A 67-year-old man comes to the physician because of numbness and burning sensation of his legs for the past week. He also complains that his stools have been larger and rougher than usual. He has non-Hodgkin lymphoma and is currently receiving chemotherapy with prednisone, vincristine, rituximab, cyclophosphamide, and doxorubicin. He has received 4 cycles of chemotherapy, and his last chemotherapy cycle was 2 weeks ago. His temperature is 37.1°C (98.8°F), pulse is 89/min, and blood pressure is 122/80 mm Hg. Examination shows decreased muscle strength in the distal muscles of the lower extremities. Ankle jerk is 1+ bilaterally and knee reflex is 2+ bilaterally. Sensation to pain, vibration, and position is decreased over the lower extremities. Serum concentrations of glucose, creatinine, electrolytes, and calcium are within the reference range. Which of the following is the most likely cause of this patient's symptoms?

Charcot–Marie–Tooth disease

A 64-year-old woman comes to the physician for her routine health maintenance examination. She feels well. She had cervical cancer and received radiotherapy 8 years ago. Her vital signs are within normal limits. On percussion, the spleen size is 15 cm. Otherwise, the physical examination shows no abnormalities. The laboratory test results are as follows: Hemoglobin 10 g/dL Mean corpuscular volume 88 μm3 Leukocyte count 65,000/mm3 Platelet count 500,000/mm3 Two images of the peripheral blood smear are shown on the image. Which of the following is the most appropriate next step in management?

Allogeneic stem cell transplantation

A 71-year-old woman presents to her hematologist-oncologist for follow up after having begun doxorubicin and cyclophosphamide in addition to radiation therapy for the treatment of her stage 3 breast cancer. Her past medical history is significant for preeclampsia, hypertension, polycystic ovarian syndrome, and hypercholesterolemia. She currently smokes 1 pack of cigarettes per day, drinks a glass of wine per day, and denies any illicit drug use. The vital signs include: temperature 36.7°C (98.0°F), blood pressure 126/74 mm Hg, heart rate 111/min, and respiratory rate 23/min. On physical examination, the pulses are strong and irregular, she has a grade 3/6 holosystolic murmur heard best at the left upper sternal border, clear bilateral breath sounds, and erythema over her site of radiation. Which of the following statements regarding doxorubicin is true?

Doxorubicin has a maximum lifetime dose, due to the risk of cardiac toxicity

Doxorubicin has a maximum lifetime dose, due to the risk of pulmonary toxicity

Doxorubicin will increase her risk for deep vein thrombosis (DVT) and pulmonary embolism (PE)

Doxorubicin frequently causes an acneiform rash

Doxorubicin frequently causes cystitis

A 67-year-old woman who was diagnosed with cancer 2 months ago presents to her oncologist with a 6-day history of numbness and tingling in her hands and feet. She is concerned that these symptoms may be related to progression of her cancer even though she has been faithfully following her chemotherapy regimen. She is not currently taking any other medications and has never previously experienced these symptoms. On physical exam, she is found to have decreased sensation to pinprick and fine touch over hands, wrists, ankles, and feet. Furthermore, she is found to have decreased reflexes throughout. Her oncologist assures her that these symptoms are a side effect from her chemotherapy regimen rather than progression of the cancer. The drug most likely responsible for her symptoms has which of the following mechanisms?

Prevention of nucleotide synthesis

Management of chemotherapy toxicities for USMLE Step 3: High-Yield Pharmacology Lessons

Myelosuppression - Bone Marrow Blues

Chemotherapy targets rapidly dividing cells, including hematopoietic stem cells, leading to ↓neutrophils, ↓RBCs, and ↓platelets.

Neutropenia:
- Febrile Neutropenia: A medical emergency defined by an Absolute Neutrophil Count (ANC) < 500/mm³ and a single oral temperature of ≥38.3°C (101°F).
- Management: Prophylaxis/treatment with Colony-Stimulating Factors (CSFs).
  - G-CSF: filgrastim, pegfilgrastim.
  - GM-CSF: sargramostim.
Anemia:
- Management: Erythropoiesis-stimulating agents (ESAs) like epoetin alfa, darbepoetin alfa.
Thrombocytopenia:
- Management: Thrombopoietin (TPO) receptor agonists (romiplostim, eltrombopag) or IL-11 (oprelvekin).

⭐ High-Yield: ESAs are used for palliative (not curative) intent chemo and can ↑ risk of thromboembolic events and potentially shorten survival in some cancer patients (Black Box Warning).

📌 Mnemonic: "Stimulate" bone marrow growth:

Filgrastim (G-CSF) -> Granulocytes
Sargramostim (GM-CSF) -> Granulocytes & Macrophages

GI Toxicity - Guts & Groans

Chemotherapy-Induced Nausea & Vomiting (CINV) is managed based on the emetogenic potential of the chemotherapy regimen.

Key Agents:
- 5-HT3 Antagonists: Ondansetron, granisetron (-setron).
- NK-1 Antagonists: Aprepitant, fosaprepitant (-pitant).
- Breakthrough: Prochlorperazine, metoclopramide.

CINV pathways: central, peripheral, and other mechanisms

Mucositis: Painful oral ulcers.
- Management: Oral hygiene, cryotherapy, palifermin (keratinocyte growth factor).
Diarrhea:
- Management: Loperamide; use octreotide for severe/refractory cases (e.g., irinotecan-induced).

⭐ Akathisia and other extrapyramidal symptoms can be a distressing side effect of dopamine antagonists like metoclopramide and prochlorperazine used for breakthrough CINV.

Organ Toxicity - Hearts, Kidneys & Lungs

Cardiotoxicity
- Doxorubicin, Daunorubicin: Dilated cardiomyopathy (cumulative dose-dependent). Lifetime dose <450-550 mg/m².
  - Prevention: Dexrazoxane (iron chelator).
  - Monitoring: MUGA scan for ejection fraction.
- Trastuzumab: Myocardial dysfunction, often reversible.
Nephrotoxicity & Hemorrhagic Cystitis
- Cisplatin: Acute tubular necrosis.
  - Prevention: Amifostine, aggressive hydration.
- Cyclophosphamide, Ifosfamide: Hemorrhagic cystitis via Acrolein metabolite.
  - Prevention: Mesna (binds acrolein). 📌 Mesna for Acrolein in Cyclophosphamide (MAC).
- Methotrexate: Tubular obstruction/necrosis.
  - Rescue: Leucovorin.
Pulmonary Fibrosis
- Bleomycin, Busulfan: Dose-related lung fibrosis.

Bleomycin-induced pulmonary fibrosis and Vitamin D effect

⭐ Cisplatin-induced nephrotoxicity classically causes acute tubular necrosis (ATN), leading to significant electrolyte wasting, especially hypomagnesemia and hypokalemia.

Neuro & Other Syndromes - Nerves on Edge

Neurotoxicity:
- Vincristine, Paclitaxel, Cisplatin → Peripheral neuropathy ('stocking-glove' distribution).
- Cisplatin also causes significant ototoxicity (hearing loss, tinnitus).
Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia):
- Painful erythema and swelling of palms/soles.
- Seen with Capecitabine, 5-FU.
Tumor Lysis Syndrome (TLS):
- Massive tumor cell lysis releases intracellular contents.

-   **Management:** Allopurinol (prophylaxis), Rasburicase (treatment).
> ⭐ Rasburicase is contraindicated in G6PD deficiency due to risk of severe hemolytic anemia.

High-Yield Points - ⚡ Biggest Takeaways

Myelosuppression is managed with filgrastim (G-CSF) and sargramostim (GM-CSF); oprelvekin (IL-11) for thrombocytopenia.

For chemotherapy-induced nausea, use 5-HT3 antagonists (ondansetron) and NK1 receptor antagonists (aprepitant).

Prevent hemorrhagic cystitis from cyclophosphamide/ifosfamide with Mesna.

Mitigate doxorubicin-induced cardiotoxicity with dexrazoxane.

Reduce cisplatin's nephrotoxicity with amifostine and vigorous hydration.

For tumor lysis syndrome, use allopurinol or rasburicase to manage hyperuricemia.

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