VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• DOCEtaxel

Chemical Name:

• [2a R -[2aα,4β,4aβ,6β,9α(α R *,β S *),11α,12α,12aα,12bα]]-12b-(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1 H -cyclodeca[3,4]benz[1,2- b ]oxet-9-yl ester β-[[(1,1-dimethylethoxy)carbonyl]amino]-α-hydroxybenzenepropanoic acid

Molecular Formula:

• C₄₃H₅₃NO₁₄

Docetaxel, a semisynthetic taxoid produced from the needles of the European yew ( Taxus baccata ) tree, is an antineoplastic agent.1,2,3,4,5,6,7,8

Breast Cancer

Adjuvant Therapy for Early-stage Breast Cancer

Docetaxel is used in combination with doxorubicin and cyclophosphamide for the adjuvant treatment of operable node-positive breast cancer.1,65,84,86

The current indication is based on a multicenter, open-label, randomized trial (the BCIRG 001 trial) in which 1491 patients with axillary node-positive breast cancer and no evidence of metastatic disease received either doxorubicin and cyclophosphamide followed by docetaxel (TAC) or doxorubicin followed by fluorouracil and cyclophosphamide (FAC).1,68 The median age of women participating in this study was 49 years.68 Treatment regimens consisted of doxorubicin 50 mg/m² as a 15-minute IV infusion and cyclophosphamide 500 mg/m² IV administered over 1-5 minutes followed by a 1-hour interval and then docetaxel 75 mg/m² as a 1-hour IV infusion on day 1 (TAC regimen), or doxorubicin 50 mg/m² followed by fluorouracil 500 mg/m² each administered as a 15-minute IV infusion and then cyclophosphamide 500 mg/m² as a 1- to 5-minute IV infusion on day 1 (FAC regimen); each regimen was administered once every 3 weeks for up to 6 cycles.1,68 Stratification was performed according to the number of positive lymph nodes (1-3, 4+).1,68 Following the completion of chemotherapy, patients with hormone receptor-positive disease received tamoxifen 20 mg daily for up to 5 years.1,68 About 70% of patients in each group received adjuvant radiation therapy.1,68

Results of a second interim analysis of the data at a median follow-up of 55 months indicate that disease-free survival was prolonged in patients receiving the docetaxel-containing regimen.1,68 The estimated rate of disease-free survival at 5 years was 75% in patients receiving the TAC regimen compared with 68% in those receiving the FAC regimen.68 An overall reduction of about 26% in risk of relapse, including local or distant recurrence, contralateral breast cancer, and death from any cause, was observed in patients receiving the TAC regimen.1 At the time of this interim analysis, overall survival also was prolonged in patients receiving the docetaxel-containing regimen.1,68 Subgroup analysis suggests that those most likely to benefit from docetaxel-containing adjuvant treatment are patients with 1-3 positive nodes.1,68 Because this trial was restricted to women who were 70 years of age or younger, the benefit and risk associated with use of the TAC regimen as adjuvant therapy for breast cancer in older patients is not known.75

Patients receiving TAC generally experienced increased toxicity compared with those receiving FAC.1,75 A higher rate of severe nonhematologic treatment-emergent adverse events occurred in patients receiving TAC (36%) than in those receiving FAC (27%).1,68 Treatment was discontinued because of adverse effects in 6% of patients receiving TAC compared with about 1% of those receiving FAC.1 Fever in the absence of infection and allergy were the most common reasons for withdrawal from the study among patients receiving TAC.1 Anemia (92 versus 72%), stomatitis (69 versus 53%), grade 3 or 4 neutropenia (66 versus 49%), fever in the absence of infection (46 versus 17%), fluid retention (35 versus 15%) including peripheral edema (27 versus 7%), myalgia (27 versus 10%), sensory neuropathy (26 versus 10%), and febrile neutropenia (25 versus 2%) occurred more frequently in patients receiving TAC.1 Neutropenia of any grade (82 versus 71%) and vomiting (59 versus 44%) occurred more frequently in those receiving FAC.1 The most frequent adverse effects in patients receiving TAC included alopecia (98%), hematologic toxicity (anemia [92%], neutropenia [71%], grade 3 or 4 neutropenia [66%]), asthenia (81%), GI toxicity (nausea [80%], stomatitis [69%], vomiting [44%]), amenorrhea (62%), and fever in the absence of infection (46%).1

In this trial (BCIRG 001), patients receiving TAC experienced a higher rate of febrile neutropenia than those receiving FAC (25 versus 2.5%).1 Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was not allowed, but use of G-CSF was mandatory in subsequent cycles for any patient experiencing febrile neutropenia or infection.1,68 Another randomized trial (RAPP-01), which compared doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as adjuvant therapy for intermediate-risk breast cancer, was prematurely terminated because of serious adverse events, including 2 deaths, associated with febrile neutropenia in patients receiving the docetaxel-containing regimen.78 Some clinicians, including the investigators in these trials (BCIRG 001 and RAPP-01), currently recommend primary prophylaxis with G-CSF in patients receiving docetaxel with an anthracycline agent as adjuvant therapy for early-stage breast cancer.76,77,78,79

Other docetaxel-containing regimens are being investigated as adjuvant therapy for early-stage breast cancer, including nonanthracycline-containing regimens†.80 In a randomized trial involving 1016 patients, patients receiving docetaxel and cyclophosphamide as adjuvant therapy for operable breast cancer had prolonged disease-free survival and similar overall survival compared with those receiving doxorubicin and cyclophosphamide.80 Grade 1 or 2 edema, myalgia, and arthralgia occurred more frequently in patients receiving docetaxel and cyclophosphamide whereas grade 1 to 4 nausea and vomiting were more frequent in patients receiving doxorubicin and cyclophosphamide.80

Docetaxel and Doxorubicin as First-line Therapy for Advanced Breast Cancer

Docetaxel is used in combination with doxorubicin for the first-line treatment of metastatic breast cancer†.65

In a multicenter, randomized, phase 3 trial, 429 patients received either doxorubicin and docetaxel or doxorubicin and cyclophosphamide for the initial treatment of metastatic breast cancer.67 Treatment consisted of doxorubicin 50 mg/m² as a 15-minute IV infusion followed 1 hour later by docetaxel 75 mg/m² as a 1-hour IV infusion, or doxorubicin 60 mg/m² as a 15-minute IV infusion followed by cyclophosphamide 600 mg/m² as a 15-minute IV infusion, on day 1 once every 3 weeks for up to 8 cycles.67 Among patients receiving doxorubicin and docetaxel, median time to progression was prolonged (37 versus 32 weeks), overall response rate was higher (59 versus 47%), and overall survival was similar compared with those receiving doxorubicin and cyclophosphamide as initial treatment for metastatic breast cancer.67 Diarrhea, febrile neutropenia, edema, neurosensory toxicity, nail changes, rashes, and grade 3 or 4 infections occurred more frequently in patients receiving doxorubicin and docetaxel whereas nausea and vomiting were more frequent in patients receiving doxorubicin and cyclophosphamide.67

Other dosage schedules have been investigated for the use of doxorubicin and docetaxel as first-line therapy for metastatic breast cancer.74 In a multicenter, randomized, phase 3 trial involving 144 patients, sequential administration of doxorubicin and docetaxel was shown to be as effective but less toxic than concomitant administration of these drugs for the first-line treatment of metastatic breast cancer.74 Patients who had not received previous treatment with anthracycline agents received either 3 cycles of doxorubicin 75 mg/m² every 21 days followed by 3 cycles of docetaxel 100 mg/m² every 21 days (sequential treatment) or 6 cycles of doxorubicin 50 mg/m² and docetaxel 75 mg/m² every 21 days (concomitant treatment).74 Dosage adjustments were made for patients who had received previous treatment with anthracycline agents, so these patients received either 2 cycles of doxorubicin 75 mg/m² every 21 days followed by 4 cycles of docetaxel 100 mg/m² every 21 days (sequential treatment) or 3 cycles of doxorubicin 50 mg/m² and docetaxel 75 mg/m² every 21 days followed by 3 cycles of docetaxel 100 mg/m² every 21 days (concomitant treatment).74 Patients received premedication with a corticosteroid regimen and prophylactic antiemetic therapy.74 The use of granulocyte colony-stimulating factor (G-CSF) was not allowed as primary prophylaxis but was allowed following a first episode of febrile neutropenia.74 Patients receiving sequential treatment with doxorubicin and docetaxel had a higher rate of completion of 6 cycles of therapy (81 versus 67%) and a lower rate of withdrawal from the study because of adverse events (1 versus 14.5%) compared with those receiving concomitant treatment with doxorubicin and docetaxel.74 Efficacy was similar between the groups, but febrile neutropenia was less frequent (29 versus 48%) in patients receiving sequential administration of doxorubicin and docetaxel than in those receiving concomitant administration of these agents.74

Because of the higher rate of febrile neutropenia and increased risk of life-threatening sepsis associated with the use of doxorubicin in combination with docetaxel as adjuvant or neoadjuvant therapy for early-stage breast cancer, some clinicians recommend use of G-CSF and/or antibiotics as primary prophylaxis in patients receiving these agents for metastatic breast cancer.78

Second-line Therapy for Advanced Breast Cancer

Docetaxel and Capecitabine

Docetaxel is used in combination with capecitabine for the treatment of metastatic breast cancer in patients with disease that has failed anthracycline-containing chemotherapy.64,65 In a randomized trial, patients receiving combination therapy with docetaxel and capecitabine for metastatic breast cancer had longer time to disease progression, prolonged survival, and higher objective response rate than those receiving docetaxel alone.66 (See Uses: Breast Cancer: Combination Therapy in Capecitabine 10:00.)

Docetaxel Monotherapy

Docetaxel is used as monotherapy for the second-line treatment of locally advanced or metastatic breast cancer after failure of prior chemotherapy.1,54,65,84,85,86 As with paclitaxel, clinical cross-resistance with anthracyclines is incomplete with docetaxel, and patients with metastatic breast cancer refractory to treatment with anthracycline antineoplastic agents (e.g., doxorubicin) may respond to docetaxel therapy.12,13,14,15,16

The current indication for docetaxel is based principally on the results of 2 large randomized trials in patients with locally advanced or metastatic breast cancer that failed to respond to prior chemotherapy regimens.1,41,42

Docetaxel (100 mg/m² IV over 1 hour every 3 weeks) was compared with a combination of mitomycin (12 mg/m² IV every 6 weeks) and vinblastine (6 mg/m² IV every 3 weeks) in an open-label, multicenter, randomized phase 3 study in 392 patients with a history of treatment failure with an anthracycline regimen.1,41 Most patients in the study had received prior anthracycline-based chemotherapy for the treatment of metastatic disease (rather than as adjuvant therapy) and 75% had measurable, visceral metastases; only 15% of patients at study entry were those whose disease had relapsed after adjuvant therapy.1 Patients receiving docetaxel experienced a longer median survival duration (11.4 versus 8.7 months), longer median time to progression (4.3 versus 2.5 months), and higher overall and complete response rates (28.1 versus 9.5% overall and 3.4 versus 1.6% complete) compared with patients receiving mitomycin and vinblastine.1 Grade 3 or 4 neutropenia, asthenia, stomatitis, neurosensory toxicity, nail disorder, diarrhea, skin toxicity, grade 3 or 4 infections, and febrile neutropenia occurred more frequently in patients receiving docetaxel whereas thrombocytopenia and constipation occurred more frequently in those receiving mitomycin and vinblastine.41

In a second open-label, multicenter phase 3 trial, 326 patients with metastatic breast cancer and a history of treatment failure with an alkylating agent-containing chemotherapy regimen were randomized to receive either docetaxel (100 mg/m² IV over 1 hour every 3 weeks) or doxorubicin (75 mg/m² IV over 15-20 minutes every 3 weeks).1,42 Prior chemotherapy was administered for metastatic disease in about half of the patients studied and as adjuvant therapy in the other half of the patients, and 75% of patients had measurable, visceral metastases.1 Higher overall and complete response rates (45.3 versus 29.7% overall and 6.8 versus 4.2% complete) were observed in patients receiving docetaxel, and a similar median survival (14.7 and 14.3 months) and median time to progression (6.5 and 5.3 months) were reported with docetaxel and doxorubicin, respectively.1 Fluid retention, diarrhea, nail disorder, neurosensory toxicity, skin toxicity, allergy, and neuromotor toxicity occurred more frequently in patients receiving docetaxel whereas nausea, vomiting, stomatitis, thrombocytopenia, cardiac toxicity, grade 3 or 4 anemia, red blood cell transfusions, febrile neutropenia, and grade 3 or 4 infections were more frequent in patients receiving doxorubicin.42

In another randomized trial, 527 patients with advanced breast cancer that had progressed or relapsed after 1 prior chemotherapy regimen received docetaxel at dose levels of 60, 75, or 100 mg/m².1,63 Most patients (94%) had metastatic disease and 79% had received prior anthracycline-containing therapy.1 Response rate and toxicity increased with increase in dose.1,63 Patients receiving docetaxel 100 mg/m² had a higher response rate (30 versus 20%) than those receiving docetaxel 60 mg/m².1 Grade 3 or 4 adverse events occurred in 49% of patients receiving docetaxel 60 mg/m², 55% of those receiving docetaxel 75 mg/m², and 66% of those receiving docetaxel 100 mg/m².1 Discontinuance of therapy because of toxicity was reported in 5% of patients receiving docetaxel 60 mg/m² compared with 16.5% of patients receiving docetaxel 100 mg/m².1 Adverse effects that occurred at higher frequency in respective order with increasing docetaxel dose (60, 75, and 100 mg/m²) included neutropenia (92, 94, and 97%), anemia (87, 94, and 97%), fluid retention (26, 38, and 46%), thrombocytopenia (7, 11, and 12%), febrile neutropenia (5, 7, and 14%), and treatment-related grade 3 or 4 infection (2, 3, and 7%).1

In phase 2 studies, docetaxel has been evaluated in patients with locally advanced or metastatic breast cancer, including those with disease resistant to treatment with anthracycline antineoplastic agents.13,14,15,16,17 Anthracycline resistance was defined as progression of disease while undergoing anthracycline-containing therapy for advanced disease or disease relapse while undergoing anthracycline-containing adjuvant therapy.1 Among 309 patients receiving a docetaxel dose of 100 mg/m² as second-line therapy for metastatic breast cancer in 6 single-arm studies, 190 patients had anthracycline-resistant disease.1 Among patients with anthracycline-resistant disease, the overall response rate was about 38% with a complete response rate of 2%.1 A similar rate of overall response (about 35%) was observed in 26 patients with anthracycline-resistant disease among a total of 174 patients receiving a docetaxel dose of 60 mg/m² as second-line therapy for locally advanced or metastatic breast cancer in 3 single-arm studies conducted in Japan.1

Non-small Cell Lung Cancer

Docetaxel and Cisplatin as First-line Therapy for Advanced Disease

Docetaxel is used in combination with cisplatin as first-line therapy for unresectable, locally advanced or metastatic non-small cell lung cancer.1,52,54,84,85,86

The current indication is based on a randomized trial in which 1218 patients with unresectable stage IIIB or stage IV non-small cell lung cancer received initial treatment with docetaxel and cisplatin, vinorelbine and cisplatin, or docetaxel and carboplatin.1,69 Treatment regimens consisted of docetaxel 75 mg/m² as a 1-hour IV infusion immediately followed by cisplatin 75 mg/m² IV over 30-60 minutes on day 1 once every 3 weeks; vinorelbine 25 mg/m² IV over 6-10 minutes on days 1, 8, 15, and 22 followed by cisplatin 100 mg/m² IV on day 1 in 4-week cycles; or docetaxel 75 mg/m² IV as a 1-hour IV infusion and carboplatin IV at the dose required to obtain an area under the concentration-time curve (AUC) of 6 mg/mL per minute on day 1 once every 3 weeks.1,69

Median survival was similar in patients receiving docetaxel and cisplatin compared with those receiving vinorelbine and cisplatin.1,69 Among patients receiving docetaxel and cisplatin, at least 62% of the known survival effect of adding vinorelbine to cisplatin was maintained.1 The use of the docetaxel/carboplatin regimen did not prolong survival compared with the vinorelbine/cisplatin regimen, and less than 50% of the known survival effect of adding vinorelbine to cisplatin was maintained.1

Hematologic toxicity was frequent for all 3 regimens.1 Alopecia (75 versus 42%), fluid retention (54 versus 42%) including peripheral edema (34 versus 18%), diarrhea (47 versus 25%), and nail disorders (14 versus less than 1%) occurred more frequently in patients receiving docetaxel and cisplatin.1 Grade 3 or 4 anemia (25 versus 7%), grade 3 or 4 nausea (17 versus 10%), and grade 3 or 4 vomiting (16 versus 8%) were more common in patients receiving vinorelbine and cisplatin.1

Docetaxel as Second-line Therapy for Locally Advanced or Metastatic Disease

Docetaxel is used alone as second-line therapy for locally advanced or metastatic non-small cell lung cancer in patients with disease that has recurred or progressed following prior treatment with platinum-based chemotherapy.1,52,54,84,85,86

A small survival benefit has been demonstrated for the use of platinum-based (cisplatin) chemotherapy in selected patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have a good performance status.52,53 Platinum-based chemotherapy regimens currently are preferred for the treatment of non-small cell lung cancer.53,54,55 (See Uses: Non-small Cell Lung Cancer in Cisplatin 10:00 for comprehensive discussion.) Use of chemotherapy for the treatment of advanced non-small cell lung cancer generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond.55 The decision to use chemotherapy must be individualized according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.52,53,55

The current indication is based on the results of 2 randomized trials that established the use of docetaxel 75 mg/m² as a tolerable dose level for patients who had previously received platinum-based chemotherapy for advanced non-small cell lung cancer.1 In a randomized trial, median survival was prolonged and the 1-year survival rate was higher in patients receiving docetaxel (75 mg/m²) versus best supportive care for the treatment of unresectable locally advanced or metastatic (stage IIIB or IV) non-small cell lung cancer that had previously been treated with platinum-containing chemotherapy.1,59 In another randomized trial, patients receiving docetaxel (75 mg/m²) experienced higher response rates (all partial responses) and a higher 1-year survival rate but similar median survival compared with those receiving a control regimen of vinorelbine or ifosfamide for advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy.1,60 In both randomized trials, the optimum dosage of docetaxel was 75 mg/m² by 1-hour IV infusion once every 3 weeks; higher doses of docetaxel (100 mg/m²) were associated with excessive toxicity.59,60 Docetaxel at a dose of 100 mg/m² caused unacceptable hematologic toxicity, infections, and treatment-related mortality, and the use of this higher dose in this patient population is not recommended.1 Of the 5 patients who died from treatment-related toxicity while receiving docetaxel 75 mg/m² in the 2 randomized trials, 3 had a performance status of 2 upon entry to the study.1

Prostate Cancer

Docetaxel is used in combination with prednisone for the treatment of androgen-independent (hormone-refractory) metastatic prostate cancer.1,84,85,86

The current indication is based on the results of a multicenter, randomized, active-control trial involving 1006 patients with androgen-independent metastatic prostate cancer receiving prednisone with either docetaxel or the active control, mitoxantrone.1,70 Treatment consisted of docetaxel 75 mg/m² as a 1-hour IV infusion once every 3 weeks for up to 10 cycles or docetaxel 30 mg/m² as a 30-minute IV infusion once weekly for the first 5 weeks in a 6-week cycle for up to 5 cycles.1,70 The active control regimen was mitoxantrone 12 mg/m² as a 30-minute IV infusion once every 3 weeks for 10 cycles.1,70 Each patient also received prednisone 5 mg orally twice daily continually.1,70

Median survival was prolonged (18.9 versus 16.5 months) in patients receiving the docetaxel once-every-3-weeks regimen and prednisone compared with those receiving mitoxantrone and prednisone.1,70 No difference in survival was observed for patients receiving the docetaxel once-weekly regimen and prednisone compared with those receiving mitoxantrone and prednisone.1,70

Anemia (66 versus 58%), alopecia (65 versus 13%), fatigue (53 versus 35%), grade 3 or 4 neutropenia (32 versus 22%), infection (32 versus 20%), diarrhea (32 versus 10%), nail changes (30 versus 8%), sensory neuropathy (30 versus 7%), fluid retention (24 versus 4%) including peripheral edema (18 versus 2%), stomatitis (20 versus 8%), and taste disturbance (18 versus 7%) occurred more frequently in patients receiving docetaxel and prednisone.1 Left ventricular cardiac dysfunction (22 versus 10%) was more frequent in patients receiving mitoxantrone and prednisone.1 The most frequent adverse effects in patients receiving docetaxel and prednisone included anemia (66%), alopecia (65%), fatigue (53%), neutropenia (41%), and nausea (41%).1

Gastric Cancer

Docetaxel is used in combination with cisplatin and fluorouracil for the initial treatment of advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction.1,84,86

The current indication is based on the results of a multicenter, open-label, randomized trial in which 445 patients received either docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil for the initial treatment of advanced gastric adenocarcinoma, including gastric adenocarcinoma of the gastroesophageal junction.1,71 Treatment regimens consisted of docetaxel 75 mg/m² as a 1-hour IV infusion on day 1 in combination with cisplatin 75 mg/m² as a 1-hour to 3-hour IV infusion on day 1 and fluorouracil 750 mg/m² as a continuous IV infusion daily for 5 days (on days 1-5) in 3-week cycles; or cisplatin 100 mg/m² on day 1 and fluorouracil 1000 mg/m² daily for 5 days (on days 1-5) in 4-week cycles.1,71 Most (71%) of the patients were Caucasian males, and the median age was 55 years; 19% of the patients had undergone prior curative surgery and 12% of patients had undergone palliative surgery.1,71 The median number of cycles of therapy administered per patient was 6 cycles (range: 1-16 cycles) for those receiving docetaxel/cisplatin/fluorouracil and 4 cycles (range: 1-12 cycles) for those receiving cisplatin/fluorouracil.1,71

Patients receiving docetaxel, cisplatin, and fluorouracil had longer median time to progression (5.6 versus 3.7 months) and prolonged survival (9.2 versus 8.6 months) compared with those receiving cisplatin and fluorouracil as first-line therapy for advanced gastric cancer.1,71

Neutropenia (96 versus 83%) including severe neutropenia (82 versus 57%), diarrhea (78 versus 50%) including severe diarrhea (20 versus 8%), alopecia (66 versus 41%), neurosensory toxicity (38 versus 25%), fever in the absence of infection (36 versus 23%), febrile neutropenia (16 versus 4%), and fluid retention (15 versus 4%) occurred more frequently in patients receiving docetaxel with cisplatin and fluorouracil.1 Thrombocytopenia (39 versus 26%) occurred more frequently in patients receiving cisplatin and fluorouracil.1 The most frequent adverse effects in patients receiving docetaxel with cisplatin and fluorouracil for advanced gastric cancer were anemia (97%), neutropenia (96%) including severe neutropenia (82%), diarrhea (78%), nausea (73%), vomiting (66%), alopecia (66%), lethargy (63%), stomatitis (59%), and anorexia (51%).1

Head and Neck Cancer

Docetaxel is used in combination with cisplatin and fluorouracil as induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck.1,84,86

The current indication is based on the results of 2 randomized trials in which patients received induction chemotherapy with cisplatin and fluorouracil, with or without docetaxel, followed by radiotherapy or chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck.1

In the first randomized trial (TAX323), a multicenter, open-label study, 358 patients with inoperable locally advanced squamous cell carcinoma of the head and neck received induction chemotherapy with either docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil.1,72 All patients had a WHO performance status of 0 or 1.1,72 The median age of patients in the study was 53 years.72

Treatment regimens consisted of docetaxel 75 mg/m² as a 1-hour IV infusion on day 1, followed by cisplatin 75 mg/m² as a 1-hour IV infusion on day 1, followed by fluorouracil 750 mg/m² daily as a continuous IV infusion on days 1-5 (the TPF regimen); or cisplatin 100 mg/m² as a 1-hour IV infusion on day 1, followed by fluorouracil 1000 mg/m² daily as a continuous IV infusion on days 1-5 (the PF regimen).1,72 Each regimen was administered every 3 weeks for up to 4 cycles.1,72 At an interval of 4-7 weeks following completion of chemotherapy, patients with disease that did not progress also received locoregional radiation therapy with either a conventional fraction regimen (1.8-2 Gy once daily for 5 days per week for a total dose of 66-70 Gy) or an accelerated or hyperfractionated regimen (twice daily with a minimum interfraction interval of 6 hours for 5 days per week for a total dose of 70 Gy or 74 Gy, respectively).1,72 Surgical resection was allowed following completion of chemotherapy, preceding or following radiation therapy.1,72

At a median follow-up of 34 months, patients receiving docetaxel in combination with cisplatin and fluorouracil for inoperable locally advanced squamous cell carcinoma of the head and neck had prolonged median progression-free survival (11 versus 8 months) compared with those receiving cisplatin and fluorouracil.1 At a median follow-up of 51 months, patients receiving the docetaxel-containing regimen also had prolonged median overall survival (19 versus 14 months).1,72

Alopecia (81 versus 43%), grade 3 or 4 neutropenia (76 versus 53%), and grade 3 or 4 leukopenia (42 versus 23%) occurred more frequently in patients receiving docetaxel/cisplatin/fluorouracil.1,72 Thrombocytopenia (47 versus 24%) including grade 3 or 4 thrombocytopenia (18 versus 5%), vomiting (39 versus 26%), toxic death (6 versus 2%), and hearing loss (3 versus 0%) occurred more frequently in patients receiving cisplatin/fluorouracil.1,72 The most frequent adverse effects in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer followed by radiotherapy were neutropenia (93%) including grade 3 or 4 neutropenia (76%), anemia (89%), alopecia (81%), nausea (47%), stomatitis (42%), and lethargy (41%).1

In the second randomized trial (TAX324), a multicenter, open-label study, 501 patients with locally advanced squamous cell carcinoma of the head and neck who had unresectable disease or disease with low chance of surgical cure, or who were candidates for organ preservation received induction chemotherapy with either docetaxel/cisplatin/fluorouracil or cisplatin/fluorouracil.1,73 All patients had a WHO performance status of 0 or 1.1,73 The median age of patients in the study was 55-56 years.73

Treatment regimens consisted of docetaxel 75 mg/m²as a 1-hour IV infusion on day 1, followed by cisplatin 100 mg/m² as a 30-minute to 3-hour IV infusion on day 1, followed by fluorouracil 1000 mg/m² daily as a continuous IV infusion on days 1-4 (the TPF regimen); or cisplatin 100 mg/m² as a 30-minute to 3-hour IV infusion on day 1, followed by fluorouracil 1000 mg/m² daily as a continuous IV infusion on days 1-5 (the PF regimen).1,73 Each regimen was administered every 3 weeks for up to 3 cycles.1,73 At 3-8 weeks following the start of the last cycle of induction chemotherapy, patients with disease that did not progress received 7 weeks of chemoradiotherapy.1,73 Radiotherapy was administered with megavoltage equipment as once daily fractionation (2 Gy daily for 5 days per week for 7 weeks for a total dose of 70-72 Gy).1 During radiotherapy, carboplatin (at the dose required to obtain an AUC of 1.5 mg/mL per minute) was administered once weekly as a 1-hour IV infusion for up to 7 doses.1,73 Surgical resection was allowed at any time following the completion of chemoradiotherapy.1,73

Patients receiving docetaxel/cisplatin/fluorouracil had prolonged overall survival (71 versus 30 months, hazard ratio for death: 0.70) compared with those receiving cisplatin/fluorouracil as induction chemotherapy for locally advanced squamous cell carcinoma of the head and neck.1,73

Neutropenia of grade 3 or 4 in severity (84 versus 56%) and alopecia (68 versus 44%) occurred more frequently in patients receiving docetaxel/cisplatin/fluorouracil.1 Constipation (38 versus 27%) was more frequent in patients receiving cisplatin/fluorouracil.1 The most frequent adverse effects in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer followed by chemoradiotherapy were neutropenia (95%) including grade 3 or 4 neutropenia (84%), anemia (90%), nausea (76%), alopecia (68%), stomatitis (66%), lethargy (61%), vomiting (56%), diarrhea (48%), and anorexia (40%).1

Ovarian Cancer

Docetaxel in combination with carboplatin is used an as alternative regimen for the first-line treatment of ovarian epithelial cancer†.54,82

In a randomized trial involving 1077 patients with stage Ic-IV ovarian epithelial cancer, patients received either docetaxel/carboplatin or paclitaxel/carboplatin.83 Treatment regimens consisted of docetaxel 75 mg/m² as a 1-hour IV infusion followed by carboplatin (at the dose required to obtain an AUC of 5 mg/mL per minute) as a 1-hour IV infusion; or paclitaxel 175 mg/m² as a 3-hour IV infusion followed by carboplatin (at the dose required to obtain an AUC of 5 mg/mL per minute) as a 1-hour IV infusion. The treatment regimens were repeated every 3 weeks for 6 cycles of therapy; patients who responded to combination therapy then could receive an additional 3 cycles of carboplatin alone.83 Median progression-free survival was similar (about 15 months) between the groups.83 Grade 3 or 4 neutropenia (94 versus 84%) and complicated neutropenia (25 versus 5%) occurred more frequently in patients receiving docetaxel and carboplatin.83 GI toxicity, peripheral edema, allergic reactions, and nail changes also were more frequent in patients receiving docetaxel and carboplatin.83 Neurotoxicity, including neurosensory toxicity (78 versus 45%) and neuromotor toxicity (16 versus 9%), occurred more frequently in patients receiving paclitaxel and carboplatin.83 Arthralgia, myalgia, alopecia, and abdominal pain also were more frequent in patients receiving paclitaxel and carboplatin.83

Docetaxel also is used for the treatment of recurrent or persistent ovarian epithelial cancer that is platinum-resistant or platinum-refractory†.54,82

Reconstitution and Administration

Docetaxel is administered by IV infusion over a 1-hour period under ambient room temperature and lighting conditions.1,84,85,86 Infusion of the drug over longer periods (e.g., 6 or 24 hours) or the use of frequently repeated infusions (e.g., over 5 days) was associated with clinically important and dose-limiting mucositis in phase 1 studies.37

Caution should be exercised when preparing and handling docetaxel solutions, and the use of protective gloves is recommended.1,84,85,86 Skin accidentally exposed to the drug should be immediately and thoroughly washed with soap and water.1,84,85,86 If the drug comes into contact with mucous membranes, the affected area should be flushed immediately and thoroughly with water.1,84,85,86

Docetaxel is commercially available as an injection concentrate and as a lyophilized powder.1,84,85,86 The lyophilized powder must be reconstituted and then diluted to prepare a final docetaxel infusion solution.85 Docetaxel injection concentrate must be diluted prior to IV administration. 1,84,86 The proper procedure for preparing a final docetaxel infusion solution from an injection concentrate may vary by manufacturer (i.e., some manufacturers' preparations may require one dilution step, whereas other manufacturers' preparations may require 2 dilution steps).1,84,86 Taxotere^® injection concentrate has been reformulated to require one dilution step rather than 2 dilution steps.88 In addition, injection concentrates available from various manufacturers may contain different concentrations of the drug.1,84,86 The manufacturer's instructions for the specific formulation should be consulted to ensure that the correct preparation procedure is followed. 1,84,85,86,87 Formulations requiring 2 dilution steps should not be used with formulations requiring one dilution step.1,86

Because reconstituted and diluted docetaxel solutions are supersaturated, crystallization may occur over time.1,85 Docetaxel injection concentrate and reconstituted and diluted solutions of the drug should be inspected visually for particulate matter and discoloration whenever solution and container permit.1,84,85,86 If the solution is not clear or appears to have precipitation, the solution should be discarded.1,84,85,86

Contact of docetaxel injection concentrate or reconstituted docetaxel solution with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended.1,36,84,85,86 Polysorbate 80 can cause leaching of diethylhexyl phthalate (DEHP) from PVC containers and, following dilution of docetaxel injection concentrate in PVC containers, substantial leaching of DEHP occurs in a time-dependent and concentration-dependent manner.36 To minimize exposure of the patient to leached DEHP, final diluted docetaxel solutions for infusion preferably should be stored in glass or polypropylene containers or in plastic (polypropylene or polyolefin) bags and administered through polyethylene-lined administration sets.1,36,84,85,86

Dilution of Docetaxel Injection Concentrate Requiring One Dilution Step

If the vial containing docetaxel injection concentrate has been stored in the refrigerator, it should be allowed to stand at room temperature for approximately 5 minutes prior to dilution.1 When the docetaxel injection concentrate is a formulation that requires one dilution step, the required amount of docetaxel injection concentrate should be withdrawn from the vial using a syringe with a 21-gauge needle and injected into a 250-mL infusion bag or bottle containing either 0.9% sodium chloride injection or 5% dextrose injection to produce a final solution with a docetaxel concentration of 0.3-0.74 mg/mL.1,84,86 If doses larger than 200 mg of docetaxel are required, the volume of IV solution should be increased accordingly so that the docetaxel concentration does not exceed 0.74 mg/mL.1,84,86 The final diluted docetaxel solution for infusion should be mixed thoroughly by gentle manual rotation.1,84,86

Dilution of Docetaxel Injection Concentrate Requiring Two Dilution Steps

When the docetaxel injection concentrate is a formulation that requires 2 dilution steps, the docetaxel injection concentrate is first diluted with the diluent supplied by the manufacturer (13% w/v polyethylene glycol 400 in water for injection) to prepare the initial diluted docetaxel solution, and then the initial diluted docetaxel solution is further diluted to make the final dilution of docetaxel solution for infusion.86

For preparation of the initial diluted docetaxel solution, the entire contents of the vial of diluent supplied by the manufacturer (approximately 1.95 mL of diluent for docetaxel 20 mg and approximately 7.2 mL of diluent for docetaxel 80 mg) should be added to the appropriate vial of docetaxel injection concentrate to create an initial diluted solution of docetaxel 10 mg/mL.86 The vial should be inverted repeatedly for at least 45 seconds to fully mix the concentrate and the diluent; the vial should not be shaken.86 The initial diluted docetaxel solution should be clear but there may be some foam on top because of the presence of polysorbate 80.86 The solution should be allowed to stand for a few minutes to let the foam dissipate, and then preparation may continue even if some foam remains.86 The initial diluted docetaxel solution may be used immediately to prepare the final diluted docetaxel solution for infusion or it may be stored either in the refrigerator or at room temperature for up to 8 hours.86

For preparation of the final diluted docetaxel solution for infusion, the required amount of the initial diluted docetaxel solution (docetaxel 10 mg/mL) should be injected into a 250-mL infusion bag or bottle containing either 0.9% sodium chloride injection or 5% dextrose injection to produce a final solution with a docetaxel concentration of 0.3-0.74 mg/mL.86 If doses larger than 200 mg of docetaxel are required, the volume of IV solution should be increased accordingly so that the docetaxel concentration does not exceed 0.74 mg/mL.86 The final diluted docetaxel solution for infusion should be mixed thoroughly by manual rotation.86

Reconstitution and Dilution of Docetaxel Lyophilized Powder

Commercially available docetaxel powder for injection must be reconstituted and diluted prior to IV infusion.85 The drug should be reconstituted with the diluent supplied by the manufacturer (ethanol 35.4% w/w and polysorbate 80).85 The appropriate number of diluent vials and vials containing docetaxel lyophilized powder should be removed from the refrigerator and allowed to stand at room temperature for approximately 5 minutes prior to reconstitution.85 The powder is reconstituted by withdrawing 1 mL of diluent using a 1-mL syringe with an 18- or 21-gauge needle and adding the diluent to a vial labeled as containing docetaxel 20 mg to provide a solution containing 20 mg in 0.8 mL or by withdrawing 4 mL of diluent using a 4-mL syringe with an 18- or 21-gauge needle and adding the diluent to a vial labeled as containing docetaxel 80 mg to provide a solution containing 24 mg/mL of the drug.85 The vial should be shaken well to ensure complete dissolution of the drug.85 The resulting solution should be clear but may contain some air bubbles because of the presence of polysorbate 80.85 The solution should be allowed to stand for a few minutes to let the bubbles dissipate.85 The reconstituted docetaxel solution may be used immediately to prepare the final diluted docetaxel solution for infusion or it may be stored either in a refrigerator or at room temperature for up to 8 hours.85

For preparation of the final diluted docetaxel solution for infusion, the required amount of reconstituted docetaxel solution should be injected into a 250-mL infusion bag or bottle containing 0.9% sodium chloride injection or 5% dextrose injection to produce a final solution with a docetaxel concentration of 0.3-0.74 mg/mL.85 If doses larger than 200 mg of docetaxel are required, the volume of IV solution should be increased accordingly so that the docetaxel concentration does not exceed 0.74 mg/mL. 85 The final diluted docetaxel solution for infusion should be mixed thoroughly by manual rotation.85

Dispensing and Administration Precautions

The manufacturer states that formation of particulate matter in docetaxel solutions has not been observed when the drug has been administered at recommended doses; therefore, the use of inline filters with docetaxel infusion solutions is neither required nor recommended.37 Medication errors have occurred that involved confusion between docetaxel (Taxotere^®) and paclitaxel (Taxol^®).62 Two pharmacists should provide independent confirmation that the correct drug is being ordered before chemotherapy is dispensed, and two nurses should confirm that the correct drug has been dispensed for the correct patient before administering the medication.62 (See Cautions: Precautions and Contraindications.)

Dosage

The incidence of mortality associated with docetaxel therapy is higher in patients with hepatic impairment (see Dosage and Administration: Dosage in Renal and Hepatic Impairment) and in patients receiving higher doses of the drug.1

Concomitant use of potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase docetaxel exposure and should be avoided.1,84,85,86 If such concomitant use cannot be avoided, a reduction in docetaxel dosage with careful monitoring for toxicity should be considered.1,84,85,86 Based on limited pharmacokinetic data, the manufacturers state that a 50% reduction in docetaxel dosage may be considered in patients requiring concomitant therapy with a potent CYP3A4 inhibitor; however, there are no clinical data with use of this adjusted docetaxel dosage.1,84,85,86 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Premedication Regimen

All patients should be premedicated with oral corticosteroids before docetaxel administration to reduce the severity of hypersensitivity reactions and to reduce the incidence and severity of fluid retention.1 For patients receiving docetaxel for hormone-refractory metastatic prostate cancer, the manufacturers recommend a regimen of oral dexamethasone 8 mg at 12 hours, 3 hours, and 1 hour prior to the infusion of docetaxel.1,84,85,86 For patients receiving docetaxel for other cancers, the manufacturer recommends a regimen of oral dexamethasone 8 mg twice daily for 3 days, starting 1 day prior to docetaxel administration.1

Breast Cancer

The manufacturers state that prophylaxis with granulocyte colony-stimulating factor (G-CSF) may be used to reduce the risk of hematologic toxicity associated with docetaxel therapy.1,84,86 Some clinicians recommend primary prophylaxis with G-CSF in patients receiving docetaxel with an anthracycline agent for breast cancer.76,77,78

Adjuvant Therapy for Breast Cancer

For the adjuvant treatment of operable node-positive breast cancer, the recommended dosage is docetaxel 75 mg/m² as a 1-hour IV infusion administered 1 hour following doxorubicin 50 mg/m² IV and cyclophosphamide 500 mg/m² IV; this regimen is administered once every 3 weeks for up to 6 courses of therapy.1,84,86

Advanced Breast Cancer

Optimum dosage of docetaxel for the treatment of advanced or metastatic breast cancer has not been established.1 The manufacturers currently recommend a docetaxel regimen of 60-100 mg/m² infused IV over 1 hour and repeated every 3 weeks as tolerated in patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.1,84,85,86

Among patients who are dosed initially at docetaxel 60 mg/m² and who do not experience severe adverse effects (e.g., febrile neutropenia, severe neutropenia for more than 1 week, severe or cumulative cutaneous reactions, or severe peripheral neuropathy), higher doses of docetaxel may be tolerated.1

In phase 2 studies, patients received a median of 4 or 5 cycles of docetaxel therapy; however, the usual course of therapy remains to be established.14,15,16,17,18,19

Non-small Cell Lung Cancer

First-line Therapy for Advanced Disease

For the first-line treatment of unresectable, locally advanced or metastatic non-small cell lung cancer, the recommended dosage is docetaxel 75 mg/m² administered as a 1-hour IV infusion followed by cisplatin 75 mg/m² IV administered over 30-60 minutes; this regimen is administered once every 3 weeks.1,84,85,86

Second-line Therapy for Advanced Disease

When used as monotherapy for the second-line treatment of non-small cell lung cancer, docetaxel 75 mg/m² IV is administered as a 1-hour infusion once every 3 weeks; higher doses of docetaxel are associated with excessive toxicity in this patient population, including increased rates of hematologic toxicity, infection, and treatment-related mortality, and are not recommended.1,59,60,84,85,86

Prostate Cancer

For the treatment of hormone-refractory metastatic prostate cancer, the recommended dosage is docetaxel 75 mg/m² administered as a 1-hour IV infusion once every 3 weeks.1,84,85,86 Prednisone 5 mg orally twice daily is administered continually.1,84,85,86

Gastric Cancer

Premedication with antiemetic agents and adequate hydration for cisplatin administration are required.1 Primary prophylaxis with G-CSF should be considered.71

For the first-line treatment of gastric adenocarcinoma, the recommended dosage is docetaxel 75 mg/m² as a 1-hour IV infusion on day 1 followed by cisplatin 75 mg/m² as a 1-hour to 3-hour IV infusion on day 1 followed by fluorouracil 750 mg/m² as a 24-hour continuous IV infusion daily for 5 days (days 1-5) initiated upon completion of the cisplatin infusion; this regimen is repeated every 3 weeks.1,84,86

Head and Neck Cancer

Premedication with antiemetic agents and adequate hydration preceding and following cisplatin administration are required.1 Prophylaxis for neutropenic infections also should be administered.1 In the randomized trials, all patients receiving the docetaxel-containing regimen were given prophylactic antibiotic therapy.1

Induction Chemotherapy Followed by Radiotherapy

For induction chemotherapy of inoperable locally advanced squamous cell carcinoma of the head and neck, the recommended dosage is docetaxel 75 mg/m² as a 1-hour IV infusion (day 1) followed by cisplatin 75 mg/m² as a 1-hour IV infusion (day 1) followed by fluorouracil 750 mg/m² as a 24-hour continuous IV infusion daily for 5 days (days 1-5) initiated upon completion of the cisplatin infusion; this regimen is administered once every 3 weeks for up to 4 cycles.1,84,86 Following the completion of chemotherapy, patients should receive radiotherapy.1,84,86

Induction Chemotherapy Followed by Chemoradiotherapy

For induction chemotherapy of locally advanced squamous cell carcinoma of the head and neck in patients who have unresectable disease or disease with low chance of surgical cure, or who are candidates for organ preservation, the recommended dosage is docetaxel 75 mg/m² as a 1-hour IV infusion (day 1) followed by cisplatin 100 mg/m² as a 30-minute to 3-hour IV infusion (day 1) followed by fluorouracil 1000 mg/m² as a 24-hour continuous IV infusion daily for 4 days (days 1-4); this regimen is administered once every 3 weeks for up to 3 cycles.1,84,86 Following the completion of chemotherapy, patients should receive chemoradiotherapy.1,84,86

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Adjustment of docetaxel dosage may be required according to toxicity.1 When docetaxel is used in combination regimens, adjustment of dosage for the other drugs may be necessary.1 In addition to the dosage adjustments for cisplatin and fluorouracil described here, also see the manufacturers' labelings.1

Hematologic Toxicity

For patients who experience neutropenia and/or thrombocytopenia, docetaxel doses should be withheld until neutrophil counts are at least 1500/mm³ and platelet counts exceed 100,000/mm³.1

For patients who have experienced severe neutropenia (neutrophil count less than 500/mm³) for at least 7 days, febrile neutropenia, or a grade 4 infection during a cycle of therapy, a 25% reduction in the dose of docetaxel is recommended for subsequent cycles.1

Among patients receiving docetaxel monotherapy for breast cancer who are dosed initially at 100 mg/m² and who experience either febrile neutropenia or severe neutropenia (neutrophil count less than 500/mm³) for more than 1 week, the manufacturer recommends a 25% reduction in the dose (from 100 to 75 mg/m²) for subsequent courses of therapy.1,37 If the patient continues to experience these reactions, either the dose of docetaxel should be reduced further to 55 mg/m² or the drug should be discontinued.1

Among patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer who are dosed initially at 75 mg/m², those who experience febrile neutropenia should receive G-CSF for all subsequent cycles of therapy.1,68 If febrile neutropenia persists, G-CSF should be continued and the docetaxel dose should be reduced to 60 mg/m².1

Among patients receiving docetaxel monotherapy for advanced non-small cell lung cancer who are dosed initially at 75 mg/m² and who experience severe neutropenia (neutrophil count less than 500/mm³) for more than 1 week or febrile neutropenia, treatment with the drug should be interrupted.1 Upon resolution of the toxicity, therapy may be resumed at a reduced dose of docetaxel 55 mg/m².1

Among patients receiving docetaxel in combination with cisplatin for advanced non-small cell lung cancer who are dosed initially at 75 mg/m² and who experience a nadir platelet count of less than 25,000/mm³ during the previous course of therapy or febrile neutropenia, the docetaxel dose should be reduced to 65 mg/m² for subsequent cycles.1 If toxicity persists, further reduction to a docetaxel dose of 50 mg/m² is recommended.1 For recommendations for cisplatin dosage reduction, consult the manufacturer's labeling.1

Among patients receiving docetaxel with prednisone for advanced prostate cancer who have experienced severe neutropenia (less than 500/mm³) for at least 7 days or febrile neutropenia, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1 If these reactions persist at a docetaxel dose of 60 mg/m², treatment should be discontinued.1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for either advanced gastric cancer or locally advanced head and neck cancer who experience neutropenia lasting more than 7 days, febrile neutropenia, or documented infection with neutropenia, the use of G-CSF during the second or subsequent cycles of therapy is recommended.1 If the patient experiences an episode of prolonged neutropenia, febrile neutropenia, or neutropenic infection despite use of G-CSF, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1 If the patient experiences subsequent episodes of complicated neutropenia, the docetaxel dose should be reduced from 60 mg/m² to 45 mg/m².1 If toxicity persists, treatment should be discontinued.1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for either advanced gastric cancer or locally advanced head and neck cancer who experience grade 4 thrombocytopenia, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1 If toxicity persists, treatment should be discontinued.1

Hypersensitivity

If signs or symptoms of a severe reaction (e.g., hypotension requiring treatment, bronchospasm/dyspnea requiring bronchodilators, generalized rash/erythema, anaphylaxis) occur during administration of the drug, the infusion should be discontinued immediately and aggressive symptomatic therapy instituted as necessary.1 Docetaxel therapy should not be reinitiated in patients experiencing severe hypersensitivity reactions.1

Mild manifestations, such as pruritus, flushing, or localized skin reactions, do not require interruption of therapy; however, decreasing the infusion rate until recovery from symptoms may be considered.1,37

Dermatologic Toxicity

Among patients receiving docetaxel monotherapy for breast cancer who are dosed initially at 100 mg/m² and who experience severe or cumulative cutaneous reactions, the manufacturer recommends a 25% reduction in the dose (from 100 mg/m² to 75 mg/m²) for subsequent courses of therapy.1 If the patient continues to experience these reactions, either the docetaxel dose should be reduced further to 55 mg/m² or the drug should be discontinued.1

Among patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer who experience severe or cumulative cutaneous reactions, the docetaxel dose should be reduced from 75 to 60 mg/m².1 If these reactions persist at docetaxel dose 60 mg/m², treatment should be discontinued.1

Among patients receiving docetaxel monotherapy for advanced non-small cell lung cancer who are dosed initially at 75 mg/m² and who experience severe or cumulative cutaneous reactions, treatment with the drug should be interrupted.1 Upon resolution of the toxicity, therapy may be resumed at a reduced dose of docetaxel 55 mg/m².1

Among patients receiving docetaxel with prednisone for advanced prostate cancer who experience severe or cumulative cutaneous reactions, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1 If these reactions persist at a docetaxel dose of 60 mg/m², treatment should be discontinued.1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil who experience palmar-plantar toxicity (hand-foot syndrome) that is grade 2 or higher in severity, fluorouracil should be stopped until recovery and then the fluorouracil dose should be reduced by 20%.1 This dose modification is based on the adjustment used for the advanced gastric cancer study.1

Neurologic Toxicity

Among patients receiving docetaxel monotherapy for advanced breast cancer or advanced non-small cell lung cancer who develop grade 3 or higher peripheral neuropathy, docetaxel therapy should be discontinued.1

Among patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer or docetaxel with prednisone for advanced prostate cancer who experience moderate neurosensory manifestations, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1 If these reactions persist at a docetaxel dose of 60 mg/m², treatment should be discontinued.1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil who experience grade 2 peripheral neuropathy, the cisplatin dose should be reduced by 20%.1 For patients who experience grade 3 peripheral neuropathy, treatment should be discontinued.1 These dose modifications are based on the adjustments used for the advanced gastric cancer study.1

GI Toxicity

Among patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer who experience grade 3 or 4 stomatitis, the docetaxel dose should be reduced from 75 mg/m² to 60 mg/m².1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for either advanced gastric cancer or locally advanced head and neck cancer who experience grade 3 diarrhea, the guidelines for dosage reduction are as follows: after the first episode, the fluorouracil dose should be reduced by 20%; after the second episode, the docetaxel dose should be reduced by 20%.1 For patients who experience grade 4 diarrhea, the guidelines for dosage reduction are as follows: after the first episode, both the docetaxel dose and the fluorouracil dose should be reduced by 20%; after the second episode, treatment should be discontinued.1

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for either advanced gastric cancer or locally advanced head and neck cancer who experience grade 3 stomatitis/mucositis, the guidelines for dosage reduction are as follows: after the first episode, the fluorouracil dose should be reduced by 20%; after the second episode, fluorouracil should be discontinued for all subsequent cycles; after the third episode, the docetaxel dose should be reduced by 20%.1 For patients who experience grade 4 stomatitis/mucositis, the guidelines for dosage reduction are as follows: after the first episode, fluorouracil should be discontinued for all subsequent cycles; after the second episode, the docetaxel dose should be reduced by 20%.1

Hepatic Toxicity

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for advanced gastric cancer who exhibit increases in serum AST and/or ALT exceeding 2.5 times the upper limit of normal (up to 5 times the upper limit of normal) and alkaline phosphatase up to 2.5 times the upper limit of normal, the docetaxel dose should be reduced by 20%.1,89 For patients with serum AST and/or ALT exceeding 1.5 times the upper limit of normal (up to 5 times the upper limit of normal) and alkaline phosphatase exceeding 2.5 times the upper limit of normal (up to 5 times the upper limit of normal), the docetaxel dose should be reduced by 20%.1,89 For patients with serum AST and/or ALT exceeding 5 times the upper limit of normal and/or alkaline phosphatase exceeding 5 times the upper limit of normal, docetaxel should be discontinued.1,89

Nephrotoxicity

Among patients receiving docetaxel in combination with cisplatin and fluorouracil who experience a rise in serum creatinine concentration that is grade 2 or higher in severity (greater than 1.5 times the normal value) despite adequate hydration, the creatinine clearance should be determined before each subsequent cycle of therapy and the following dose reductions should be considered.1 These dose modifications are based on the adjustments used for the advanced gastric cancer study.1

For patients with a creatinine clearance of 60 mL/minute or higher, the full dose of cisplatin may be given for the subsequent cycle, and the creatinine clearance should be measured prior to each treatment cycle.1

For patients with a creatinine clearance of 40-59 mL/minute, the cisplatin dose should be reduced by 50% for the subsequent cycle.1 If the creatinine clearance exceeds 60 mL/minute at the end of the cycle using the 50% cisplatin dose, the full cisplatin dose may be given for the next cycle.1 If recovery does not occur at the end of the cycle using the 50% cisplatin dose, cisplatin should be omitted from the next treatment cycle.1

For patients with a creatinine clearance less than 40 mL/minute, the cisplatin dose should be omitted for that treatment cycle only.1 If the creatinine clearance remains low (less than 40 mL/minute) at the end of the treatment cycle omitting the cisplatin dose, cisplatin should be discontinued.1 If the creatinine clearance exceeds 40 mL/minute but is less than 60 mL/minute at the end of the treatment cycle omitting the cisplatin dose, a 50% cisplatin dose may be given for the next cycle.1 If the creatinine clearance exceeds 60 mL/minute at the end of the treatment cycle using the 50% cisplatin dose, the full cisplatin dose may be given for the next cycle.1

Ototoxicity

Among patients receiving docetaxel in combination with cisplatin and fluorouracil who experience grade 3 ototoxicity, treatment should be discontinued.1 This dose modification is based on the adjustment used for the advanced gastric cancer study.1

Ocular Toxicity

If cystoid macular edema is diagnosed, docetaxel therapy should be discontinued and appropriate treatment initiated.1 Alternative therapy with a nontaxane antineoplastic agent should be considered.1

Other Toxicity

For patients receiving docetaxel alone or in combination with cisplatin for advanced non-small cell lung cancer who experience grade 3 or 4 nonhematologic toxicities, the same recommendations for reduction of the docetaxel dose should be followed as for patients experiencing hematologic toxicities.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

Among patients receiving docetaxel in combination with cisplatin and fluorouracil who experience toxicity (except alopecia and anemia) that is higher than grade 3 in severity, chemotherapy should be delayed for up to 2 weeks from the planned date of infusion until resolution of the toxicity to grade 1 or less in severity occurs and then resumption of chemotherapy may be considered.1 These dose modifications are based on the adjustments used for the advanced gastric cancer study.1

Dosage in Renal and Hepatic Impairment

Urinary excretion of docetaxel has been reported to be low (less than 10%),2,3,6,7 and reduction of dosage in patients with impaired renal function does not appear to be necessary.37

Docetaxel clearance appears to be reduced in patients with abnormal liver function, and an increased incidence of adverse effects (including treatment-related mortality) has been reported in patients with moderate to severe hepatic impairment.1 Therefore, patients with serum total bilirubin exceeding the upper limit of normal, and patients with serum AST and/or ALT exceeding 1.5 times the upper limit of normal concomitant with alkaline phosphatase exceeding 2.5 times the upper limit of normal, generally should not receive docetaxel.1,8,37,38

For further information on the handling of antineoplastic agents, see the guidelines at the end of Antineoplastic Agents 10:00.

The principal, dose-limiting adverse effect of docetaxel is bone marrow suppression, manifested by neutropenia, leukopenia, thrombocytopenia, and anemia.1

The incidence of treatment-related adverse effects associated with docetaxel therapy is increased in patients with abnormal liver function and in those receiving higher doses.1 (See Cautions: Precautions and Contraindications.) The incidence of adverse effects reported here is based principally upon data from 2045 patients with normal liver function receiving docetaxel 100 mg/m² for various solid tumors, including a subset of 965 patients with locally advanced or metastatic breast cancer and a subset of 61 patients with various tumor types and hepatic dysfunction manifested by elevated results of liver function tests.1 The incidence of selected adverse effects is reported for differing dose levels (e.g., 60 mg/m² in 174 patients with metastatic breast cancer), combination regimens, and/or patient populations receiving docetaxel for specific cancers when the rates or types of adverse effects differed substantially from the patterns of toxicity reported for the 2045 patients with various solid tumors.1 This information may include selected adverse effects for patients receiving docetaxel every 3 weeks as follows: at doses of 60, 75, and 100 mg/m² for advanced breast cancer; or at a dose of 75 mg/m² as adjuvant therapy for breast cancer (with doxorubicin and cyclophosphamide), as second-line therapy for advanced non-small cell lung cancer, as first-line therapy for advanced non-small cell lung cancer (with cisplatin), for androgen-independent (hormone-refractory) metastatic prostate cancer (with prednisone), as first-line therapy for advanced gastric cancer (with cisplatin and fluorouracil), and as induction chemotherapy for advanced head and neck cancer (with cisplatin and fluorouracil).1 Additional incidence data for adverse effects and information on the comparative toxicity of chemotherapy regimens evaluated in clinical trials is discussed in the corresponding Uses section for each cancer.1 In general, the safety profile of docetaxel in patients being treated for breast cancer or other types of solid tumors is similar.1 The most common adverse effects of docetaxel across all labeled indications for the drug are infection, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia.1

Death possibly or probably related to treatment occurred in 2% of patients with normal hepatic function receiving docetaxel 100 mg/m² for metastatic breast cancer and in 11.5% of patients receiving docetaxel 100 mg/m² for various tumor types who had hepatic dysfunction.1 Among patients receiving docetaxel 60 mg/m² for breast cancer, treatment-related mortality occurred in about 1% of patients with normal liver function and in 3 of 7 patients with hepatic dysfunction.1 Approximately half of these deaths occurred during the first treatment cycle, and sepsis accounted for a majority of the deaths.1

Hematologic Effects and Infectious Complications

The frequency and severity of docetaxel-induced hematologic toxicity, febrile reactions and infections, and rates of death caused by sepsis increase with dose and in the presence of hepatic dysfunction.1,7,22 As with paclitaxel, docetaxel-induced myelosuppression may be more severe in patients who have received prior radiation therapy.30

Docetaxel-induced neutropenia generally is reversible.1,7,13,23 Neutropenia secondary to docetaxel, in contrast to that caused by paclitaxel, is not schedule-dependent.24 Neutropenia (neutrophil count less than 2000/mm³) occurred in almost all patients (96%) receiving docetaxel for solid tumors.1 Severe (grade 4) neutropenia (less than 500/mm³) occurred in 75% of patients with solid tumors and lasted more than 7 days in about 3% of treatment cycles.1 Severe neutropenia occurred at a higher rate among the subsets of patients receiving docetaxel for locally advanced or metastatic breast cancer (86%) or patients with hepatic dysfunction (88%).1 Similarly high rates of neutropenia were reported in patients receiving docetaxel in combination therapy for other cancers except for advanced prostate cancer (41%, grade 3 or 4 in 32%).1

The onset of neutropenia is rapid, with neutrophil nadirs generally occurring 7-8 days following docetaxel administration;1,8,13,14,19,20 the median duration of severe (grade 4) neutropenia is about 7 days.1,5,7,13 Subsequent courses of docetaxel therapy generally do not result in lower neutrophil nadirs than in the initial course, suggesting that the drug may not be irreversibly toxic to stem cells.1,7,13,18

Leukopenia (leukocyte count less than 4000/mm³) occurred in almost all patients (96%) receiving docetaxel for solid tumors.1 Severe leukopenia (less than 1000/mm³) occurred in 32% of patients with solid tumors and at a higher rate among the subsets of patients receiving docetaxel for locally advanced or metastatic breast cancer (44%) or patients with hepatic dysfunction (47%).1

Anemia (hemoglobin less than 11 g/dL) occurred in 90% of patients receiving docetaxel for solid tumors.1 Severe anemia (hemoglobin less than 8 g/dL) occurred in 9% of patients with solid tumors and in 31% of the subset of patients with hepatic dysfunction.1 Similarly high rates of anemia were reported in patients receiving docetaxel in combination therapy for other cancers except advanced prostate cancer (66%).1 A lower rate of anemia was reported in patients receiving docetaxel 60 mg/m² for advanced breast cancer (65%).1 Packed red blood cell transfusions may be required in some patients.13,14

Fever in the absence of infection occurred in 31% of patients receiving docetaxel for solid tumors and in 41% (severe in 8%) of the subset of patients with hepatic dysfunction.1 Fever in the absence of infection was reported in 46% of patients receiving docetaxel with doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer.1

Febrile neutropenia (neutrophil count less than 500/mm³ with fever greater than 38°C and IV anti-infectives and/or hospitalization required) occurred in 11% of patients receiving docetaxel for solid tumors and in 26% of the subset of patients with hepatic dysfunction.1 Patients with isolated elevations of serum aminotransferase concentrations (more than 1.5 times the upper limit of normal) had a higher rate of grade 4 febrile neutropenia but the incidence of toxic death was not increased in these patients.1 Febrile neutropenia (grade 3 or 4 neutropenia with fever greater than 38.1°C) occurred in none of 174 patients receiving docetaxel 60 mg/m² for advanced breast cancer.1 Febrile neutropenia was reported in 25% of patients receiving docetaxel with doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer.1 Among patients receiving docetaxel with cisplatin and fluorouracil for gastric cancer, febrile neutropenia and/or neutropenic infection occurred in 28% of patients who did not receive granulocyte colony-stimulating factor (G-CSF) versus 12% of patients who did receive G-CSF.1

Infection occurred in 22% of patients receiving docetaxel for solid tumors and was severe in 6%.1 The rate of infection (33%) and severe infection (16%) was higher in the subset of patients with hepatic dysfunction.1 Fatal sepsis occurred in about 2% of patients receiving docetaxel for solid tumors and in 5% of the subset of patients with hepatic dysfunction.1 Higher rates of infection were reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (39%), for advanced non-small cell lung cancer (35%), for advanced prostate cancer (32%), and for advanced gastric cancer (29%, grade 3 or 4 in 16%).1 Neutropenic infection was reported in patients receiving docetaxel in combination regimens for gastric cancer (16%), head and neck cancer (14 or 12%), and adjuvant treatment of breast cancer (12%).1 Infection occurred in 1% of patients receiving docetaxel 60 mg/m² for advanced breast cancer.1

Thrombocytopenia (platelet count less than 100,000/mm³) occurred in 8% of patients receiving docetaxel for solid tumors and in 25% of the subset of patients with hepatic dysfunction.1 A higher rate of thrombocytopenia (44%), including grade 4 thrombocytopenia (17%), was reported in 18 patients with hepatic dysfunction receiving docetaxel 100 mg/m² for metastatic breast cancer.1 Higher rates of thrombocytopenia also were reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (39%), for advanced gastric cancer (26%), for locally advanced head and neck cancer (24 or 28%), and for advanced non-small cell lung cancer (15%).1

Bleeding episodes have occurred in patients receiving docetaxel in clinical trials, including 3 breast cancer patients with severe liver impairment (serum total bilirubin value exceeding 1.7 times the upper limit of normal) who developed fatal GI hemorrhage associated with severe docetaxel-induced thrombocytopenia.1 GI bleeding also was reported in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer (approximately 5%).1 Epistaxis occurred in 6% of patients receiving docetaxel and prednisone for advanced prostate cancer.1 Disseminated intravascular coagulation, often associated with sepsis or multiorgan failure, has occurred in patients receiving docetaxel.1

Sensitivity Reactions

Docetaxel frequently causes hypersensitivity reactions, which can be severe, and all patients receiving the drug should be premedicated to reduce the severity of these reactions.1 (See Dosage and Administration: Dosage.) Severe hypersensitivity reactions, characterized by generalized rash/erythema, hypotension and/or bronchospasm, or rarely, fatal anaphylaxis, have occurred in patients receiving docetaxel who received the recommended premedication regimen.1 Discontinuance of therapy and aggressive management is required in patients experiencing severe hypersensitivity reactions associated with docetaxel.1 (See Hypersensitivity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

Hypersensitivity reactions occurred in 21% of patients receiving docetaxel for solid tumors and were severe in 4%; in the subset of 92 patients receiving the 3-day premedication regimen, hypersensitivity reactions occurred in 15% and were severe in 2%.1 In the subset of patients with hepatic dysfunction, severe hypersensitivity reactions occurred in 10%.1 Hypersensitivity reactions or allergic reactions were reported in patients receiving docetaxel in combination therapy for adjuvant treatment of breast cancer (13%), for advanced non-small cell lung cancer (12%), for advanced gastric cancer (10%), and for advanced prostate cancer (8%) and in patients receiving docetaxel alone for non-small cell lung cancer (6%).1 Allergy (6 or 2%) was reported in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer.1 A lower rate of hypersensitivity reactions (about 1%, none severe) was reported in patients receiving docetaxel 60 mg/m² for advanced breast cancer.1

Docetaxel-induced hypersensitivity reactions almost always occur with the first or second cycle of therapy,1,5,8,9 usually within a few minutes following initiation of docetaxel infusion.1,9,25 In clinical trials, mild reactions (e.g., flushing, localized skin reactions) generally did not require interruption of docetaxel administration or prevent completion of treatment with the drug.1,13,15,18,19,20,23 Some mild adverse effects, such as flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, resolved after completion of the infusion and appropriate therapy.1

The exact cause of hypersensitivity reactions associated with docetaxel therapy is not known, but they may result from the polysorbate 80 in commercially available docetaxel injection concentrate and/or from docetaxel itself.26 Both docetaxel and paclitaxel can cause hypersensitivity reactions, despite the fact that the vehicles used for formulation are different; the Cremophor^® EL in paclitaxel concentrate for injection has been suggested as a possible cause of hypersensitivity reactions with paclitaxel therapy.11

Nervous System Effects

Because of the alcohol content of parenteral formulations of docetaxel, alcohol intoxication has been reported during postmarketing experience in patients receiving the drug.1,90,91 After a review of the Adverse Event Reporting System (AERS) database and case reports, the US Food and Drug Administration (FDA) identified 3 cases of alcohol intoxication following administration of docetaxel.90,91 In these cases, onset of alcohol intoxication occurred during administration or within 24 hours of administration of the drug.90 Symptoms of alcohol intoxication were transient in one patient.90 In another patient, symptoms subsided and the infusion was completed at a slower infusion rate.90

Adverse neurosensory effects occurred in 49% of patients receiving docetaxel for solid tumors and were severe in 4%.1 The rate of adverse neurosensory effects was 58% in the subset of patients receiving docetaxel for locally advanced or metastatic breast cancer and 20% in patients receiving docetaxel 60 mg/m² for advanced breast cancer.1 Severe neurosensory effects (i.e., paresthesia, dysesthesia, pain) were reported in 5.5% of patients receiving docetaxel for metastatic breast cancer in clinical trials and required treatment discontinuance in 6.1% of these patients.1 Adverse neurosensory effects were reported in patients receiving docetaxel in combination therapy for advanced non-small cell lung cancer (47%), advanced gastric cancer (38%), and locally advanced head and neck cancer (18 or 14%) and in patients receiving docetaxel alone for advanced non-small cell lung cancer (23%).1 Sensory neuropathy was reported in patients receiving docetaxel in combination therapy for advanced prostate cancer (30%) and the adjuvant treatment of breast cancer (26%).1

Docetaxel can cause a predominantly sensory neuropathy similar to that reported with paclitaxel administration.1,27 The neuropathy usually is characterized by paresthesia or dysesthesia with numbness and tingling in a stocking-and-glove distribution.1,13,20,29 Some patients also have experienced pain (including burning sensation) in the hands and/or feet.1,28

The frequency and severity of docetaxel-induced neurotoxicity increase with cumulative dose, especially at cumulative doses exceeding 400-600 mg/m².27,28,29 Sensory manifestations usually improve or resolve following discontinuance of docetaxel, with most patients experiencing improvement within 9 weeks from onset (range: 0-106 weeks);1 however, neuropathy may continue to worsen after stopping docetaxel in some patients.28,29

Neuromotor toxicity also has been reported with docetaxel.1,27,28,29 Motor involvement is less frequent than sensory involvement and is usually only seen in patients who experience relatively severe neuropathy secondary to docetaxel therapy.27,29 Neuromotor toxicity has been manifested principally as both proximal and distal muscle weakness in the extremities, predominantly in the legs.1,29 Neuromotor toxicity was reported in patients receiving docetaxel in combination therapy for advanced non-small cell lung cancer (19%), advanced gastric cancer (9%), advanced prostate cancer (7%), and locally advanced head and neck cancer (2 or 9%) and in patients receiving docetaxel alone for advanced non-small cell lung cancer (16%).1 Severe peripheral neuromotor toxicity, consisting principally of distal extremity weakness, was reported in about 4% of patients receiving docetaxel for breast cancer in clinical trials.1 Although docetaxel-induced neuropathy has been reported in some patients with prior cisplatin therapy,28,29 no apparent relationship between docetaxel-induced neuropathy and prior treatment with cisplatin has been observed,28 and prior neurotoxic therapy may not necessarily predispose patients to docetaxel neuropathy.29 Neurocortical (5%), neuromotor (4%), and neurocerebellar (2%) toxicity were reported in patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer.1

Asthenia occurred in 62% of patients receiving docetaxel for solid tumors and was severe in 13%.1 Severe asthenia occurred in 25% of the subset of patients with hepatic dysfunction.1 Severe asthenia was reported in about 15% of patients with metastatic breast cancer treated with docetaxel in clinical trials and required discontinuance of the drug in approximately 2% of patients.1 Higher rates of asthenia were reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (81%) and for advanced non-small cell lung cancer (74%).1 Symptoms of fatigue and weakness may persist for a few days to several weeks and may be associated with a deterioration in performance status in patients with progressive disease.1 Among patients receiving docetaxel in combination therapy, lethargy was reported in patients with advanced gastric cancer (63%, grade 3 or 4 in 21%) and in patients with locally advanced head and neck cancer (41% in TAX323 and 61% in TAX324), and fatigue was reported in patients with advanced prostate cancer (53%).1

Dizziness occurred in patients receiving docetaxel in combination therapy for advanced gastric cancer (16%) and locally advanced head and neck cancer (2% in TAX323 and 16% in TAX324).1 Confusion has been reported in patients receiving docetaxel.1 Seizures or transient loss of consciousness has been reported rarely in patients receiving docetaxel, sometimes occurring during infusion of the drug.1

Cardiovascular Effects

Hypotension associated with severe hypersensitivity reactions has occurred in patients receiving docetaxel.1 (See Cautions: Sensitivity Reactions.)

Hypotension was reported in about 3% of patients receiving docetaxel for solid tumors in clinical trials, with approximately 1% of such patients requiring treatment.1 In selected phase 1 studies of docetaxel therapy in which continuous Holter monitoring was used, no clinically relevant bradycardia or cardiac rhythm disturbances were observed.3,9,22 However, adverse cardiovascular events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension have been reported rarely in patients receiving the drug.1 A deterioration in left-ventricular ejection fraction (LVEF) by 10% or more associated with a decline to below the institutional lower limit of normal occurred in 8% of patients with metastatic breast cancer receiving docetaxel 100 mg/m².1

Fluid retention, sometimes severe, has occurred in patients receiving docetaxel despite premedication with dexamethasone.1 Fluid retention generally is manifested by peripheral edema and weight gain; less frequently, pleural or pericardial effusion and/or ascites may occur.1,3,8,9,11 During docetaxel therapy, pleural effusion has been reported in patients with non-small cell lung cancer and lymphedema has been reported in patients with breast cancer.1

The exact mechanism by which docetaxel causes fluid retention is unknown; renal, hepatic, cardiac, or endocrinologic abnormalities have not been documented.3,15 However, limited data based on capillary filtration tests with technetium-99m albumin and capillaroscopy suggest that an abnormality in capillary permeability may be the cause of the fluid retention.3 Docetaxel-induced fluid retention usually starts in the lower extremities but may become generalized and appears to be completely (although sometimes slowly) reversible;1,3 a median weight gain of 2 kg has been reported1,3 with resolution of fluid retention after a median of 16 weeks (range: 0-42+ weeks) from the last infusion of docetaxel.1 Peripheral edema can be treated with standard measures (e.g., sodium restriction, diuretics).1

Fluid retention occurred in 47% of patients receiving docetaxel for solid tumors and was severe in 7%; in the subset of 92 patients receiving the 3-day premedication regimen, fluid retention occurred in 64% and was severe in 6.5%.1 In the subset of patients receiving docetaxel for locally advanced or metastatic breast cancer, fluid retention occurred in 60% and was severe in 9%.1 Among patients receiving docetaxel in combination therapy, rates reported for fluid retention were 54% for advanced non-small cell lung cancer, 35% for adjuvant treatment of breast cancer (including peripheral edema in 27% and weight gain in 13%), 15% for advanced gastric cancer (plus edema in 13%), 24% for advanced prostate cancer (including peripheral edema in 18% and weight gain in 7.5%), and 20% (TAX323) or 13% (TAX324) for locally advanced head and neck cancer.1 Fluid retention was reported in 13% of patients receiving docetaxel 60 mg/m² for advanced breast cancer.1

The incidence and severity of fluid retention appear to be related to the cumulative dose of docetaxel, increasing in incidence with cumulative doses of 400 mg/m² or greater.8,9,25 Premedication with oral corticosteroids has been reported to delay the onset and decrease the severity of fluid retention.1,3 In a phase 2 clinical trial of docetaxel as first-line therapy in patients with breast cancer in whom no routine premedication was used, 76% of responding patients discontinued treatment because of fluid retention after a median cumulative dose of 574 mg/m².18 In 92 patients with metastatic breast cancer receiving docetaxel in clinical trials with the recommended 3-day corticosteroid premedication regimen, moderate or severe fluid retention occurred in 27 or 6.5%, respectively; the median cumulative dose associated with the onset of moderate or severe fluid retention was 819 mg/m².1 Severe fluid retention, characterized by poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, and/or pronounced abdominal distention (caused by ascites), may lead to discontinuance of docetaxel therapy.1 Discontinuance of docetaxel therapy secondary to fluid retention was required in about 10% of these patients; median cumulative dose to treatment discontinuance was 1021 mg/m².1

Vasodilatation was reported in 27% of patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer.1 Left ventricular cardiac dysfunction was reported in 10% of patients receiving docetaxel and prednisone for advanced prostate cancer.1 Cardiac dysrhythmias were reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (8%), for advanced gastric cancer (4%), and for locally advanced head and neck cancer (2% in TAX323 and 6% in TAX324).1 Congestive heart failure (CHF) was reported in 2% of patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer in the randomized trial, including fatal CHF in 1 patient.1

Venous thromboembolic events, including superficial and deep-vein thrombosis and pulmonary embolism, were reported in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer (3 or 4%).1 Other adverse cardiovascular effects that have been reported in patients receiving docetaxel include ECG abnormalities, atrial fibrillation, tachycardia, thrombophlebitis, acute pulmonary edema, myocardial ischemia, myocardial infarction, and syncope.1

GI Effects

Fatal GI hemorrhage associated with thrombocytopenia has been reported in patients receiving docetaxel for locally advanced or metastatic breast cancer.1 GI bleeding was reported in 4 or 5% of patients receiving docetaxel in combination therapy for locally advanced head and neck cancer.1 Colitis/enteritis/large intestine perforation was reported in 7 patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer; discontinuance of therapy was required in 5 of these patients.1

Pronounced abdominal distention caused by ascites may be a manifestation of severe fluid retention in patients receiving docetaxel.1 (See Cautions: Cardiovascular Effects.)

Nausea occurred in 39%, diarrhea in 39%, and vomiting in 22% of patients receiving docetaxel for solid tumors; these adverse GI effects generally are mild to moderate in severity in most patients but were severe in 3-5% of patients.1 Higher rates of nausea, typically ranging from 70-80%, were reported in patients receiving docetaxel in combination therapy for other cancers in some randomized trials, such as advanced non-small cell lung cancer, gastric cancer (grade 3 or 4 in 16%), locally advanced head and neck cancer (grade 3 or 4 in 14% in TAX324), and breast cancer (adjuvant treatment).1 Higher rates of vomiting and diarrhea also have been reported in patients receiving docetaxel in combination therapy, particularly when docetaxel is used in combination with cisplatin.1 Among patients receiving docetaxel with cisplatin and fluorouracil, vomiting occurred in 66% (grade 3 or 4 in 15%) of patients with advanced gastric cancer and 56% of patients with locally advanced head and neck cancer in TAX324.1 Among patients receiving docetaxel with cisplatin and fluorouracil, diarrhea occurred in 78% (grade 3 or 4 in 20%) of patients with advanced gastric cancer and 48% of patients with locally advanced head and neck cancer in TAX324.1 Among patients receiving docetaxel and cisplatin for advanced non-small cell lung cancer, vomiting was reported in 55% and diarrhea in 47% of patients.1 Among patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer, vomiting occurred in 44% and diarrhea in 35% of patients.1

Stomatitis occurred in 42% of patients receiving docetaxel for solid tumors and was severe in 5.5%.1 Stomatitis occurred in 52% of the subset of patients receiving docetaxel for locally advanced or metastatic breast cancer, and severe stomatitis was more frequent (13%) in the subset of patients with hepatic dysfunction.1 Stomatitis was reported at various rates in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (69%), for locally advanced head and neck cancer (42% in TAX323; 66% in TAX324, grade 3 or 4 in 21%), and for advanced gastric cancer (59%, grade 3 or 4 in 21%).1 Similar rates of stomatitis were reported in patients receiving docetaxel for advanced non-small cell lung cancer as monotherapy (26%) or in combination therapy (24%).1 Stomatitis/pharyngitis was reported in 20% of patients receiving docetaxel and prednisone for advanced prostate cancer.1 Lower rates of stomatitis (19%) and severe stomatitis (about 1%) were reported in patients receiving docetaxel 60 mg/m² for advanced breast cancer.1

Docetaxel-induced stomatitis (mucositis),1 is characterized by diffuse ulceration of the lips, tongue, and oral cavity.8 Mucositis reportedly is schedule-dependent and was observed more commonly in patients receiving longer infusions of docetaxel;9,11 radiation-recall mucositis also has been reported with docetaxel therapy.30

Anorexia was reported in patients receiving docetaxel in combination therapy for gastric cancer (51%, grade 3 or 4 in 13%), advanced non-small cell lung cancer (42%), adjuvant treatment of breast cancer (22%), advanced prostate cancer (17%), and locally advanced head and neck cancer (16% in TAX323 and 40% in TAX324).1 Constipation was reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (34%), for advanced gastric cancer (25%), and for locally advanced head and neck cancer (17% in TAX323 and 27% in TAX324).1 Taste perversion/disturbance was reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (28%) and advanced prostate cancer (18%) and in patients receiving docetaxel alone for non-small cell lung cancer (6%).1 Altered taste or sense of smell was reported in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer (10% in TAX323 and 20% in TAX324).1 Esophagitis/dysphagia/odynophagia was reported in patients receiving docetaxel in combination therapy for advanced gastric cancer (16%) and locally advanced head and neck cancer (13% in TAX323 and 25% in TAX324).1 Also reported in patients receiving docetaxel in combination therapy were abdominal pain (11% of patients receiving adjuvant treatment for breast cancer), GI pain/cramping (11% of patients with advanced gastric cancer; 8% of patients in TAX323 and 15% of patients in TAX324 for locally advanced head and neck cancer), and heartburn (6% of patients in TAX323 and 13% of patients in TAX324 for locally advanced head and neck cancer).1

Other adverse GI effects reported in patients receiving docetaxel include duodenal ulcer, ischemic colitis, intestinal obstruction, ileus, and dehydration caused by adverse GI events.1 In addition, at least one case of typhlitis (neutropenic enterocolitis)1,39 and fatal sepsis secondary to Clostridium septicum has been reported with docetaxel.39

Dermatologic Effects

Alopecia occurred in 76% of patients receiving docetaxel for solid tumors and at similar rates in patients receiving the drug in combination regimens for other cancers.1 Alopecia occurred in almost all patients (98%) receiving docetaxel with doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer.1 A lower rate of alopecia was reported in patients receiving docetaxel alone for advanced non-small cell lung cancer (56%).1

Alopecia has a sudden onset and occurs 14-21 days after administration of docetaxel.7 Patients often experience loss of all body hair, including axillary and pubic hair and that on the extremities, eyelashes, and eyebrows.7,14 Alopecia is dose-related and generally occurs at docetaxel doses exceeding 55 mg/m².3,7 Docetaxel-induced alopecia is fully reversible after treatment discontinuance.9,25 Limited data suggest that the use of a cold cap during docetaxel infusion may lessen the incidence and severity of alopecia.32

Adverse cutaneous reactions occurred in 48% of patients receiving docetaxel for solid tumors and were severe in 5%.1 In the subset of patients receiving docetaxel for locally advanced or metastatic breast cancer, 1.6% of patients discontinued therapy because of skin toxicity.1 A lower rate of cutaneous toxicity (30.5%) was reported in patients receiving docetaxel 60 mg/m² for advanced breast cancer.1 Skin toxicity was reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (26%) and for advanced non-small cell lung cancer (16%) and in patients receiving docetaxel alone for advanced non-small cell lung cancer (20%).1 Also reported in patients receiving docetaxel in combination therapy were rash/itch (12% of patients with advanced gastric cancer; 12% of patients in TAX323 and 20% of patients in TAX324 for locally advanced head and neck cancer), rash/desquamation (6% of patients with advanced prostate cancer), dry skin (6 or 5% of patients with locally advanced head and neck cancer), and desquamation (4 or 2% of patients with locally advanced head and neck cancer; 2% of patients with advanced gastric cancer).1

Generalized rash/erythema associated with severe hypersensitivity reactions have occurred in patients receiving docetaxel.1 (See Cautions: Sensitivity Reactions.) As with paclitaxel, transient skin changes have been observed in patients experiencing hypersensitivity reactions to docetaxel.1 In addition, cutaneous reactions, which occasionally are severe, appear to occur more frequently with docetaxel than with paclitaxel therapy.5,7,9 Reversible cutaneous reactions,1,5,7,9 characterized by rash, including localized eruptions (usually on the feet and/or hands, and less commonly on the arms, face, or trunk) usually associated with pruritus, occur frequently1 in patients receiving docetaxel. Such eruptions generally occurred within 1 week after docetaxel administration, resolved before the next infusion, and were not disabling.1 Severe cutaneous toxicity, such as localized erythema and edema of the extremities followed by desquamation, has been observed in patients receiving docetaxel.1

Other skin reactions such as macular erythema have been observed at sites of previous tissue injury in patients receiving docetaxel.3,4,14 Cutaneous reactions are dose-dependent and cumulative and rarely have been seen at doses less than 85 mg/m².7 A syndrome of erythrodysesthesia, characterized by a painful, tender, erythematous eruption, frequently followed by tingling and decreased sensation, has been reported with docetaxel therapy.31 In addition, there have been reports of scleroderma-like changes, usually preceded by peripheral lymphedema and affecting the lower extremities, associated with docetaxel therapy.1,33

In cases of severe skin toxicity, the dosage of docetaxel should be reduced or therapy with the drug should be discontinued.1 (See Dermatologic Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

Treatment of docetaxel-induced cutaneous reactions, when necessary, generally has been symptomatic.31 Cutaneous reactions in some patients have been successfully treated with an ointment consisting of glycerin and chlorhexidine.3,7,25 Topical corticosteroids and cool compresses also have been used, especially in patients with erythrodysesthesia.31 A decreased incidence and severity of cutaneous reactions to docetaxel with recommended corticosteroid premedication has been reported by some clinicians,14 while others have found no benefit.13,34 A severe case of erythrodysesthesia that occurred despite pretreatment with corticosteroids and failed to respond to oral pyridoxine treatment reportedly was treated successfully with localized hypothermia during docetaxel infusion.34

Nail changes occurred in 31% of patients receiving docetaxel for solid tumors and were severe in 2.5%.1 Severe nail disorders were characterized by hypopigmentation or hyperpigmentation and, occasionally, onycholysis and pain; onycholysis occurred in about 1% of patients receiving docetaxel for solid tumors.1 Nail disorders were reported in patients receiving docetaxel in combination therapy for advanced prostate cancer (30%), adjuvant treatment of breast cancer (18%), advanced non-small cell lung cancer (14%), and advanced gastric cancer (8%) and in patients receiving docetaxel alone for advanced non-small cell lung cancer (11%).1 Thinning and ridging of the nail plates as well as subungual erythema and subungual hemorrhage also have been reported in patients receiving docetaxel.8 Nail toxicity appears to be related to the cumulative dose of docetaxel.11

Cutaneous lupus erythematosus and bullous eruptions, such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have occurred rarely in patients receiving docetaxel.1

Musculoskeletal Effects

Musculoskeletal effects, including arthralgia and/or myalgia, have been reported with docetaxel therapy but appear to be less common than with paclitaxel.9,11 Myalgia occurred in 19% of patients receiving docetaxel for solid tumors and was severe in 1.5%; arthralgia occurred in 9%.1 A similar rate of myalgia was reported in patients receiving docetaxel in combination therapy for advanced non-small cell lung cancer.1 Myalgia was reported in 27% and arthralgia in 19% of patients receiving docetaxel with doxorubicin and cyclophosphamide for the adjuvant treatment of breast cancer.1 Lower rates of adverse musculoskeletal effects were reported in patients receiving docetaxel in combination therapy for locally advanced head and neck cancer (myalgia in 10 or 7%), patients receiving docetaxel alone for advanced non-small cell lung cancer (myalgia in 6%, arthralgia in 3%), and patients receiving docetaxel 60 mg/m² for advanced breast cancer (myalgia in 3%).1 Musculoskeletal manifestations usually are mild and transient, occurring within a few days after docetaxel administration and lasting about 4 days,8 and have been reported to respond to mild analgesics (e.g., acetaminophen) when needed.8,9

Hepatic Effects

Hepatitis, sometimes fatal, has been reported rarely in patients receiving docetaxel.1 Fatal hepatitis occurred mainly in patients with pre-existing liver disorders.1 Abnormalities in liver function test results have occurred in patients receiving docetaxel.1 In clinical trials in the US and Europe in patients with normal liver function test results at baseline, serum total bilirubin values exceeding the upper limit of normal occurred in 8.9% of patients.1 Increases in serum AST (SGOT) or ALT (SGPT) values to greater than 1.5 times the upper limit of normal were observed in 18.9% of patients, and serum alkaline phosphatase concentrations exceeding 2.5 times normal were observed in 7.3% of patients.1 In clinical trials, increases in AST or ALT to greater than 1.5 times the upper limit of normal concomitant with increases in serum alkaline phosphatase to greater than 2.5 times the normal value were reported in 4.3% of patients with normal liver function test results at baseline.1

Respiratory Effects

Bronchospasm associated with severe hypersensitivity reactions has occurred in patients receiving docetaxel.1 (See Cautions: Sensitivity Reactions.) Pleural effusion requiring urgent drainage or dyspnea at rest may be manifestations of severe fluid retention in patients receiving docetaxel.1 (See Cautions: Cardiovascular Effects.)

Adverse pulmonary effects occurred in patients receiving docetaxel (41%), best supportive care (49%), or either vinorelbine or ifosfamide (45%) for advanced non-small cell lung cancer in randomized trials.1 Dyspnea was reported in 15% of patients receiving docetaxel and prednisone for advanced prostate cancer.1

Other adverse pulmonary effects reported in patients receiving docetaxel include acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, and interstitial pneumonia.1 Pulmonary fibrosis has been reported rarely.1 Radiation pneumonitis has been reported rarely in patients receiving concomitant radiation therapy.1

Local Effects

Local reactions at the injection site occurred in about 4% of patients receiving docetaxel for solid tumors and generally were mild and consisted of hyperpigmentation, inflammation, erythema or dryness of the skin, phlebitis, extravasation, or venous swelling.1 Extravasation of docetaxel has led to localized pain, discoloration, and erythema, and desquamation has continued for up to 6 weeks in some cases.3,7,22 Specific treatment for docetaxel-induced extravasation reactions currently has not been fully determined.22 However, the manufacturer recommends using general conservative measures and avoiding the application of warm compresses (which may result in skin discoloration, blistering, and peeling) in the treatment of docetaxel extravasation.22,37 Reversible peripheral vein inflammation has been reported rarely with docetaxel administration.3

Ocular Effects

Cystoid macular edema has been reported in patients receiving docetaxel.1

Lacrimation disorder occurred in 11% and conjunctivitis in 5% of patients receiving docetaxel in combination therapy as adjuvant treatment for breast cancer.1 Conjunctivitis was reported in 1% of patients receiving docetaxel in combination therapy for locally advanced head and neck cancer.1 Tearing was reported in patients receiving docetaxel in combination therapy for advanced prostate cancer (10%), advanced gastric cancer (8%), and locally advanced head and neck cancer (2%).1 Excessive tearing may be caused by lacrimal duct obstruction.1 Transient visual disturbances, such as flashes, flashing lights, and scotomata, have been reported rarely in patients receiving docetaxel; these visual disturbances typically occurred during the infusion in association with hypersensitivity reactions and were reversible upon discontinuance of the drug.1

Otic Effects

Adverse otic effects, including ototoxicity, hearing disorders, and/or hearing loss, have been reported in patients receiving docetaxel, including some cases associated with other ototoxic agents.1 Altered hearing was reported in patients receiving docetaxel with cisplatin and fluorouracil for advanced gastric cancer (6%) or locally advanced head and neck cancer (6% in TAX323 and 13% in TAX324).1

Other Adverse Effects

Amenorrhea was reported in patients receiving either docetaxel (62%) or fluorouracil (52%) (each in combination with doxorubicin and cyclophosphamide) for the adjuvant treatment of breast cancer.1 Weight loss (21 or 14%) and cancer pain (21 or 17%) were reported in patients receiving docetaxel with cisplatin and fluorouracil as induction chemotherapy for locally advanced head and neck cancer.1 Cough was reported in patients receiving docetaxel in combination therapy for the adjuvant treatment of breast cancer (14%) and for advanced prostate cancer (12%).1

Other adverse effects reported in patients receiving docetaxel include diffuse pain, chest pain, radiation recall phenomenon, and hyponatremia.1 Renal insufficiency and renal failure also have been reported, generally in patients receiving docetaxel concomitantly with nephrotoxic drugs.1

Precautions and Contraindications

Docetaxel is a toxic drug with a low therapeutic index at the maximum recommended dose of 100 mg/m².1 Appropriate diagnostic and treatment facilities must be readily available in case the patient develops any severe adverse effects, such as severe hypersensitivity reactions to docetaxel (e.g., hypotension requiring treatment, bronchospasm/dyspnea requiring bronchodilators, generalized rash/erythema, anaphylaxis).1 Patients who respond to docetaxel may not experience an improvement and/or may experience worsening in performance status while receiving the drug.1 The relationship between changes in performance status, response to therapy, and treatment-related adverse effects has not been established.1

Docetaxel should not be given to patients with baseline neutrophil counts less than 1500/mm³.1 Bone marrow suppression with docetaxel is dose-dependent and is the dose-limiting toxicity.1,3,7,8 To monitor for the occurrence of docetaxel-induced bone marrow suppression, mainly neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed in all patients receiving the drug.1 Patients receiving docetaxel with cisplatin and fluorouracil should be monitored closely for the occurrence of febrile neutropenia and neutropenic infection.1

Because of the alcohol content of parenteral formulations of docetaxel, patients should be advised that alcohol-induced CNS effects (e.g., intoxication) can occur during or following infusions of the drug.1,90 Patients should be advised to avoid driving, operating machinery, or performing other dangerous activities for 1-2 hours following administration of the drug.90 Patients also should be instructed to inform a clinician of symptoms of alcohol intoxication (e.g., confusion, stumbling, drowsiness) during or after docetaxel administration.90 Clinicians should consider the alcohol content of docetaxel formulations available from various manufacturers, especially when administering the drug to patients with hepatic impairment, patients in whom alcohol intake should be avoided or minimized, patients who experienced alcohol intoxication with a previous infusion of docetaxel, and those receiving concomitant therapy with drugs with CNS depressant effects (see Drug Interactions: CNS Depressants).1,90,91 Patients should be monitored for symptoms of alcohol intoxication during and following infusions of the drug.90 If such symptoms occur, reduction of the infusion rate may resolve symptoms.90 For patients who experience alcohol intoxication, use of a formulation of docetaxel containing the least amount of alcohol should be considered.90 The manufacturer's labeling should be consulted for the alcohol content of the specific formulation, as formulations of docetaxel available from various manufacturers may contain different amounts of alcohol.1,84,85,86,90

Patients experiencing impaired vision during docetaxel therapy should promptly receive a comprehensive ophthalmologic examination.1 If cystoid macular edema is diagnosed, docetaxel therapy should be discontinued and appropriate treatment initiated.1 Alternative therapy with a nontaxane antineoplastic agent should be considered.1

Fluid retention, generally manifested by peripheral edema and weight gain, occurs frequently in patients receiving docetaxel.1 Patients with preexisting effusions should be monitored closely beginning with the first dose of docetaxel to detect possible exacerbation of effusions.1

Among patients receiving docetaxel with doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer, continued hematologic monitoring is required because of the risk of delayed myelodysplasia or treatment-related acute myeloid leukemia.1 (See Cautions: Mutagenicity and Carcinogenicity.)

Among patients receiving docetaxel in combination with cisplatin and fluorouracil for advanced gastric cancer in the randomized trial, neurologic examination was performed before entry into the study, periodically during the study (at least after every 2 cycles of therapy), and at the completion of treatment.1 In patients experiencing peripheral neuropathy or other neurologic manifestations, examinations should be performed more frequently and dosage reduction and/or discontinuance of the drug may be required.1 (See Neurologic Toxicity under Dosage: Dosage Modification for Toxicity and Contraindications for Continued Therapy, in Dosage and Administration.)

Docetaxel injection concentrate contains polysorbate 80 and should not be used in patients with known severe hypersensitivity to polysorbate 80 or to the drug.1 To reduce the severity of hypersensitivity reactions and to reduce the incidence and severity of fluid retention, the manufacturers recommend that all patients be pretreated with oral corticosteroids.1,84,85,86 (See Premedication Regimen under Dosage and Administration: Dosage.) Patients should be observed closely for hypersensitivity reactions, particularly during the first and second infusions of docetaxel.1 Docetaxel therapy should not be undertaken in any patient who experienced a severe hypersensitivity reaction during a previous course of therapy with the drug.1

Medication errors have occurred that involved confusion between docetaxel (Taxotere^®) and paclitaxel (Taxol^®).62 To avoid medication errors, the prescriber should print both the brand and generic names for docetaxel on the prescription order form.62 If a handwritten prescription is difficult to read, the pharmacist should confirm the drug name with the prescriber.62 If the prescription is confirmed verbally, the drug names should be spelled out.62 Pharmacy labels and preprinted order forms should list both the generic and brand names using upper-case and lower-case fonts (i.e., DOCEtaxel and TaxoTERE).62 Two pharmacists should provide independent confirmation that the correct drug is being ordered before chemotherapy is dispensed, and two nurses should confirm that the correct drug has been dispensed for the correct patient before administering the medication.62

Docetaxel generally should not be given to patients with serum total bilirubin concentrations exceeding the upper limit of normal, or to patients with serum AST (SGOT) and/or ALT (SGPT) concentrations exceeding 1.5 times the upper limit of normal concomitant with serum alkaline phosphatase concentrations exceeding 2.5 times the upper limit of normal.1 Patients with elevations of serum bilirubin or abnormalities of serum transaminases concurrent with serum alkaline phosphatase are at increased risk for the development of severe or life-threatening complications, including severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.1 Determinations of serum bilirubin, AST and/or ALT, and alkaline phosphatase concentrations should be obtained prior to each cycle of docetaxel therapy and reviewed by the clinician.1

The incidence of mortality was higher in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy who received docetaxel as a single agent at a dose of 100 mg/m².1 Because of excessive toxicity with higher doses, such patients should receive the recommended dosage of (i.e., docetaxel 75 mg/m² once every 3 weeks).1 (See Non-small Cell Lung Cancer under Dosage and Administration: Dosage.)

The patient should be instructed to notify a clinician immediately about difficulty breathing or swallowing, facial swelling, or rash during or shortly after the infusion of docetaxel because this may indicate an allergic reaction to the drug.1 The patient should be informed of the importance of routine monitoring of blood cell counts and should be advised to notify a clinician immediately if he or she develops a fever, because this may be an early sign of infection.1 The patient should be instructed to monitor for signs of fluid retention (e.g., edema in the lower extremities, weight gain, dyspnea) and should be advised of the importance of taking the corticosteroid premedication as directed to lessen fluid retention and to reduce the severity of hypersensitivity reactions.1 Patients also should be instructed to inform a clinician of excessive or persistent fatigue, muscle pain, rash, or sensations (numbness, tingling, or burning) in the hands and/or feet after treatment with docetaxel.1

Pediatric Precautions

Clinicians should consider the alcohol content of docetaxel formulations available from various manufacturers when administering the drug to pediatric patients.1 (See Cautions: Nervous System Effects and Cautions: Precautions and Contraindications.)

Efficacy of docetaxel administered as monotherapy or in combination chemotherapy regimens has not been established in pediatric patients.1 In clinical trials to date, the safety profile of docetaxel in pediatric patients has been similar to that in adults.1 Clearance of the drug (adjusted for body surface area) also has been similar in pediatric patients and adults.1

In a dose-finding study in 61 patients 1-22 years of age (median age: 12.5 years) with various refractory solid tumors, the primary dose-limiting toxicity of docetaxel was neutropenia.1 The dosage identified in this study (125 mg/m² IV every 21 days) subsequently was evaluated in a phase 2 noncomparative trial in 178 patients 1-26 years of age (median age: 12 years) with various recurrent or refractory solid tumors.1 This phase 2 trial failed to establish efficacy of docetaxel monotherapy in pediatric patients; tumor responses in this trial included one complete response in a patient with undifferentiated sarcoma and 4 partial responses, one each in patients with Ewing's sarcoma, neuroblastoma, osteosarcoma, and squamous cell carcinoma.1

In a study in 75 patients 9-21 years of age (median age: 16 years) with nasopharyngeal carcinoma, 1 of 50 patients receiving an induction regimen of docetaxel, cisplatin, and fluorouracil prior to chemoradiation consolidation achieved a complete response following the induction regimen compared with none out of 25 patients receiving an induction regimen of cisplatin and fluorouracil.1

Geriatric Precautions

Certain toxicities associated with docetaxel therapy may occur more frequently and with greater severity in geriatric patients.1 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, caution is advised in dose selection for geriatric patients.1

Among patients receiving docetaxel and cisplatin as first-line treatment of advanced non-small cell lung cancer in the randomized trial, 36% were 65 years of age or older.1 Geriatric patients experienced similar survival but greater toxicity than younger patients.1,81 Among patients receiving docetaxel and cisplatin, median survival was 12 months in geriatric patients compared with about 10 months in younger patients.1 Adverse effects that occurred more frequently in geriatric patients than in younger patients receiving docetaxel and cisplatin include diarrhea (55 versus 43%), infections (42 versus 31%), peripheral edema (39 versus 31%), and stomatitis (28 versus 21%).1 Among geriatric patients, diarrhea (55 versus 24%), peripheral edema (39 versus 20%), and stomatitis (28 versus 20%) occurred more frequently in those receiving docetaxel and cisplatin than in those receiving vinorelbine and cisplatin.1 Among patients receiving docetaxel and carboplatin as first-line treatment of advanced non-small cell lung cancer in the same randomized trial, 28% were 65 years of age or older.1 Among geriatric patients, those receiving docetaxel and carboplatin had a higher frequency of infection than those receiving docetaxel and cisplatin and a higher frequency of diarrhea, infection, and peripheral edema than those receiving vinorelbine and cisplatin.1

Among patients receiving docetaxel and prednisone for the treatment of androgen-independent (hormone-refractory) advanced prostate cancer in the randomized trial, 63% were 65 years of age or older and 20% were older than 75 years of age.1 Treatment-emergent adverse effects that occurred more frequently in geriatric patients than in younger patients receiving docetaxel and prednisone included anemia (71 versus 59%), infection (37 versus 24%), nail changes (34 versus 23%), anorexia (21 versus 10%), and weight loss (15 versus 5%).1

Among patients receiving docetaxel with cisplatin and fluorouracil for advanced gastric cancer in the randomized trial, 24% were 65 years of age or older.1 Although this trial did not include sufficient numbers of elderly patients to determine whether geriatric patients respond differently than younger patients, the incidence of serious adverse effects was higher.1 The incidence rates of lethargy, stomatitis, diarrhea, dizziness, edema, and febrile neutropenia/neutropenic infection were at least 10% higher in geriatric patients than in younger patients, and close monitoring is advised for elderly patients.1

Among patients receiving docetaxel with cisplatin and fluorouracil as induction therapy for advanced head and neck cancer in randomized trials, the number of patients 65 years of age or older (10% in TAX323 and 13% in TAX324) was not sufficient to determine whether geriatric patients respond differently than younger patients.1 Other clinical experience has not revealed age-related differences in response for patients receiving this regimen.1

Among patients receiving docetaxel with doxorubicin and cyclophosphamide as adjuvant therapy for breast cancer in the randomized trial, the number of patients 65 years of age or older (6%) was not sufficient to determine age-related differences in response or tolerance.1

Mutagenicity and Carcinogenicity

Docetaxel has been shown to be clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleus test in mice; however, the drug was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.1

Studies to determine the carcinogenic potential of docetaxel have not been performed to date.1

Acute myeloid leukemia and myelodysplastic syndrome have been reported in patients receiving docetaxel in combination therapy with other antineoplastic agents with or without radiation therapy.1 Acute myeloid leukemia (AML) or myelodysplasia related to treatment has occurred in patients receiving anthracycline agents and/or cyclophosphamide, including those receiving these drugs as adjuvant therapy for breast cancer.1 In the randomized trial, AML occurred in 3 of 744 patients receiving docetaxel, doxorubicin, and cyclophosphamide and in 1 of 736 patients receiving fluorouracil, doxorubicin, and cyclophosphamide as adjuvant therapy for breast cancer.1

Pregnancy, Fertility, and Lactation

Pregnancy

Docetaxel may cause fetal harm when administered to pregnant women, but potential benefits may be acceptable in certain conditions despite possible risks to the fetus.1,35 Reproduction studies in rats and rabbits given docetaxel doses greater than or equal to 0.3 and 0.03 mg/kg (about 1/50 and 1/300 the maximum daily recommended human dose on a mg/m² basis), respectively, during organogenesis revealed evidence of maternal toxicity, embryotoxicity, and fetotoxicity; fetotoxicity was characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay.1 There are no adequate and well-controlled studies to date using docetaxel in pregnant women.1 Docetaxel should be used during pregnancy only in life-threatening situations or in diseases for which safer drugs cannot be used or are ineffective.35 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with docetaxel.1 When docetaxel is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.1

Fertility

When administered in multiple IV doses of up to 0.3 mg/kg (about 1/50 of the recommended human dose on a mg/m² basis), docetaxel produced no impairment of fertility in rats, but decreased testicular weights were reported.1 These findings correlate with those of a 10-cycle toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at IV doses of 5 mg/kg in rats and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended human dose on a mg/m² basis, respectively).1 An increased frequency of dosing in rats produced similar effects at lower dose levels.1

Lactation

It is not known whether docetaxel is distributed into milk.1 Because of the potential for serious adverse reactions to docetaxel in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Formal drug interaction studies of docetaxel have not been conducted.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Results of in vitro studies show that the metabolism of docetaxel may be altered by the concomitant administration of drugs that induce, inhibit, or are metabolized by cytochrome P-450 isoenzyme 3A4 (CYP3A4).1,84,85,86 In a limited number of patients, administration of ketoconazole (200 mg orally once daily for 3 days) concomitantly with docetaxel (10 mg/m² IV) resulted in a 2.2-fold increase in exposure and a 49% reduction in clearance of docetaxel.1,84,85,86 Concomitant use of potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) with docetaxel should be avoided.1,84,85,86 If such concomitant use cannot be avoided, a reduction in docetaxel dosage with careful monitoring for toxicity should be considered.1,84,85,86 Based on extrapolation of limited pharmacokinetic data for ketoconazole, the manufacturers state that a 50% reduction in docetaxel dosage may be considered in patients requiring concomitant therapy with a potent CYP3A4 inhibitor; however, there are no clinical data with use of this adjusted docetaxel dosage in patients receiving potent CYP3A4 inhibitors.1,84,85,86

CNS Depressants

Because of the alcohol content of parenteral formulations of docetaxel, concomitant use of drugs with CNS depressant effects (e.g., opiate analgesics, sedatives) may worsen the effects of alcohol.90 (See Cautions: Nervous System Effects.)

Acute Toxicity

Limited information is available on the acute toxicity of docetaxel.1 In male and female rats, lethality occurred at a dose of 20 mg/kg (comparable to a human dose of 100 mg/m² on a mg/m² basis) and was associated with abnormal mitosis and necrosis of multiple organs.1 In mice, lethality was observed following single IV doses of 154 mg/kg (about 4.5 times a human dose of 100 mg/m² on a mg/m² basis) or greater.1 In mice, at a dose of 48 mg/kg (about 1.5 times a human dose of 100 mg/m² on a mg/m² basis), neurotoxicity associated with paralysis, nonextension of hind limbs, and myelin degeneration was observed.1

Overdosage of docetaxel produces symptoms that are mainly extensions of common adverse reactions, including bone marrow suppression, peripheral neurotoxicity, and mucositis.1 In 2 reports of overdosage, one in a patient receiving docetaxel 150 mg/m² and another in a patient receiving docetaxel 200 mg/m² (both as 1-hour IV infusions), both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesias.1 These patients recovered without incident.1

There is no known antidote for docetaxel overdosage.1 In case of overdosage, the patient should be moved to a specialized unit that allows close monitoring of vital functions.1 As soon as possible after the discovery of docetaxel overdosage, therapeutic G-CSF should be administered.1 Other supportive and symptomatic treatment should be initiated as clinically indicated.1

Pharmacology

Like paclitaxel, docetaxel is an antimicrotubule antineoplastic agent.2,4,5,6,7,8,9,10,11 Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), however, docetaxel and paclitaxel promote rather than inhibit microtubule assembly while simultaneously preventing microtubule disassembly.1,3,4,8,9,10 Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers.2,4,7,8,9 They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell.2,6,7,8,9,10

Docetaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]); as a result, the drug induces the formation of stable, nonfunctional microtubules.1,3,4,7 While the precise mechanism of action of the drug is not understood fully, docetaxel disrupts the dynamic equilibrium within the microtubule system and arrests the cell cycle in the late G₂ and M phases, inhibiting cell replication.4,5,6,7

Docetaxel results in the formation of tubulin polymers that differ structurally from those generated by paclitaxel and, unlike paclitaxel, does not alter the number of protofilaments in the microtubules.1,3,4,8,9 As an inhibitor of microtubule depolymerization, docetaxel is approximately twice as potent as paclitaxel;4,9,11 the increased potency of docetaxel may be related to its higher affinity for microtubules, its higher achievable intracellular concentration, and its slower cellular efflux.2 In addition, higher radiosensitivity effects have been observed with docetaxel as compared with paclitaxel (at equimolar concentrations).3 Preclinical evidence suggests that cross-resistance between docetaxel and paclitaxel is incomplete;3,12 a lack of cross-resistance between docetaxel and fluorouracil or cisplatin also has been noted.4

Docetaxel is a schedule-independent antineoplastic agent.3 Preclinical studies using different dosage schedules revealed no alteration in antitumor activity with splitting of the total dose of docetaxel.3

Pharmacokinetics

Absorption

Docetaxel exhibits linear, dose-dependent pharmacokinetics.1 The area under the concentration-time curve (AUC) was dose-proportional following docetaxel doses of 70-115 mg/m² IV administered over 1-2 hours.1

Distribution

The pharmacokinetic disposition of docetaxel is consistent with a 3-compartment model with initial rapid decline indicating distribution to peripheral compartments and a late (terminal) phase with a half-life of about 11 hours suggesting relatively slow efflux of docetaxel from the peripheral compartment.1 Following docetaxel doses of 70-115 mg/m² IV administered over 1-2 hours, the steady-state volume of distribution averaged 113 L.1

About 94% of docetaxel is bound to plasma proteins (97% in patients with cancer).1 It is not known whether docetaxel is distributed into milk.1

Elimination

Following docetaxel doses of 70-115 mg/m² IV administered over 1-2 hours, total body clearance averaged 21 L/hour per m².1

Docetaxel is metabolized in the liver and undergoes oxidative metabolism of the tert -butyl ester group.1 (See Drug interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.) Docetaxel is excreted mainly in the feces (75% of the dose) with minimal excretion (about 6% of the dose) in the urine.1 Following the administration of a radioactive dose, about 80% of the dose is excreted in the feces during the first 48 hours as a major metabolite and 3 minor metabolites with small amounts (less than 8% of the dose) excreted as unchanged drug.1

In patients with mild to moderate hepatic impairment (serum AST and/or ALT concentration exceeding 1.5 times the upper limit of normal and serum alkaline phosphatase concentration exceeding 2.5 times the upper limit of normal), total body clearance was lowered by an average of 27% and resulted in a 38% increase in systemic exposure (AUC) for docetaxel.1 Docetaxel has not been studied in patients with severe hepatic impairment.1

The pharmacokinetics of docetaxel do not appear to be influenced by age or gender.1

Chemistry and Stability

Chemistry

Docetaxel, a semisynthetic taxoid produced from the needles of the European yew ( Taxus baccata ) tree, is an antineoplastic agent.1,2,3,4,5,6 The drug is derived from a noncytotoxic precursor (10-deacetyl baccatin III) and is structurally and pharmacologically similar to paclitaxel.2,4,5,7,8

Docetaxel is a complex diterpene with a taxane ring system linked at positions 4 and 5 to a four-membered oxetane ring and at position 13 to an ester side chain.1,3,9 The taxane nucleus is important for binding of docetaxel to microtubules, and this binding is stabilized by the ester side chain at position 13 of the taxane ring, which is required for the drug's cytotoxic activity.7,9 Docetaxel differs structurally from paclitaxel by the presence of a hydroxyl group rather than an acetyl group on position 10 of the baccatin III ring and by a trimethylmethoxy moiety instead of a benzamide phenyl group on the 3' position of the side chain at position 13 of the taxane ring.2

Docetaxel occurs as a white to almost-white powder.1 Docetaxel is highly lipophilic and practically insoluble in water; however, docetaxel is more water soluble than paclitaxel, permitting its formulation in polysorbate (Tween^®) 80 rather than Cremophor^® EL (polyoxyl 35 castor oil).1,7,10,11

Commercially available docetaxel injection concentrate (Taxotere^®) is a sterile solution of the drug in a 50/50 v/v mixture of polysorbate 80 and dehydrated alcohol.1 The injection concentrate is a pale yellow to brownish-yellow solution.1 The injection concentrate must be diluted with an appropriate infusion solution prior to administration (one dilution step).1

Commercially available docetaxel injection concentrate (Hospira) is a sterile solution of the drug in a vehicle containing polysorbate 80, citric acid, polyethylene glycol 300, and dehydrated alcohol 23% v/v.84 The injection concentrate is a clear, colorless to pale yellow solution.84 The injection concentrate must be diluted with an appropriate infusion solution prior to administration (one dilution step).84

Commercially available docetaxel injection concentrate requiring one dilution step (one-vial formulation, Accord) is a sterile solution of the drug in a vehicle containing polysorbate 80, citric acid, and dehydrated alcohol.86 The injection concentrate is a pale yellow to brownish-yellow solution.86 The injection concentrate must be diluted with an appropriate infusion solution prior to administration (one dilution step).86

Commercially available docetaxel injection concentrate requiring 2 dilution steps (2-vial formulation, Accord) is a sterile solution of the drug in polysorbate 80 and dehydrated alcohol with an accompanying diluent of 13% w/v polyethylene glycol 400 in water for injection; citric acid may be added to adjust the pH.86 The injection concentrate is a clear yellow to brownish-yellow viscous solution.86 The injection concentrate must be diluted with the diluent supplied by the manufacturer, followed by dilution with an appropriate infusion solution prior to administration (2 dilution steps).86

Docetaxel also is commercially available as a lyophilized powder (Docefrez^®) with an accompanying diluent of ethanol 35.4% w/w and polysorbate 80. 85 The lyophilized powder must be reconstituted with the diluent supplied by the manufacturer, followed by dilution with an appropriate infusion solution.85

Stability

Commercially available docetaxel injection concentrate (Taxotere^®) should be stored in unopened vials at 2-25°C and retained in the original package for protection from light.1 Freezing does not adversely affect docetaxel for injection concentrate.1 The final diluted docetaxel solution for infusion (prepared by mixing the required amount of the injection concentrate with either 0.9% sodium chloride injection or 5% dextrose injection) is stable for up to 6 hours at 2-25°C.1 The infusion solution should be used within 6 hours, so it may be stored for up to 5 hours at 2-25°C before initiating the 1-hour IV infusion.1 When prepared as directed and stored in non-PVC bags at 2-8°C, the final diluted docetaxel infusion solution is stable for up to 48 hours.1

Commercially available docetaxel injection concentrate (Hospira) should be stored in unopened vials at 20-25°C and retained in the original package for protection from light.84 Between uses, multiple-dose vials of the injection concentrate are stable for up to 28 days when stored at 2-8°C and protected from light.84 Freezing does not adversely affect docetaxel for injection concentrate.84 The final diluted docetaxel solution for infusion (prepared by mixing the required amount of the injection concentrate with either 0.9% sodium chloride injection or 5% dextrose injection) is stable for up to 4 hours at 2-25°C.84 The infusion solution should be used within 4 hours, so it may be stored for up to 3 hours at 2-25°C before initiating the 1-hour IV infusion.84

Commercially available docetaxel injection concentrate requiring one dilution step (one-vial formulation, Accord) should be stored in unopened vials at 15-25°C and protected from light.86 Between uses, multiple-dose vials of the injection concentrate are stable for up to 28 days when stored at room temperature and protected from light.86 Freezing does not adversely affect this formulation.86 The final diluted docetaxel solution for infusion (prepared by mixing the required amount of the injection concentrate with either 0.9% sodium chloride injection or 5% dextrose injection) is stable for up to 4 hours at 2-25°C.86 The infusion solution should be used within 4 hours, so it may be stored for up to 3 hours at 2-25°C before initiating the 1-hour IV infusion.86

Commercially available docetaxel injection concentrate requiring 2 dilution steps (2-vial formulation, Accord) should be stored in unopened vials at 25°C (but may be exposed to temperatures ranging from 15-30°C) and protected from light.86 The initial diluted docetaxel solution (prepared by mixing the contents of the diluent vial with the docetaxel injection concentrate) may be used immediately to prepare the final diluted docetaxel solution for infusion or it may be stored either in the refrigerator or at room temperature for up to 8 hours.86 The final diluted docetaxel solution for infusion (prepared by mixing the required amount of the initial diluted docetaxel solution with either 0.9% sodium chloride injection or 5% dextrose injection) is stable for up to 4 hours at 2-25°C.86 The final diluted docetaxel solution for infusion should be used within 4 hours, so it may be stored for up to 3 hours at 2-25°C before initiating the 1-hour IV infusion.86

Commercially available docetaxel lyophilized powder (Docefrez^®) should be stored at 2-8°C and retained in the original package for protection from bright light.85 The reconstituted docetaxel solution may be used immediately to prepare the final diluted docetaxel solution for infusion or it may be stored either in the refrigerator or at room temperature for up to 8 hours.85 The final diluted docetaxel solution for infusion (prepared by mixing the required amount of the reconstituted docetaxel solution with either 0.9% sodium chloride injection or 5% dextrose injection) is stable for up to 6 hours at 2-25°C.85 The final diluted docetaxel solution for infusion should be used within 6 hours, so it may be stored for up to 5 hours at 2-25°C before initiating the 1-hour IV infusion.85 When prepared as directed and stored in non-PVC bags at 2-8°C, the final diluted docetaxel infusion solution is stable for up to 48 hours.85

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Sanofi-Aventis. Taxotere^® (docetaxel) injection concentrate prescribing information. Bridgewater, NJ; 2014 Nov.

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