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Docetaxel: Mechanism, Side Effects, Contraindications and Dosage

Mechanism of Action of Docetaxel

Docetaxel inhibits intracellular microtubule depolymerization. Its stabilization of the tubular structures by docetaxel leads to a cell cycle stop in the G₂M phase and to apoptosis.

Urological Indications for Docetaxel

• Metastatic prostate carcinoma with high tumor load (Gillessen et al., 2015): six cycles of docetaxel are given after the onset of hormonal therapy.
• Castration-resistant prostate cancer with a rapid PSA-doubling time (under 3–6 months) or tumor-related pain.

Pharmacokinetics of Docetaxel

Intravenous administration of docetaxel, cytochrome P450-mediated metabolism, Half-life time 11 h, mainly fecal excretion of docetaxel metabolites.

Side Effects of Docetaxel

Cooling hands and feet before and during infusion reduces the side effects on the skin and nervous system. 

Skin:

(Maculopapulous) exanthema of the feet, hands, and forearms in 50–70%. Nail toxicity is 35%.

Nervous system:

The occurrence of peripheral sensory neuropathy is frequent and usually reversible. A severe peripheral neuropathy requires a dose reduction and, if there is no improvement, a termination of docetaxel chemotherapy.

Hematological side effects:

32% have neutropenia grade 3–4. The nadir is observed after 7 days and lasts 7 days. Neutropenic fever is rare.

Gastrointestinal tract:

The side effects of docetaxel are nausea, vomiting, diarrhea, and mucositis.

Further side effects:

Interstitial pneumonia, liver toxicity, lacrimal stenosis. In the case of extravasation, severe delayed necrosis has been reported.

Contraindications for Docetaxel:

Patients in poor general condition, previous radionuclide therapy, signs of hepatic failure (bilirubin or liver enzyme elevation over 3.5 times the upper normal limit), creatinine over 2 mg/dl, allergic reaction following docetaxel infusion.

Dosage of docetaxel:

Several different regiments of docetaxel are possible. Docetaxel 3-weekly (75 mg/m²) is standard and shows advantages over the weekly dosage (25 mg/m²) in terms of survival (18.9 vs. 17.4 months), pain reduction, and tumor responses (12.1 vs. 8.2%) (Tannock et al., 2004). The weekly regime offers a higher safety profile. The 2-weekly regimen (50 mg/m²) is better tolerated with the same efficacy as the 3-weekly regimen (Kellokumpu et al., 2013).

Docetaxel dose reduction is necessary in cases of severe peripheral neuropathy, neutropenia below 1000/μl, thrombopenia below 100000/μl, or neutropenic fever (see below). If side effects persist, the treatment should be discontinued. Pause docetaxel if neutropenia (below 500/μl) or thrombopenia (below 50000/μl) is present.

Premedication before docetaxel infusion

Premedication with dexamethasone 8 mg orally, 12 hours, 3 hours, and 1 hour before the docetaxel infusion. Odansetron 8 mg p.o. 2 hours before infusion of docetaxel. 5 mg Prednisolone 1-0-1 p.o. for the remaining days of the course. Cooling hands and feet before and during infusion reduces the side effects on the skin and nervous system. 

Docetaxel every three weeks:

75 mg/m^{2 docetaxel in 60 min i. v. on day one of the cycle (duration 21 days).}

Docetaxel weekly:

30 mg/m² docetaxel in 60   min i. v. on days 1, 8, 15, 22 and 29 of the cycle (duration 42 days).

References

  Deutsche Version: Docetaxel