Docetaxel

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It is a semisynthetic taxane prepared with a precursor extracted from european yew plants. Docetaxel is slightly more water soluble than paclitaxel and a more potent antimicrotubule agent in vitro, reduction in peripheral neuropathies as compared to paclitaxel.

Mechanism of Action

  • Binds to free tubulin and promotes assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly.
  • Stabilization of microtubules results in loss of normal function of microtubules with resultant inhibition of mitosis.
  • Antiangiogenic effects
  • In vitro analyses demonstrate docetaxel to be 100-fold more potent than paclitaxel in bcl-2 phosphorylation and apoptotic cell death.

Mechanism of Resistance

  • Alterations in tubulin with decreased affinity for drug.
  • Multidrug-resistant (MDR-1) phenotype with increased expression of P170 glycoprotein. Results in enhanced drug efflux with decreased intracellular accumulation of drug.
  • Cross-resistant to other  products, including vinca alkaloids, anthracyclines.

Metabolism

  • Extensive binding (>90%) to plasma and cellular proteins.
  • Extensively metabolized by the hepatic P450 microsomal system.
  • About 75% of drug is excreted via fecal elimination.
  • Renal clearance is less than 10% . Terminal half-lives ranging from 11.1 to 18.5 hours have been reported.
  • Use with caution in patients with abnormal liver function. Patients with abnormal liver function are at significantly higher risk for toxicity, including treatment-related mortality.

Doses or Concentrations Available

  • Docetaxel injection concentrate: 20 mg( 1 ml) , 80 mg(4 ml) , 120 mg(6 ml) .Stored below 25 degrees
  • Solvent for Docetaxel injection concentrate:     5 ml vial for 20 mg, 6 ml for 80 mg, 9 ml for 120 mg.
  • We have to bring the concentrate at room temperature by allowing it to stand at room temperature for 5 minutes after taking from refrigerator. Then reconstitute with solvent. Inject this premix into 250 ml NS or 5% Dextrose. Mix thoroughly, solution should be clear and there should be no precipitation.

Indications

Breast cancer

FDA-approved for the treatment of  metastatic or recurrent breast cancer after failure of prior anthracycline based chemotherapy .

Docetaxel  single agent 60-100 mg/m2 every 3 weeks.

AT ( Doxorubicin  50 mg/m2+ Docetaxel 75 mg/m2 everv 3 weeks ) ;

Docetaxel ( 75 mg/m2 on day 1) + Capecitabine 950 mg/2 BD for 14 days every 3 weeks

For adjuvant treatment of patients with node positive breast cancer.

FEC→ Docetaxel ( 100 mg/m2 every 3 weeks)

TAC ( Docetaxel+ Doxoru + Cyclophos)

TC   ( Docetaxel + Cyclophos)

TCH ( Docetaxel + Carboplatin + Trastuzumab )

Metastatic or locally advanced gastric adenocarcinoma – Adjuvant CT :DCF ( 75 mg/m2 every 3 weeks)

Head and neck cancer – FDA-approved for use in combination with cisplatin and 5-fluorouracil for induction treatment of patients with inoperable, locally advanced disease. 75 mg/m2 every 3 weeks.

Prostate cancer—FDA-approved in combination with prednisone for androgen-independent (hormone-refractory) metastatic prostate cancer.

Non–small cell lung cancer—Locally advanced or metastatic disease after failure of prior platinum-based chemotherapy. FDA-approved 75 mg/m 2 IV every 3 weeks or 35–40 mg/m 2 IV weekly for 3 weeks with 1 week rest.

Non–small cell lung cancer: non resectable 75 mg/m 2 IV every 3 weeks in combination with cisplatin in patients who have not received prior chemotherapy.

Recurrent ovarian cancer : platinum sensitive ( Docetaxel + carboplatin ) ; platinum resistant ( Docetaxel single agent).

Adverse Effects

HAEMATOLOGIC TOXICITY

  • Neutropenia is the main toxicity of docetaxel.
  • Grade 4 neutropenia with ANC < 500/mm3 occurs   100 % with 100 mg/m2 and 75-80% with 60-75 mg/m2).
  • When docetaxel is administered on an every 3-week schedule, the onset of neutropenia is usually noted on day 8 with complete resolution by days 15 to 21.
  • Neutropenia is significantly less when low doses are administered weekly.
  • Closely monitor CBCs, and docetaxel therapy should not be given to patients with neutrophil counts of <1,500 cells/mm 3 .
  • Thrombocytopenia and anemia are also observed

FLUID RETENTION

  • The solvent used for Docetaxel is poly-oxy-ethylated surfactant, polysorbate-80 which causes alteration of membrane fluidity, increased capillary permeability
  • Fluid retention is cumulative and Incidence increases with total doses >400 mg/m 2 . Occurs in about 50% of patients.
  • Prophylactic Dexamethasone 8 mg BD for 3-5 days beginning one day prior to docetaxel infusion. Aggressive and early treatment with diuretics has been successfully used to manage fluid retention.
  • This syndrome resolves slowly once docetaxel therapy is stopped, with complete resolution occurring several months after treatment in patients who experience severe toxicity.

HYPERSENSITIVITY

  • Hypersensitivity reactions with generalized skin rash, erythema, hypotension,dyspnea, and/or bronchospasm.
  • The most popular prophylactic regimen for prevention of hypersensitivity reaction and fluid retention syndrome is dexamethasone 8 mg orally twice daily for 3 or 5 days starting 1 or 2 days before docetaxel, with or without H1– and H2-receptor antagonists given 30 minutes before docetaxel. Overall incidence decreased to less than 3%.

SKIN TOXICITY

  • Maculopapular skin rash and dry, itchy skin. Most commonly affect forearms and hands. Brown discoloration of fingernails may occur. Observed in up to 50% of patients usually within 1 week after therapy.
  • Other cutaneous effects include palmar-plantar erythrodysesthesia.

OTHERS

  • Alopecia occurs in up to 80% of patients.
  • Mucositis and/or diarrhea seen in 40% of patients. Mild to moderate nausea and vomiting, usually of brief duration.
  • Peripheral neuropathy is less commonly observed with docetaxel than with paclitaxel.
  • Generalized fatigue and asthenia are common, occurring in 60%–70% of patients. Arthralgias and myalgias also observed.
  • Reversible elevations in serum transaminases, alkaline phosphatase, and bilirubin.
  • Phlebitis and/or swelling can be seen at the injection site

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