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Docetaxel: Mechanism, Adverse Effects, Contraindications and Dosage

Mechanism of Action of Docetaxel

Docetaxel stabilizes microtubules by inhibiting microtubule depolymerization. This stabilization leads to a cell-cycle arrest at the G2/M phase and subsequently induces apoptosis.

Urologic Indications for Docetaxel:

• De novo metastatic hormone-sensitive prostate cancer with high tumor burden: Administer six cycles of docetaxel at the initiation of androgen deprivation therapy (ADT). Current standard practice includes intensifying ADT with darolutamide (triplet therapy: ADT + docetaxel + androgen receptor inhibitor).
• Metastatic castration-resistant prostate cancer (mCRPC), particularly in symptomatic disease (tumor-related pain) or with rapid progression (PSA doubling time < 3 months).

Pharmacokinetics of Docetaxel

Intravenous administration of docetaxel, hepatic metabolism via CYP3A4/5, half-life time 11 hours, biliary–fecal elimination of metabolites.

Adverse Effects of Docetaxel

Cooling the hands and feet before and during the infusion may reduce cutaneous and peripheral nerve toxicities.

Skin:

(Maculopapulous) exanthema of the feet, hands, and forearms in 10–20%. Nail changes (onychodystrophy and onycholysis) occur in 35%, mostly mild.

Nervous system:

Peripheral sensory neuropathy occurs frequently and is usually reversible. In cases of higher-grade neuropathy, reduce the dose or discontinue docetaxel if symptoms persist.

Hematological side effects:

Grade 3/4 neutropenia occurs in approximately 32%, with a nadir at 7–10 days that lasts about one week. Febrile neutropenia can occur.

Gastrointestinal tract:

Common adverse effects of docetaxel include nausea, vomiting, diarrhea, and mucositis.

Other Adverse Effects of Docetaxel:

Interstitial pneumonitis, hepatotoxicity, and lacrimal duct stenosis have been reported. In the event of extravasation, severe delayed tissue necrosis may occur.

Contraindications for Docetaxel:

Patients in poor general condition, use caution after prior radionuclide therapy. Evidence of hepatic impairment (elevated bilirubin, or AST/ALT > 1.5 × ULN with alkaline phosphatase > 2.5 × ULN). Severe hypersensitivity to docetaxel. Neutropenia (<1,500/µL). Pregnancy and lactation.

Dosing of Docetaxel:

The every-3-week regimen with 75 mg/m² docetaxel is the standard dose. In mCRPC, it improves overall survival compared with mitoxantrone (Tannock et al., 2004), whereas weekly regimens generally offer a more favorable hematologic safety profile at the expense of efficacy. A biweekly regimen of 50 mg/m² was better tolerated with similar efficacy to the every-3-week regimen in one study (Kellokumpu et al., 2013).

Premedication Before Docetaxel Infusion

Premedicate with dexamethasone 8 mg orally, 12 hours, 3 hours, and 1 hour before the docetaxel infusion. Administer odansetron 8 mg p.o. 2 hours before infusion of docetaxel as antiemetic. Cooling the hands and feet before and during the infusion. Give 5 mg Prednisolone twice daily continuously.

Docetaxel Every Three Weeks:

Administer 75 mg/m² docetaxel intravenously over 60 minutes on day 1 of each 21-day cycle.

Prerequisites for the Next Cycle:

Absolute neutrophil count >1,500/µL; platelets >100,000/µL; liver tests as outlined under contraindications; no fever or significant unresolved adverse effects.

References

Kellokumpu-Lehtinen, P.-L.; Harmenberg, U.; Joensuu, T.; McDermott, R.; Hervonen, P.; Ginman, C.; Luukkaa, M.; Nyandoto, P.; Hemminki, A.; Nilsson, S.; McCaffrey, J.; Asola, R.; Turpeenniemi-Hujanen, T.; Laestadius, F.; Tasmuth, T.; Sandberg, K.; Keane, M.; Lehtinen, I.; Luukkaala, T.; Joensuu, H. & , P. R. O. S. T. Y. s. g. 2-Weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial.
Lancet Oncol 2013, 14, 117-124

Tannock u.a. 2004 TANNOCK, I. F. ; WIT, R. de ; BERRY, W. R. ; HORTI, J. ; PLUZANSKA, A. ; CHI, K. N. ; OUDARD, S. ; THEODORE, C. ; JAMES, N. D. ; TURESSON, I. ; ROSENTHAL, M. A. ; EISENBERGER, M. A.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
In: N Engl J Med
351 (2004), Nr. 15, S. 1502–12

C. J. Sweeney et al., “Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer.,” N Engl J Med, vol. 373, no. 8, pp. 737–746, 2015.

  Deutsche Version: Docetaxel

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