Medical Pharmacology: Chapter 33 — Anti-Cancer Drugs Part I: Principles of Cancer Pharmacology -- Module 1 — Principles of Cancer Pharmacology: Clinical Vignette

Chapter 33 — Anti-Cancer Drugs Part I: Principles of Cancer Pharmacology — Module 1 — Principles of Cancer Pharmacology: Clinical Vignette

1. A 54-year-old man with newly diagnosed acute myeloid leukemia is admitted for induction chemotherapy. The protocol calls for cytarabine, an S-phase-specific antimetabolite, given as a continuous intravenous infusion over seven days rather than as a single daily bolus. A trainee asks why the same total dose is not simply given as one rapid daily injection. Which response best reflects the pharmacologic reasoning?

A) A single daily bolus is preferred in practice, and the continuous infusion is used only to reduce nursing workload on the unit
B) The continuous infusion is chosen to raise the peak plasma concentration far above what a bolus achieves, since peak concentration determines cytarabine cell kill
C) Because cytarabine kills only cells transiting S phase, a single bolus would expose only the small fraction in S phase at that instant; the continuous infusion maintains cytotoxic levels so that successive cohorts of leukemic cells are killed as they enter S phase across the full infusion period
D) The continuous infusion converts cytarabine into a cycle-nonspecific agent capable of killing quiescent G0 leukemic cells that a bolus cannot reach
E) The infusion is used because cytarabine has no relationship between exposure duration and cell kill, so the schedule is arbitrary

ANSWER: C

Rationale:

Cytarabine is S-phase specific, so at any single moment it can kill only the fraction of leukemic cells actively synthesizing DNA. A rapid bolus is present only briefly and therefore kills only the cells in S phase at that instant, missing the many cells that enter S phase minutes to hours later. A seven-day continuous infusion maintains cytotoxic concentrations throughout, so that each successive cohort of dividing marrow cells is exposed as it enters S phase, which is why continuous-infusion cytarabine produces deeper remissions than equivalent bolus dosing. For this patient, the schedule is the mechanism of benefit: extending exposure, not raising a single peak, is what increases leukemic cell kill for a phase-specific agent.

Option A: Option A is incorrect because the continuous infusion is mechanistically driven, not a matter of nursing convenience.
Option B: Option B is incorrect because for an S-phase agent it is exposure duration, not peak concentration, that governs cell kill; a higher bolus peak does not help once the cells then in S phase are killed.
Option D: Option D is incorrect because schedule cannot change a drug's intrinsic mechanism; cytarabine remains S-phase specific and does not acquire the ability to kill G0 cells.
Option E: Option E is incorrect because cytarabine cell kill is strongly dependent on exposure duration relative to the cell cycle, which is precisely why the infusion schedule is used.

2. A 38-year-old woman with osteosarcoma is scheduled for high-dose methotrexate. On review she has a large right pleural effusion and has been taking ibuprofen daily for bone pain. Which action is most appropriate before administering the methotrexate?

A) Proceed with the methotrexate at the planned dose without changes, since neither the effusion nor the ibuprofen affects methotrexate handling
B) Drain the pleural effusion and withhold the ibuprofen before administration, because the effusion sequesters methotrexate and slowly releases it back into the circulation while the NSAID reduces renal tubular secretion, and together they can prolong exposure and cause severe toxicity
C) Increase the methotrexate dose to overcome anticipated sequestration of the drug in the effusion
D) Continue the ibuprofen but give an extra dose of methotrexate to compensate for reduced absorption caused by the effusion
E) Replace the ibuprofen with a proton pump inhibitor, which has no interaction with methotrexate, and proceed without draining the effusion

ANSWER: B

Rationale:

Two mechanisms threaten this patient and both must be addressed before high-dose methotrexate. Methotrexate is hydrophilic and distributes into third-space collections such as a pleural effusion; after the plasma level falls, the sequestered drug is slowly released back into the circulation, prolonging exposure far beyond the expected duration. Independently, NSAIDs such as ibuprofen reduce renal tubular secretion of methotrexate, slowing its clearance. Because methotrexate toxicity is exposure-dependent, these effects compound and can precipitate severe mucositis and myelosuppression. The correct preparation is therefore to drain the effusion, removing the reservoir, and to withhold the NSAID, restoring tubular secretion, before the drug is given. This is the standard pre-treatment safeguard for high-dose methotrexate in a patient with an effusion and concurrent NSAID use.

Option A: Option A is incorrect because both the effusion and the NSAID materially affect methotrexate handling and ignoring them risks life-threatening toxicity.
Option C: Option C is incorrect and dangerous because the problem is prolonged exposure, not underdosing; raising the dose worsens toxicity.
Option D: Option D is incorrect because the effusion does not reduce absorption of intravenous methotrexate, and adding drug compounds the exposure problem.
Option E: Option E is incorrect because proton pump inhibitors also reduce methotrexate tubular secretion and are not a safe substitute, and the effusion still must be drained.

3. A 61-year-old woman receiving doxorubicin through a peripheral forearm IV reports sudden burning at the site. The nurse notes swelling and reduced infusion flow, and extravasation is suspected. Which immediate management is correct?

A) Apply a cold pack to the site and inject hyaluronidase, then resume the infusion at a slower rate to dilute the drug already in the tissue
B) Take no action beyond observation, because doxorubicin is an irritant that produces only transient phlebitis without tissue injury
C) Inject sodium thiosulfate into the site as the specific neutralizing antidote for anthracycline extravasation
D) Apply warm compresses and continue the infusion, since warming disperses the anthracycline and prevents necrosis
E) Stop the infusion immediately, aspirate residual drug, and administer dexrazoxane intravenously within six hours while avoiding cooling, because anthracycline extravasation is a time-critical emergency and dexrazoxane is the only FDA-approved antidote

ANSWER: E

Rationale:

Anthracycline extravasation is a genuine oncologic emergency because doxorubicin binds tissue DNA and is released slowly from necrotic tissue, producing injury that continues to advance for weeks. The correct response is to stop the infusion immediately, aspirate residual drug through the existing catheter, and administer dexrazoxane intravenously within six hours — the only FDA-approved antidote for anthracycline extravasation. The six-hour window is not flexible, and cooling is avoided in this setting because it reduces local blood flow and therefore dexrazoxane delivery to the affected tissue. Prompt recognition and early dexrazoxane administration are what limit the progression to deep necrosis in this patient.

Option A: Option A is incorrect on multiple counts: cooling plus hyaluronidase is not the anthracycline protocol (hyaluronidase with warming is used for vinca alkaloids), and the infusion must be stopped, never resumed.
Option B: Option B is incorrect and dangerous because doxorubicin is a vesicant, not an irritant, and untreated extravasation causes progressive necrosis.
Option C: Option C describes the antidote for mechlorethamine extravasation, not anthracyclines.
Option D: Option D is incorrect because the infusion must be stopped immediately rather than continued, and continuing delivers more vesicant into the tissue.

4. A 19-year-old man of Mediterranean ancestry presents with Burkitt lymphoma, a white blood cell count of 200,000 cells per microliter, and a baseline uric acid of 11 mg/dL. Chemotherapy must begin urgently, and he is at very high risk for tumor lysis syndrome. Rasburicase is considered, but his glucose-6-phosphate dehydrogenase (G6PD) status is not yet known and results will take time. Which prophylactic approach is safest while testing is pending?

A) Begin aggressive intravenous hydration and allopurinol now as the safer default while awaiting G6PD results, because rasburicase is absolutely contraindicated in G6PD deficiency and his ancestry places him at elevated risk for that deficiency
B) Administer rasburicase immediately without waiting for G6PD results, since the tumor lysis risk outweighs any concern about G6PD status
C) Withhold all tumor lysis prophylaxis until the G6PD result returns, then decide on an agent
D) Give a double dose of rasburicase to ensure rapid uric acid clearance given the very high baseline level
E) Start allopurinol alone without intravenous hydration, since hydration is unnecessary when allopurinol is used

ANSWER: A

Rationale:

This patient has the classic profile for the highest tumor lysis risk — large, rapidly proliferating, highly chemosensitive tumor with a high white cell count and an already-elevated uric acid — so effective prophylaxis must begin without delay. The complicating factor is that rasburicase is absolutely contraindicated in G6PD deficiency, because the hydrogen peroxide generated by the rasburicase reaction causes severe hemolysis in G6PD-deficient erythrocytes, and his Mediterranean ancestry places him at elevated risk for that deficiency. Because the G6PD result is not yet available and treatment cannot wait, the safe default is aggressive intravenous hydration plus allopurinol now: hydration maximizes uric acid excretion and dilutes crystallizing anions, and allopurinol blocks new uric acid formation. Rasburicase can be reconsidered once G6PD status is confirmed safe.

Option B: Option B is incorrect and dangerous because giving rasburicase before excluding G6PD deficiency in a high-risk patient could precipitate life-threatening hemolysis.
Option C: Option C is incorrect because withholding all prophylaxis in a patient at very high tumor lysis risk is unsafe; hydration and allopurinol should start immediately.
Option D: Option D is incorrect because not only does it ignore the G6PD contraindication, but escalating the rasburicase dose would amplify the hemolytic danger if he is deficient.
Option E: Option E is incorrect because aggressive hydration is a cornerstone of tumor lysis prophylaxis and should not be omitted when allopurinol is used.

5. A 70-year-old woman with ovarian cancer and a reduced glomerular filtration rate (estimated GFR 45 mL/min) is to receive carboplatin. The covering physician proposes calculating the dose from body surface area, as is done for many cytotoxic drugs. Why is a Calvert AUC-based calculation preferred for this patient instead?

A) Body-surface-area dosing already incorporates renal function, so either method yields the same carboplatin dose in this patient
B) Carboplatin is cleared by the liver, so neither GFR nor body surface area is relevant, and the dose should be fixed
C) Body-surface-area dosing is preferred because carboplatin clearance is independent of kidney function
D) Because carboplatin is cleared predominantly by glomerular filtration, the Calvert formula uses the patient's GFR to set a dose targeting a specific AUC; in a patient with reduced GFR this prevents the overdose that body-surface-area dosing would produce by ignoring her impaired renal clearance
E) The Calvert formula is invalid in renal impairment, so a body-surface-area dose with empiric reduction is the only option

ANSWER: D

Rationale:

Carboplatin is eliminated almost entirely by glomerular filtration, so its clearance falls as GFR falls. The Calvert formula sets the dose to achieve a target AUC as a function of GFR, which is exactly what this patient with an estimated GFR of 45 mL/min requires: her reduced renal clearance means a body-surface-area dose, which ignores kidney function, would deliver a relative overdose and risk severe myelosuppression. Targeting exposure directly through the Calvert formula calibrates the dose to her actual clearance, delivering the intended AUC safely. This is the canonical example of pharmacokinetically guided dosing, and renal impairment is precisely the circumstance in which it most clearly outperforms body-surface-area dosing.

Option A: Option A is incorrect because body surface area does not incorporate renal function, so the two methods diverge substantially in a patient with impaired GFR.
Option B: Option B is incorrect because carboplatin is renally, not hepatically, cleared, making GFR central to dosing.
Option C: Option C is incorrect because carboplatin clearance depends strongly on kidney function, which is why GFR-based dosing is required.
Option E: Option E is incorrect because the Calvert formula is specifically valid and preferred in renal impairment; reverting to body-surface-area dosing reintroduces the very error the formula corrects.

6. A 66-year-old cachectic man with advanced lung cancer and a serum albumin of 2.1 g/dL develops unexpectedly severe neuropathy and myelosuppression after a dose of paclitaxel that was calculated correctly for his body surface area. Paclitaxel is highly albumin-bound. Which mechanism best explains the severe toxicity despite the nominally appropriate dose?

A) The low albumin reduced the free fraction of paclitaxel, so the toxicity must reflect a calculation error rather than protein binding
B) Because paclitaxel is highly albumin-bound and only the unbound fraction is pharmacologically active, his markedly low albumin left fewer binding sites and raised the free fraction, so his effective active exposure was higher than the administered dose implied, producing severe toxicity
C) Protein binding is clinically irrelevant for paclitaxel, so albumin level cannot explain the toxicity
D) The low albumin accelerated hepatic clearance of paclitaxel, paradoxically increasing toxicity through a metabolite
E) The hypoalbuminemia increased the bound fraction of paclitaxel, lowering the active free concentration, which would reduce rather than increase toxicity

ANSWER: B

Rationale:

For a highly albumin-bound drug such as paclitaxel, only the unbound (free) fraction can distribute to tissues and exert pharmacologic effect, and that free fraction is normally small because most drug is bound to albumin. When albumin is markedly low, as in this cachectic patient with an albumin of 2.1 g/dL, fewer binding sites are available, so a larger proportion of the drug circulates unbound. His effective active exposure is therefore higher than the administered dose suggests, which explains severe neuropathy and myelosuppression despite a dose that was correct on a body-surface-area basis. This is the clinical signature of altered protein binding in hypoalbuminemic oncology patients and the reason such patients warrant heightened vigilance even when the calculated dose appears appropriate.

Option A: Option A reverses the effect: low albumin increases, not decreases, the free fraction of a highly bound drug.
Option C: Option C is incorrect because protein binding is clinically significant for highly bound agents with narrow therapeutic windows, where small shifts in free fraction matter.
Option D: Option D is incorrect because the mechanism is the increased free fraction from reduced binding, not accelerated hepatic clearance generating a toxic metabolite.
Option E: Option E is incorrect because reduced albumin means fewer binding sites and thus a higher free fraction and active concentration, which increases rather than decreases toxicity.

7. A 58-year-old woman presents 10 days after chemotherapy with a temperature of 38.9 degrees Celsius, a blood pressure of 92/54 mmHg, and an absolute neutrophil count of 200 cells per microliter. Which management is most appropriate?

A) Discharge her on oral fluoroquinolone plus amoxicillin-clavulanate with outpatient follow-up, since this regimen adequately covers her risk category
B) Withhold antibiotics until blood culture results return to avoid unnecessary antibiotic exposure
C) Admit her and start empiric intravenous anti-pseudomonal beta-lactam therapy, most commonly piperacillin-tazobactam, within one hour of presentation, because she has high-risk febrile neutropenia with hemodynamic instability
D) Give a single intravenous dose of an antifungal agent as initial monotherapy, since fungal infection is the predominant early concern
E) Start an intravenous agent targeting gram-positive organisms only, since gram-negative coverage is unnecessary in neutropenic patients

ANSWER: C

Rationale:

This patient meets the definition of febrile neutropenia — fever with an absolute neutrophil count well below 500 cells per microliter — and her hypotension and profound neutropenia place her firmly in the high-risk category. High-risk febrile neutropenia requires hospital admission and prompt empiric intravenous therapy with an anti-pseudomonal beta-lactam, most commonly piperacillin-tazobactam, administered within one hour of presentation, because gram-negative organisms including Pseudomonas can cause rapid, fatal deterioration in the neutropenic host. Empiric therapy must begin before culture data are available; waiting risks irreversible decompensation. Carbapenems are reserved for patients with prior resistant organisms or clinical deterioration, not as routine first-line.

Option A: Option A describes the management of low-risk febrile neutropenia and is unsafe for this hemodynamically unstable, high-risk patient.
Option B: Option B is incorrect and dangerous because empiric antibacterial therapy must start within an hour, not after cultures return.
Option D: Option D is incorrect because empiric antibacterial coverage, not antifungal monotherapy, is the immediate priority; antifungal therapy is added later for persistent fever.
Option E: Option E is incorrect because empiric coverage must include anti-pseudomonal gram-negative activity; restricting to gram-positive organisms leaves the most dangerous pathogens uncovered.

8. A 64-year-old man with lymphoma and hepatic involvement is to receive doxorubicin. His total bilirubin is 2.5 mg/dL, reflecting impaired biliary excretory function. Doxorubicin is cleared predominantly by hepatic metabolism and biliary excretion. Which dose adjustment is most consistent with standard guidance?

A) Administer the full planned dose, since hepatic function does not affect doxorubicin clearance
B) Increase the dose, because impaired hepatic function reduces the active concentration that reaches the tumor
C) Withhold doxorubicin entirely and substitute a renally cleared agent, since no dose of an anthracycline is ever acceptable at this bilirubin level
D) Reduce the dose by approximately 90 percent, the standard reduction at any degree of hyperbilirubinemia
E) Reduce the doxorubicin dose by approximately 50 percent, consistent with guidance recommending roughly a 50 percent reduction when total bilirubin is 1.2 to 3.0 mg/dL

ANSWER: E

Rationale:

Doxorubicin is cleared predominantly by hepatic metabolism and biliary excretion, so impaired hepatobiliary function reduces its clearance and raises exposure, increasing toxicity. Serum bilirubin is the standard surrogate for biliary excretory function used to guide anthracycline dose reduction. For doxorubicin, guidelines commonly recommend approximately a 50 percent dose reduction when total bilirubin is 1.2 to 3.0 mg/dL, and approximately a 75 percent reduction when bilirubin exceeds 3.0 mg/dL. This patient's bilirubin of 2.5 mg/dL falls in the 1.2 to 3.0 range, so an approximately 50 percent reduction is appropriate. These thresholds are practical risk-management conventions that balance the risk of undertreatment against the danger of severe toxicity from impaired clearance.

Option A: Option A is incorrect because hepatic function strongly affects doxorubicin clearance, and giving the full dose risks severe toxicity.
Option B: Option B is incorrect because impaired hepatic clearance raises, not lowers, drug exposure, so the dose should be reduced, not increased.
Option C: Option C overstates the situation: a reduced dose is appropriate at this bilirubin level rather than complete avoidance of the anthracycline.
Option D: Option D misstates the magnitude; the approximately 75 percent (not 90 percent) reduction applies only when bilirubin exceeds 3.0 mg/dL, which is above this patient's level.

9. A 47-year-old woman with relapsed sarcoma has disease that is now simultaneously refractory to doxorubicin, vincristine, and etoposide, three drugs from different classes with distinct mechanisms. Which single resistance mechanism best explains simultaneous resistance to all three agents?

A) Overexpression of P-glycoprotein, an ATP-dependent efflux pump whose broad substrate range includes anthracyclines, vinca alkaloids, and epipodophyllotoxins, lowering intracellular concentrations of all three structurally diverse drugs at once
B) Amplification of the dihydrofolate reductase gene, which raises the enzyme level beyond what the drugs can inhibit
C) Deficiency of dihydropyrimidine dehydrogenase, which slows catabolism of these agents
D) Loss of the copper influx transporter CTR1, which reduces cellular uptake of these drugs
E) A mutation in topoisomerase I that prevents binding of all three agents

ANSWER: A

Rationale:

Simultaneous resistance to three structurally unrelated drugs from different classes is the defining signature of classic multidrug resistance, and its most extensively characterized cause is overexpression of P-glycoprotein. This ATP-dependent efflux pump has an unusually broad substrate range that includes the anthracyclines (doxorubicin), the vinca alkaloids (vincristine), and the epipodophyllotoxins (etoposide), among others. By actively pumping all of these hydrophobic compounds out of the cell, a single overexpressed transporter lowers the intracellular concentration of each below cytotoxic thresholds at the same time, producing cross-resistance across agents that share no common structure or mechanism. Recognizing this pattern explains why a salvage regimen should favor agents that are not P-glycoprotein substrates.

Option B: Option B is incorrect because dihydrofolate reductase amplification confers resistance specifically to methotrexate, not to anthracyclines, vinca alkaloids, and etoposide.
Option C: Option C is incorrect because dihydropyrimidine dehydrogenase deficiency relates to 5-fluorouracil toxicity and metabolism, not to these three drugs.
Option D: Option D is incorrect because loss of the copper influx transporter CTR1 reduces uptake of platinum agents such as cisplatin, not the drugs in this case.
Option E: Option E is incorrect because a topoisomerase I mutation would affect camptothecin-type agents; doxorubicin and etoposide act on topoisomerase II and vincristine on tubulin, so a single topoisomerase I mutation cannot explain resistance to all three.

10. A 7-year-old boy with high-risk acute lymphoblastic leukemia achieves a complete remission in the bone marrow and peripheral blood after systemic chemotherapy. His protocol nonetheless includes chemotherapy delivered by lumbar puncture into the cerebrospinal fluid. What is the rationale for adding this intrathecal therapy?

A) Intrathecal therapy is given because systemic chemotherapy is ineffective against leukemia anywhere in the body
B) Intrathecal therapy is used solely to reduce the nausea produced by systemic chemotherapy
C) The cerebrospinal fluid is the principal site of chemotherapy metabolism, so injecting there accelerates drug breakdown
D) The central nervous system is a sanctuary site protected by the blood-brain barrier, which most systemic agents cannot cross in adequate concentration; intrathecal delivery places drug directly into the cerebrospinal fluid to eradicate leukemic cells that systemic therapy cannot reach, preventing later central nervous system relapse
E) The blood-brain barrier concentrates systemic chemotherapy in the brain, so intrathecal dosing is needed to prevent a central nervous system overdose

ANSWER: D

Rationale:

The central nervous system is the most clinically important sanctuary site: the blood-brain barrier, formed by tight junctions between cerebral endothelial cells, restricts entry of most hydrophilic and high-molecular-weight chemotherapy agents, so leukemic cells can survive in the CNS even after systemic therapy has cleared the marrow and blood. Without CNS-directed treatment, these surviving cells can later seed a central nervous system relapse. Intrathecal administration injects drug directly into the cerebrospinal fluid by lumbar puncture, bypassing the barrier and delivering cytotoxic concentrations to the protected compartment. This is why CNS prophylaxis is standard in high-risk acute lymphoblastic leukemia, and the rationale is anatomical drug access, not a deficiency of systemic efficacy.

Option A: Option A is incorrect because systemic chemotherapy is in fact effective against marrow and blood disease, as the complete remission demonstrates; the problem is only the protected CNS compartment.
Option B: Option B is incorrect because intrathecal therapy targets sanctuary disease, not nausea, which is managed with antiemetics.
Option C: Option C is incorrect because the cerebrospinal fluid is not a site of drug metabolism; intrathecal dosing concerns access, not breakdown.
Option E: Option E inverts the physiology: the blood-brain barrier excludes most drugs rather than concentrating them, which is precisely why the CNS is a sanctuary requiring direct intrathecal delivery.

11. A 49-year-old woman with node-positive breast cancer is receiving adjuvant chemotherapy with curative intent. After the first cycle she develops neutropenia that threatens to delay the next cycle. The oncologist wants to maintain full dose intensity. Which approach best achieves that goal while applying sound kinetic principles?

A) Reduce the dose of all agents in every subsequent cycle, since dose reduction is the standard response to any neutropenia regardless of treatment intent
B) Use a dose-dense schedule with granulocyte colony-stimulating factor support, compressing the inter-cycle interval while maintaining the per-cycle dose, because this denies residual disease its regrowth window and preserves dose intensity, and the growth-factor support makes the shortened interval feasible by accelerating neutrophil recovery
C) Lengthen the interval between cycles to allow fuller marrow recovery, accepting that the reduced dose intensity will not affect the curative outcome
D) Discontinue chemotherapy entirely, since neutropenia after the first cycle indicates the regimen cannot be safely completed
E) Switch to a single cycle-nonspecific agent given as one large dose, eliminating the need for any further cycles or growth-factor support

ANSWER: B

Rationale:

In a node-positive breast cancer patient treated with curative intent, preserving delivered dose intensity is important to outcome, and the kinetic rationale favors dose density. Compressing the inter-cycle interval while keeping the per-cycle dose constant shortens the window during which small-volume residual disease — sitting in the high-growth-fraction region of the Gompertz curve — can regrow between cycles, consistent with the Norton-Simon hypothesis. The limiting toxicity is hematologic, and granulocyte colony-stimulating factor support accelerates neutrophil recovery so the shortened interval is deliverable without forcing delay or dose reduction. Thus dose-dense scheduling with growth-factor support both applies the correct kinetic principle and solves the practical neutropenia problem, preserving the curative potential of the regimen rather than sacrificing intensity.

Option A: Option A is incorrect because reflexive dose reduction in a curative-intent regimen can compromise outcome when growth-factor support could instead preserve intensity.
Option C: Option C is incorrect because lengthening the interval lowers dose intensity and, contrary to the option's claim, reduced intensity can worsen outcome in responsive curable disease.
Option D: Option D is incorrect because neutropenia after the first cycle is an expected, manageable toxicity that does not warrant abandoning a curative regimen.
Option E: Option E is incorrect because substituting a single large dose of one agent abandons the rationale for combination, dose-intense, multi-cycle therapy and is not a sound kinetic strategy for this curable disease.