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Docetaxel

Taxoid derived semisynthetic from the precursor 10-decacetyl buccatin III.

Promotes microtubule assembly and inhibits tubulin depolymerization, thereby stabilizing microtubules.

Binds to intracellular microtubules inhibiting their disassembly and preventing the transition from metaphase to anaphase.

By stabilizing microtubules against depolymerization by binding to beta-subunit of tubulin and leading to the formation of abnormal microtubule bundles that can inhibit cell proliferation and promote cell death.

Radiation sensitizer.

Uses a non-Cremophor EL vehicle and a polysorbate preservative.

Approved for breast cancer, prostate cancer, NSCLC, head and neck cancer and gastric cancer.

Using 20 mg/m2 weekly with concurrent radiation in stage III NSCLC associated with unacceptable toxicity with 47% grade 3-5 radiation pneumonitis (Onishi) and 9% incidence of death related to radiation pneumonitis.

In a phase 3 prospective randomized trial of docetaxel versus best supportive care in NSCLC patients previously treated with platinum-based chemotherapy, docetaxel treatment resulted in significant probation of survival of 7.5 months versus 4.6 months (Shepherd FA et al).

Concurrent chemoradiation in inoperable esophageal cancer associated with 6% radiation pneumonitis deaths (Font).

Previous treatment with weekly chemotherapy may predispose patients to radiation pneumonitis when radiation added at a later date.

A dose response relationship for antitumor activity and toxicity is suggested.

Taxanes arrest cells in the G2M phase of cell cycle, which is the most radiosensitive phase.

Polysorbate and ethanol diluent are the vehicles.

Undergoes hepatic metabolism via cytochrome P450 (CYP) 3A4.

Cause severe hypersensitivity reactions characterized by generalized rash, erythema, hypotension, bronchospasm.

Fatal anaphylaxis has been reportedly, rarely.

Docetaxel is characterized by significant pharmacokinetic variability, we have up to 10 fold differences in drug clearance, even in patients with normal liver function (Baker SD et al).

Hepatic metabolism is the primary mode of clearance of docetaxel.

A 50% decrease in docetaxel clearance is associated with a greater than 430% increase in the risk of developing severe neutropenia (Bruno R et al).

Reduced area under the curve (AUC) is associated with shorter survival in patients with non-small cell lung cancer receiving this agent (Bruno et al).

Neutropenia occurs in virtually all patients given between 60-and 100 mg meter squared intravenous treatment.

Severe neutropenia is reduced in castrate patients with prostate cancer compared to 9 castrate patients with prostate cancer or patients with other solid tumors, despite similarity and total dose administered per course (Hussain A et al ).

Adding docetaxel to initial androgen deprivation therapy significantly prolongs overall survival among men with metastatic, hormone sensitive prostate cancer (Sweeney C et al).

In the above study the median overall survival was 57.6 months with docetaxel plus ADT compared with 44 months in the ADT arm alone.

The above study suggests upfront docetaxel chemotherapy in addition to hormone therapy suggested significant improvement in survival in early use in newly diagnosed patients with metastatic prostatic disease.

Docetaxel upfront treatment is supported for patients with high volume metastatic prostate cancer.

The first chemotherapeutic agent proven to have survival benefit in metastatic prostate cancer.

Docetaxel added to androgen deprivation therapy does not improve overall survival over androgen deprivation alone in hormone naïve metastatic prostate cancer (GETUG-AFU): this refers to low volume disease.

In the above study there was a significant survival difference in high volume metastatic prostate cancer when docetaxel was added to hormonal therapy.

Adding docetaxel to androgen deprivation therapy significantly improves recurrence free survival compared to a ADT alone in patients with high-risk localized prostate cancer with no apparent long-term toxicity: Whether this benefit translates into improved metastasis free survival is yet unknown (Fizazi K et al).

Docetaxel clearance is increased by approximately 100% in castrated men and is associated with a twofold reduction in area under the curve.

It is presumed that the clearance of docetaxel this increased after castration, probably because of increase in hepatocellular uptake of the drug.

It is suggested that in castrated patients with prostate cancer undergoing docetaxel treatment may benefit from utilizing higher doses of drug.

In high risk prostate cancer patients the treatment with hormone therapy and the addition of docetaxel chemotherapy improved survival (James ND et al).

Regarded as the single most active cytotoxic agent in advanced breast cancer with objective response rates in untreated patients of up to 68% in phase II trials and 30-40% response rates in anthracycline pretreated patients in phase III trials.

Taxotere is indicated as a single agent for locally advanced or metastatic breast cancer after chemotherapy failure, and with doxorubicin, and cyclophosphamide as adjuvant treatment of operable node positive breast cancer.

Indicated as a single agent for locally advanced the metastatic non-small cell lung cancer after platinum failure, and with Cisplatinum for unresectable, locally advanced or metastatic untreated NSCLC, with prednisone in androgen independent metastatic prostate cancer, with Cisplatinum and five if you for advanced gastric adenocarcinoma, including the gastroesophageal junction, and with Cisplatinum and fluorouracil for locally advanced squamous cell carcinoma of the head and neck.

18% of patients with metastatic breast cancer resistant to paclitaxel respond to docetaxel.

Has an intrinsic inflammatory toxicity profile.

Non-hematologic toxicity includes pleural effusions, conjunctivitis, lower extremity edema, fluid retention, rash, nail changes, alopecia, and diarrhea.

In pooled analysis of two adjuvant chemotherapy trials this agent had no significantly different effect on the risk of recurrence or death in ER positive and ER negative patients with breast cancer (Andre).

Docetaxel has proved to prolong survival in advanced castrate resistant prostate cancer (PCa) but in a trial of six courses of docetaxel it does not improve biochemical disease free survival (BDFS) after radical prostatectomy for high risk PCa.

Adjuvant docetaxel without hormonal therapy did not improve BDFS after radical prostatectomy for high risk prostate cancer.

CHAARTED study showed adding docetaxel to ADT extended overall survival by a median of 13.6 months, compared with ADT alone in metastatic prostate cancer.

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