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Docetaxel; Uses, Dosage, Side Effects, Interactions

Docetaxel Anhydrous is the anhydrous form of docetaxel, a semisynthetic side-chain analog of paclitaxel with the antineoplastic property. Docetaxel binds specifically to the beta-tubulin subunit of microtubules and thereby antagonizes the disassembly of the microtubule proteins. This results in the persistence of aberrant microtubule structures and results in cell-cycle arrest and subsequent cell death.

Mechanism of Action of Docetaxel

Docetaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, docetaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell’s ability to use its cytoskeleton in a flexible manner. Specifically, docetaxel binds to the β-subunit of tubulin. Tubulin is the “building block” of microtubules, and the binding of docetaxel locks these building blocks in place. The resulting microtubule/docetaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that docetaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function.

Docetaxel, a semisynthetic taxane, has exhibited significant single-agent activity against prostatic tumors. In phase I/II studies, single-agent docetaxel and the combination of docetaxel plus estramustine were effective in inducing prostate-specific antigen reductions of > or = 50% in men with androgen-independent prostate cancer (AIPC). The underlying reason for docetaxel’s clinical activity against prostate cancer has been a focus of ongoing research. Docetaxel is believed to have a twofold mechanism of antineoplastic activity: (1) inhibition of microtubular depolymerization, and (2) attenuation of the effects of bcl-2 and bcl-xL gene expression. Taxane-induced microtubule stabilization arrests cells in the G(2)M phase of the cell cycle and induces bcl-2 phosphorylation, thereby promoting a cascade of events that ultimately leads to apoptotic cell death. In preclinical studies, docetaxel had a higher affinity for tubulin and was shown to be a more potent inducer of bcl-2 phosphorylation than paclitaxel. Laboratory evidence also supports the clinical evaluation of docetaxel-based combinations that include agents such as trastuzumab and/or estramustine. The pathways for docetaxel-induced apoptosis appear to differ in androgen-dependent and androgen-independent prostate cancer cells. Further elucidation of these differences will be instrumental in designing targeted regimens for the treatment of localized and advanced prostate cancer.

Indications of Docetaxel

For the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Also used as a single agent in the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy.
It is also used in combination with prednisone, in the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer. Furthermore, docetaxel has uses in the treatment of gastric adenocarinoma and head and neck cancer.
Non-Small Cell Lung Cancer
Breast Cancer
Gastric Cancer
Head and Neck Cancer
Prostate Cancer
Esophageal Cancers
Ewing’s Sarcoma
Locally Advanced Breast Cancer
Lung Cancer Small Cell Lung Cancer
Metastatic Bladder Cancer
Metastatic Breast Cancer
Metastatic Hormone Refractory Prostate Cancer
Metastatic Non-Small Cell Lung Cancer
Node-Positive Breast Cancer
Ovarian Cancer Metastatic
Soft Tissue Sarcoma (STS)
Advanced untreated gastric adenocarcinoma
Locally advanced Squamous cell carcinoma of head and neck
Locally advanced untreated nonsmall cell lung cancer
Metastatic Squamous cell carcinoma of head and neck
Refractory, locally advanced Nonsmall cell lung cancer
Refractory, metastatic Nonsmall cell lung cancer

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Therapeutic Uses

Antineoplastic Agents; Tubulin Modulators
Taxotere is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy. Taxotere in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
Taxotere as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum-based chemotherapy. Taxotere in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
Taxotere in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer. /Included in US product labeling/
Taxotere in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
Taxotere in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Docetaxel is used in combination with doxorubicin for the first-line treatment of metastatic breast cancer
Docetaxel in combination with carboplatin is used an as alternative regimen for the first-line treatment of ovarian epithelial cancer.

Contra-Indications of Docetaxel

Severe infection
Anemia
Decreased Blood Platelets
Decreased Neutrophils a Type of White Blood Cell
Peripheral neuropathy
Disorder of the Peripheral Nerves that Cause Movement
Macular Swelling and Degeneration of the Eye
Heart Compression caused by Excess Fluid in the Covering
Failure of the Left Ventricle of the Heart
Escape of Fluid into the Lungs
Fluid in the Lungs
Painful
Red or Swollen Mouth
Liver problems
Visible Water Retention
Fluid Retention in the Legs
Feet
Arms or Hands
High Amount of Bilirubin in the Blood
Diarrhea
Ascites
Abnormal liver function tests
Pregnancy
A mother who is producing milk and breastfeeding
Severely Decreased Levels of Neutrophils in the Blood
Lung Tissue Problems
Allergies to Docetaxel & Paclitaxel/Docetaxel

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Dosage of Docetaxel

Strengths: 10 mg/mL; 40 mg/mL; 20 mg/mL; 20 mg; 80 mg

Breast Cancer

Single-agent – 60 to 100 mg/m2 IV over 1 hour every 3 weeks
Adjuvant – 75 mg/m2 IV over 1 hour administered 1 hour after doxorubicin 50 mg/m2 IV and cyclophosphamide 500 mg/m2 IV every 3 weeks for 6 cycles; prophylactic G-CSF may be used to mitigate the risk of hematological toxicities

Non-Small Cell Lung Cancer

As a single agent after failure of prior platinum-based chemotherapy – 75 mg/m2 IV over 1 hour every 3 weeks
Chemotherapy-naive patients – 75 mg/m2 IV over 1 hour immediately followed by cisplatin 75 mg/m2 IV over 30 to 60 minutes; repeat every 3 weeks

Gastric Cancer

75 mg/m2 IV over 1 hour followed by cisplatin 75 mg/m2 IV over 1 to 3 hours (both on Day 1 only), followed by fluorouracil 750 mg/m2 daily given as a 24-hour continuous IV infusion for 5 days, starting at the end of the cisplatin infusion; repeat every 3 weeks

Head and Neck Cancer

Induction therapy of locally advanced inoperable SCCHN

Day 1: 75 mg/m2 IV over 1 hour followed by cisplatin 75 mg/m2 IV over 1 hour, on Day 1, followed by fluorouracil 750 mg/m2 as a continuous IV infusion daily for 5 days
Administer this regimen every 3 weeks for 4 cycles.
Following chemotherapy, patients should receive radiotherapy.

Induction therapy for locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN

Day 1: 75 mg/m2 IV over 1 hour followed by cisplatin 100 mg/m2 administered as a 30-minute to 3-hour IV infusion, followed by fluorouracil 1000 mg/m2/day as a continuous IV infusion from Day 1 to Day
Repeat therapy every 3 weeks for 3 cycles.
Following chemotherapy, patients should receive radiotherapy.

Prostate Cancer

75 mg/m2 IV over 1 hour every 3 weeks; prednisone 5 mg orally 2 times a day is administered continuously

Side Effects of Docetaxel

More Common

Congestion
diarrhea
dryness or soreness of the throat
Burning, numbness, tingling, or pain in the arms, hands, legs, or feet
swelling of the stomach, face, fingers, hands, feet, or lower legs
unusual tiredness or weakness
weight gain
nausea
skin rash or redness (mild)
sores or ulcers on the lips or tongue or inside the mouth
weakness in the arms, hands, legs, or feet

Less Common

Black, tarry stools
blood in the urine or stools
cough or hoarseness (accompanied by fever or chills)
difficult or labored breathing
difficult or painful urination (accompanied by fever or chills)
difficulty with swallowing
dizziness
fast heartbeat
fever or chills
hives or skin rash
itching, puffiness, or swelling of the eyelids or around the eyes, face, lips, or tongue
lower back or side pain (accompanied by fever or chills)
noisy, rattling breathing
pinpoint red spots on the skin
red, scaly, swollen, or peeling areas of the skin (severe)
tightness in the chest
troubled breathing while at rest
unusual bleeding or bruising

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Drug Interactions of Docetaxel

Docetaxel may interact with following drugs, supplements & may change the efficacy of drugs

other cancer medications (e.g., cisplatin, doxorubicin, teniposide, etoposide, vincristine)
amiodarone
“azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
barbiturates (e.g., phenobarbital, secobarbital)
boceprevir
bosentan
carbamazepine
carvedilol
clozapine
conivaptan
cyclosporine
deferasirox
desipramine
dexamethasone
diltiazem
echinacea
grapefruit juice
HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delaviridine, efavirenz, etravirine, nevirapine)
HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
leflunomide
lomitapide
macrolide antibiotics (e.g., clarithromycin, erythromycin)
mefloquine
natalizumab
nefazodone
norfloxacin
phenytoin
pimecrolimus
primidone
progesterone
propranolol
quinidine
quinine
rifabutin
rifampin
“statin” cholesterol medications (e.g., atorvastatin, pravastatin, simvastatin)
tacrolimus
tamoxifen
telaprevir
tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib)
vaccines
verapamil

Pregnancy Category of

FDA Pregnancy Category – D

Pregnancy

There are no adequate studies of use of this medication by pregnant women. This medication should not be taken during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if docetaxel passes into breast milk. Women should not breast-feed while using docetaxel. The safety and effectiveness of using this medication have not been established for children.