is carboplatin-pattern thrombocytopenia; reduce the dose by area under the curve and continue cisplatin unchanged
C) This is oxaliplatin-type neuropathy presenting atypically; add calcium and magnesium infusions to prevent dysesthesias
D) This is hepatic sinusoidal obstruction syndrome; begin defibrotide and restrict fluids
E) This is expected and benign; no change in hydration, electrolytes, or agent selection is warranted
ANSWER: A
Rationale:
Option A is correct. Cisplatin causes dose-dependent, cumulative proximal tubular injury with renal magnesium, potassium, and calcium wasting and a rising creatinine. The directed response is intensified saline hydration with magnesium repletion in each cycle, and when nephrotoxicity is progressive, considering a switch to the less nephrotoxic carboplatin where clinically appropriate.
Option B: Option B is incorrect because thrombocytopenia, not electrolyte wasting and rising creatinine, is the carboplatin pattern; the findings here are renal-tubular.
Option C: Option C is incorrect because the picture is nephrotoxicity with electrolyte wasting, not the cold-triggered sensory neuropathy of oxaliplatin.
Option D: Option D is incorrect because sinusoidal obstruction syndrome is a hepatic complication of high-dose busulfan, not a renal-tubular cisplatin toxicity, and fluid restriction would worsen cisplatin nephrotoxicity.
Option E: Option E is incorrect because progressive nephrotoxicity with hypomagnesemia is not benign and requires active hydration, repletion, and reassessment of the agent.
4. A frail 74-year-old woman with ovarian cancer and low muscle mass receives carboplatin dosed by the Calvert formula using an estimated GFR (glomerular filtration rate) derived from her serum creatinine. Ten days later she develops grade 4 thrombocytopenia far exceeding expectations. What best explains this outcome?
A) Her tumor developed acute platinum resistance, paradoxically increasing marrow toxicity
B) She received too little carboplatin, and the thrombocytopenia reflects disease progression rather than drug effect
C) Her low muscle mass produced a low creatinine that overestimated GFR, so the formula assigned an excessive carboplatin dose and exposure
D) Carboplatin accumulated in the central nervous system, secondarily suppressing the marrow
E) The thrombocytopenia is unrelated to carboplatin, since its dose-limiting toxicity is nephrotoxicity
ANSWER: C
Rationale:
Option C is correct. In a patient with low muscle mass, serum creatinine underrepresents true renal impairment, so the estimated GFR is falsely high. Because the Calvert formula sets carboplatin dose as target AUC multiplied by (GFR plus 25), an overestimated GFR yields an excessive dose and greater-than-intended exposure, producing the severe thrombocytopenia that is carboplatin's exposure-related dose-limiting toxicity.
Option A: Option A is incorrect because resistance reduces antitumor effect and does not increase marrow toxicity.
Option B: Option B is incorrect because the overestimated GFR caused overdosing, not underdosing, and severe thrombocytopenia here is a drug effect.
Option D: Option D is incorrect because carboplatin does not accumulate in the central nervous system to cause marrow suppression; the toxicity is a direct exposure effect.
Option E: Option E is incorrect because carboplatin's dose-limiting toxicity is myelosuppression, predominantly thrombocytopenia, and it is directly related to exposure.
5. A 58-year-old man with newly diagnosed glioblastoma has a methylated MGMT (O6-methylguanine-DNA methyltransferase) promoter and begins the Stupp protocol with concurrent temozolomide and radiation. Which statement best combines the prognostic interpretation with a necessary supportive measure?
A) The methylated promoter predicts poor temozolomide response; switch to a nitrosourea and omit antimicrobial prophylaxis
B) The methylated promoter predicts a favorable temozolomide response; initiate Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole during concurrent chemoradiation
C) The methylated promoter is irrelevant to prognosis; no prophylaxis is needed during temozolomide therapy
D) The methylated promoter predicts increased nephrotoxicity; begin saline hydration with each temozolomide dose
E) The methylated promoter mandates intrathecal temozolomide; antifungal prophylaxis is the key supportive measure
ANSWER: B
Rationale:
Option B is correct. A methylated MGMT promoter silences the repair enzyme, so temozolomide-induced O6-methylguanine lesions persist and the tumor is more likely to respond, predicting a favorable outcome. Because concurrent chemoradiation produces sustained lymphodepletion, Pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole is required during the concurrent phase.
Option A: Option A is incorrect because methylation predicts a better, not worse, temozolomide response, and prophylaxis is needed rather than omitted.
Option C: Option C is incorrect because MGMT methylation is the strongest predictor of temozolomide benefit and is highly relevant, and prophylaxis is indicated.
Option D: Option D is incorrect because temozolomide's dose-limiting toxicity is myelosuppression, not nephrotoxicity, and methylation does not predict renal injury.
Option E: Option E is incorrect because temozolomide is given orally with good central nervous system penetration, and the key supportive measure during chemoradiation is Pneumocystis prophylaxis, not antifungal prophylaxis.
6. A 49-year-old woman with stage III colon cancer reports that within hours of finishing her FOLFOX (folinic acid, fluorouracil, oxaliplatin) infusion, reaching into the freezer or drinking a cold beverage triggers intense tingling and discomfort in her hands and throat. The sensation resolves over a few days. What is the best interpretation and advice?
A) This is the cumulative, irreversible peripheral neuropathy that mandates immediate permanent discontinuation of all therapy
B) This is fluorouracil-induced coronary vasospasm; obtain an electrocardiogram and stop the regimen
C) This is an allergic infusion reaction; premedicate with antihistamines and corticosteroids before the next cycle
D) This is hypocalcemia from the leucovorin; check ionized calcium and replete before the next infusion
E) This is the acute, cold-triggered sensory neuropathy of oxaliplatin; counsel the patient to avoid cold exposure around infusions
ANSWER: E
Rationale:
Option E is correct. Oxaliplatin produces an acute, cold-triggered sensory neuropathy with dysesthesias provoked by cold objects, air, or drinks within hours of infusion and reversible over days. The appropriate advice is to avoid cold exposure in the peri-infusion period; this acute phenomenon is distinct from the cumulative sensory neuropathy that develops with higher total doses.
Option A: Option A is incorrect because the cold-triggered, rapidly reversible symptom is the acute neuropathy, not the cumulative irreversible form, and it does not by itself mandate permanent discontinuation.
Option B: Option B is incorrect because the cold-triggered dysesthesias are an oxaliplatin neuropathy, not fluorouracil coronary vasospasm.
Option C: Option C is incorrect because the temporal cold trigger identifies oxaliplatin neuropathy rather than an allergic infusion reaction.
Option D: Option D is incorrect because the syndrome is a cold-triggered neuropathy, not leucovorin-induced hypocalcemia.
7. A 60-year-old man with recurrent glioma received oral lomustine. He returns 5 weeks later with profound pancytopenia. Records show a covering clinician had scheduled his next lomustine dose for week 4, which was administered. What is the best explanation and corrective action?
A) Nitrosoureas have a delayed nadir at 4 to 6 weeks; the week-4 dose preceded recovery from the first, causing cumulative myelosuppression — extend the interval to at least 6 weeks
B) The pancytopenia reflects disease progression into the marrow; continue lomustine on the 4-week schedule
C) This is an idiosyncratic immune reaction to lomustine; rechallenge is safe once counts recover
D) The marrow suppression is from acrolein toxicity; add mesna and maintain the 4-week interval
E) This is expected nitrosourea behavior with no scheduling implication; resume dosing immediately at full dose
ANSWER: A
Rationale:
Option A is correct. Nitrosoureas produce a characteristically delayed myelosuppressive nadir at 4 to 6 weeks with recovery requiring 6 to 8 weeks, which is why cycles are spaced no more often than every 6 weeks. Administering a dose at week 4 delivered it before recovery from the first, producing overlapping cumulative myelosuppression; the correction is to extend the interval to at least 6 weeks.
Option B: Option B is incorrect because the timing and scheduling error point to cumulative drug toxicity, and continuing the 4-week schedule would repeat the harm.
Option C: Option C is incorrect because this is predictable delayed myelosuppression from overlapping dosing, not an idiosyncratic immune reaction, and rechallenge on the same schedule is unsafe.
Option D: Option D is incorrect because acrolein causes hemorrhagic cystitis, not the delayed marrow suppression of nitrosoureas, and the 4-week interval is the core error.
Option E: Option E is incorrect because, although delayed nadir is expected nitrosourea behavior, it has a critical scheduling implication: the interval must be lengthened, not ignored.
8. A 45-year-old woman who underwent high-dose busulfan conditioning for allogeneic hematopoietic stem cell transplantation develops, on day +18, tender hepatomegaly, a 4-kg weight gain with ascites, rising bilirubin, and worsening thrombocytopenia. What is the diagnosis and the appropriate directed therapy?
A) Acute graft-versus-host disease of the liver; begin calcineurin inhibitor monotherapy
B) Cisplatin-type nephrotoxicity with fluid overload; restrict fluids and replete magnesium
C) Ifosfamide encephalopathy with hepatic involvement; administer methylene blue
D) Hepatic sinusoidal obstruction syndrome from busulfan conditioning; administer defibrotide
E) Carmustine pulmonary fibrosis presenting with right heart failure; begin corticosteroids
ANSWER: D
Rationale:
Option D is correct. The constellation of tender hepatomegaly, fluid retention with weight gain and ascites, hyperbilirubinemia, and thrombocytopenia following high-dose busulfan is hepatic sinusoidal obstruction syndrome (SOS, formerly veno-occlusive disease). Defibrotide is the approved therapy for established severe SOS.
Option A: Option A is incorrect because the syndrome of tender hepatomegaly with weight gain and a falling platelet count after busulfan is SOS, not hepatic graft-versus-host disease, which presents differently and is not treated primarily with a calcineurin inhibitor alone here.
Option B: Option B is incorrect because the findings are hepatic congestion, not renal-tubular cisplatin toxicity, and fluid restriction with magnesium does not treat SOS.
Option C: Option C is incorrect because the picture is hepatic SOS, not ifosfamide encephalopathy, and methylene blue is not the treatment.
Option E: Option E is incorrect because the presentation is hepatic SOS, not carmustine pulmonary fibrosis, and corticosteroids are not the directed therapy.
9. A 27-year-old man with Hodgkin lymphoma on a procarbazine-containing regimen is also taking a selective serotonin reuptake inhibitor (SSRI) for depression. After a dinner of aged cheeses and red wine, he presents with severe headache, hypertension, agitation, diaphoresis, and tremor. What is the most likely explanation?
A) An acute disulfiram-like reaction to the red wine alone, unrelated to his other medications
B) Procarbazine's weak monoamine oxidase inhibition precipitated a hypertensive and serotonergic crisis from tyramine-rich food combined with the SSRI
C) Tumor lysis syndrome from the chemotherapy, producing the autonomic findings
D) Acrolein-mediated systemic toxicity from procarbazine, requiring mesna
E) Ifosfamide-type encephalopathy, requiring methylene blue
ANSWER: B
Rationale:
Option B is correct. Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Tyramine-rich foods such as aged cheeses and red wine can precipitate a hypertensive crisis, and concurrent serotonergic agents such as an SSRI add the risk of serotonin syndrome. This patient's headache, hypertension, agitation, diaphoresis, and tremor reflect that combined MAOI-related crisis, managed by stopping the offending exposures and providing supportive blood pressure and serotonergic control.
Option A: Option A is incorrect because, although procarbazine can cause a disulfiram-like reaction with alcohol, the hypertensive-serotonergic picture here reflects MAO inhibition with tyramine and the SSRI, not alcohol alone.
Option C: Option C is incorrect because tumor lysis syndrome causes metabolic derangements and renal injury, not this tyramine-and-SSRI autonomic crisis.
Option D: Option D is incorrect because procarbazine is not associated with acrolein-mediated toxicity, and mesna is not the treatment.
Option E: Option E is incorrect because the presentation is an MAOI-related crisis, not ifosfamide encephalopathy, so methylene blue is not indicated.
10. A 66-year-old man with non-small cell lung cancer has progressed on cisplatin-based therapy. Tumor profiling reports high ERCC1 (excision repair cross-complementation group 1) expression. How should this finding be interpreted in planning further therapy?
A) High ERCC1 predicts enhanced cisplatin sensitivity; rechallenge with a higher cisplatin dose is favored
B) ERCC1 is a uptake transporter; its high level means the tumor is accumulating excessive platinum and dosing should be reduced
C) High ERCC1 reflects efficient nucleotide excision repair of platinum adducts and predicts platinum resistance; a non-platinum-based approach should be considered
D) ERCC1 expression predicts response to temozolomide; switch to an oral alkylator on that basis
E) ERCC1 is irrelevant to platinum outcomes and should not influence the treatment plan
ANSWER: C
Rationale:
Option C is correct. ERCC1 is a key incision endonuclease of nucleotide excision repair, the pathway that removes platinum-DNA adducts. High ERCC1 expression indicates efficient adduct repair and correlates with platinum resistance, so progression on cisplatin in this setting supports moving toward a non-platinum-based strategy rather than simple platinum rechallenge.
Option A: Option A is incorrect because high ERCC1 predicts resistance, not enhanced sensitivity; a higher cisplatin dose is not the answer.
Option B: Option B is incorrect because ERCC1 is a repair endonuclease, not an uptake transporter; the issue is adduct repair, not platinum accumulation.
Option D: Option D is incorrect because ERCC1 governs platinum-adduct repair, not temozolomide response; MGMT methylation, not ERCC1, predicts temozolomide benefit.
Option E: Option E is incorrect because ERCC1 is a recognized predictive marker that correlates inversely with platinum sensitivity and is relevant to planning.
11. A 52-year-old man treated with multiple cycles of carmustine for anaplastic glioma, now with a cumulative dose exceeding 1,200 mg/m^2, develops progressive exertional dyspnea and a nonproductive cough. Pulmonary function testing shows a restrictive pattern with reduced diffusing capacity, and imaging shows bibasilar fibrosis without infection. What is the correct interpretation and action?
A) This is an infectious pneumonitis; treat with antibiotics and continue carmustine on schedule
B) This is reversible bronchospasm; add an inhaled bronchodilator and proceed with the next carmustine dose
C) This is cardiogenic pulmonary edema from cumulative cardiomyopathy; begin diuresis and resume carmustine
D) This is an allergic reaction to carmustine; premedicate and rechallenge at a reduced dose
E) This is cumulative carmustine pulmonary fibrosis; discontinue carmustine, as established fibrosis is an absolute contraindication to further treatment
ANSWER: E
Rationale:
Option E is correct. Carmustine causes cumulative, dose-related pulmonary fibrosis, characteristically after high total doses (above roughly 1,200 mg/m^2). The restrictive physiology with reduced diffusing capacity and bibasilar fibrosis in this context identifies carmustine pulmonary fibrosis, which once established is an absolute contraindication to further carmustine; the drug must be discontinued.
Option A: Option A is incorrect because imaging shows fibrosis without infection, so antibiotics are not indicated, and continuing carmustine would worsen the injury.
Option B: Option B is incorrect because the restrictive, low-diffusing-capacity pattern with fibrosis is not reversible bronchospasm, and proceeding with carmustine is contraindicated.
Option C: Option C is incorrect because the picture is pulmonary fibrosis, not cardiogenic edema from cardiomyopathy, and resuming carmustine is unsafe.
Option D: Option D is incorrect because cumulative fibrosis is a dose-related toxicity, not an allergic reaction, and rechallenge is contraindicated once fibrosis is established.
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