Introduction
Yew refers to medicinal compounds derived from various Taxus species (particularly Taxus brevifolia, the Pacific yew), which are the source of the chemotherapeutic agent paclitaxel. While not a drug itself, yew-derived compounds represent one of the most significant botanical contributions to modern oncology. This monograph focuses on the pharmaceutical applications of yew-derived taxanes, primarily paclitaxel, which revolutionized cancer treatment upon its FDA approval in 1992.
Mechanism of Action
Paclitaxel exerts its antineoplastic effects through a unique mechanism involving microtubule stabilization. Unlike vinca alkaloids that inhibit microtubule assembly, paclitaxel promotes microtubule assembly and stabilizes microtubules by binding to the β-tubulin subunit. This stabilization prevents microtubule depolymerization, effectively freezing the mitotic spindle during cell division. The resulting arrest in the G2/M phase of the cell cycle ultimately leads to apoptosis (programmed cell death) in rapidly dividing cancer cells.
Indications
FDA-Approved Indications:- Ovarian cancer (first-line and subsequent therapy)
- Breast cancer (node-positive and metastatic)
- Non-small cell lung cancer
- AIDS-related Kaposi's sarcoma
- Pancreatic cancer (in combination with gemcitabine)
- Bladder cancer
- Esophageal cancer
- Cervical cancer
- Head and neck cancers
- Endometrial cancer
Dosage and Administration
Standard Dosing:- Ovarian cancer: 135-175 mg/m² IV over 3 hours every 3 weeks
- Breast cancer: 175 mg/m² IV over 3 hours every 3 weeks
- NSCLC: 135 mg/m² IV over 24 hours every 3 weeks (with cisplatin)
- Kaposi's sarcoma: 135 mg/m² IV over 3 hours every 3 weeks or 100 mg/m² IV over 3 hours every 2 weeks
- Hepatic impairment: Reduce dose for bilirubin >1.5 mg/dL
- Renal impairment: No adjustment needed for CrCl >30 mL/min
- Elderly: Monitor closely for increased toxicity
- Premedication: Required with corticosteroids, H1/H2 antagonists to prevent hypersensitivity reactions
Pharmacokinetics
Absorption: Administered exclusively intravenously due to poor oral bioavailability Distribution: Extensive tissue binding (>89-98% protein bound), high volume of distribution (50-650 L) Metabolism: Primarily hepatic via CYP2C8 and CYP3A4 to inactive metabolites Elimination: Primarily fecal excretion (≥70%), with minimal renal clearance (<10%) Half-life: Biphasic elimination with terminal half-life of 5.8-65 hoursContraindications
- History of severe hypersensitivity reactions to paclitaxel or Cremophor EL (polyoxyethylated castor oil)
- Baseline neutrophil count <1,500 cells/mm³
- Pregnancy (Category D)
- Concurrent use with live vaccines during treatment
Warnings and Precautions
Boxed Warning:- Severe hypersensitivity reactions (occur in 2-4% of patients)
- Severe myelosuppression (neutropenia is dose-limiting toxicity)
- Requires administration by experienced personnel in equipped facilities
- Cardiac conduction abnormalities (bradycardia, heart block)
- Peripheral neuropathy (dose-dependent and cumulative)
- Alopecia (nearly universal)
- Hepatic impairment increases toxicity risk
- Extravasation may cause tissue necrosis
Drug Interactions
Major Interactions:- CYP3A4 inhibitors (ketoconazole, ritonavir): ↑ paclitaxel levels
- CYP3A4 inducers (rifampin, carbamazepine): ↓ paclitaxel levels
- CYP2C8 inhibitors (gemfibrozil): ↑ paclitaxel levels
- Other myelosuppressive agents: Additive bone marrow toxicity
- Cisplatin: ↑ myelosuppression and neurotoxicity (administer paclitaxel first)
Adverse Effects
Very Common (>10%):- Neutropenia (90%)
- Peripheral neuropathy (60%)
- Alopecia (90%)
- Myalgia/arthralgia (60%)
- Nausea/vomiting (50%)
- Diarrhea (40%)
- Severe hypersensitivity reactions (2-4%)
- Sepsis (2%)
- Febrile neutropenia (2%)
- Bradycardia (<1%)
- Stevens-Johnson syndrome (rare)
Monitoring Parameters
Prior to Each Dose:- Complete blood count with differential
- Liver function tests
- Renal function
- Vital signs (especially heart rate)
- Continuous cardiac monitoring for first hour
- Frequent assessment for hypersensitivity reactions
- Neurological examination for peripheral neuropathy
- Symptom assessment for mucositis, arthralgias, myalgias
- Growth factor support assessment
- Cardiac function in patients with pre-existing conditions
- Cumulative neurotoxicity assessment
Patient Education
- Premedication regimen is crucial to prevent allergic reactions
- Report immediately: breathing difficulties, chest tightness, rash, or itching during infusion
- Expect hair loss; consider scalp cooling or wig preparation
- Neuropathy symptoms: report numbness, tingling, or pain in hands/feet
- Fever >100.4°F or chills may indicate infection (neutropenia)
- Use reliable contraception during and after treatment
- Avoid grapefruit juice and St. John's wort during therapy
- Arrange for transportation after treatment due to fatigue
- Maintain hydration and nutritional status
- Report unusual bruising or bleeding
References
1. National Cancer Institute. Paclitaxel (Taxol) - Health Professional Version. Accessed 2023. 2. FDA Prescribing Information: Paclitaxel Injection. Revised 2022. 3. Rowinsky EK, et al. J Natl Cancer Inst. 1990;82(15):1247-59. 4. Wani MC, et al. J Am Chem Soc. 1971;93(9):2325-7. 5. Weiss RB, et al. J Clin Oncol. 1990;8(7):1263-8. 6. Gelderblom H, et al. Eur J Cancer. 2001;37(13):1590-8. 7. Arbuck SG, et al. Semin Oncol. 1993;20(4 Suppl 3):31-5. 8. Crown J, et al. Ann Oncol. 2004;15(3):440-9. 9. Postma TJ, et al. Ann Oncol. 1995;6(5):489-94. 10. Markman M, et al. Gynecol Oncol. 2003;90(3 Pt 2):S3-S10.
Note: This monograph focuses on the pharmaceutical applications of yew-derived compounds. Raw yew plant materials are highly toxic and should never be consumed without pharmaceutical processing and medical supervision.