Docetaxel (Taxotere) Form
Background for this Policy
U.S. Food and Drug Administration (FDA)-Approved Indications
Breast Cancer (BC)
Non-Small Cell Lung Cancer (NSCLC)
Prostate Cancer
Docetaxel in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer.
Gastric Adenocarcinoma (GC)
Docetaxel in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
Head and Neck Cancer
Docetaxel in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
Compendial Uses
Docetaxel (brand name Taxotere; brand name Docefrez has been discontinued) and is an antineoplastic agent belonging to the taxoid family that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubules, a feature which differs from most spindle poisons currently in clinical use. ) remove brand Docefrez from the title and the policy due to product discontinuation
Docetaxel is FDA approved for the treatment of breast cancer, non-small cell lung cancer (NSCLC), castration-resistant prostate cancer, gastric cancer, and squamous cell cancer of the head and neck; it also has several off-label indications. Treatment-related mortality is increased in patients with abnormal liver function, in patients receiving higher doses, and at a monotherapy dose of 100 mg/m
2, in patients with NSCLC and a history of prior treatment with platinum-based chemotherapy. It should not be given to patients with increased liver function tests or in patients with neutrophil counts less than 1,500 cells/mm3. All patients should be premedicated with oral corticosteroids prior to each dose of docetaxel to reduce the incidence and severity of hypersensitivity, fluid retention, and skin toxicity.
Breast Cancer
The efficacy and safety of docetaxel have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy (alkylating agent-containing regimens or anthracycline-containing regimens). In one randomized trial, patients with a history of prior treatment with an anthracycline-containing regimen were assigned to treatment with docetaxel (100 mg/m
2every 3 weeks) or the combination of mitomycin (12 mg/m
2every 6 weeks) and vinblastine (6 mg/m
2every 3 weeks). Two hundred three patients were randomized to docetaxel and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the docetaxel arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The median survival time was 11.4 months in the docetaxel group compared with 8.7 months in the mitomycin/vinblastine group (p = 0.01; 95% CI:0.58-0.93). The median time to progression was 4.3 months in the docetaxel group compared with 2.5 months in the mitomycin/vinblastine group (p=0.01; 95% CI: 0.61-0.94). The overall response rate and complete response rates were 28.1% and 3.4%, respectively, in the docetaxel group compared with 9.5% and 1.6%, respectively in the mitomycin/vinblastine groups (p<0.0001).
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with docetaxel (100 mg/m
2) or doxorubicin (75 mg/m
2) every 3 weeks. One hundred sixty-one patients were randomized to docetaxel and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The median survival time was 14.7 months in the docetaxel group (n=203)compared with 14.3 months in the doxorubicin group (p = 0.39; 95% CI:0.68-1.16). The median time to progression was 6.5 months in the docetaxel group compared with 5.3 months in the doxorubicin group (p = 0.45; 95% CI: 0.71-1.16). The overall response rate and complete response rates were 45.3% and 6.8% respectively, in the docetaxel group compared with 29.7% and 4.2%, respectively in the doxorubicin groups (p<0.004).
In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive docetaxel monotherapy 60 mg/m
2(n = 151), 75 mg/ m
2(n = 188) or 100 mg/ m
2(n = 188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with docetaxel dose: 19.9% for the 60 mg/ m
2group compared to 22.3% for the 75 mg/ m
2and 29.8% for the 100 mg/ m
2group; pair-wise comparison between the 60 mg/ m
2and 100 mg/m
2groups was statistically significant (p = 0.037). Single Arm Studies Docetaxel at a dose of 100 mg/m
2was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0-44.8) and the complete response rate was 2.1%. Docetaxel was also studied in three single arm Japanese studies at a dose of 60 mg/m
2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2-55.7), similar to the response rate in single arm studies of 100 mg/m
2.
A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of docetaxel for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m
2administered 1-hour after doxorubicin 50 mg/m
2and cyclophosphamide 500 mg/m
2(TAC arm), or doxorubicin 50 mg/m
2followed by fluorouracil 500 mg/m
2and cyclophosphamide 500 mg/m
2(FAC arm). Both regimens were administered every 3 weeks for 6 cycles. Docetaxel was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC. Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio = 0.74; 2-sided 95% CI = 0.60, 0.92, stratified log rank p = 0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients (see Figure 1). At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio = 0.69, 2-sided 95% CI = 0.53, 0.90) (see Figure 2). There will be further analysis at the time survival data mature.
Gastric Cancer
Locally advanced or metastatic stomach cancer has a poor prognosis with a low long-term survival of only 11.5 percent. The FDA based its decision on results from the TAX 325 study, the largest international phase III clinical trial in previously untreated advanced stomach cancer, involving 445 patients. This study was undertaken to evaluate the benefits of adding docetaxel to a standard chemotherapy regimen. The primary study endpoint was time to tumor progression (TTP), which was significantly improved with docetaxel based therapy (5.6 months) compared to standard treatment (3.7 months) with a 32 percent reduction in the risk of progression (log-rank test p=0.0004). The main secondary endpoint was to detect a statistically significant increase in overall survival. Patients treated with the docetaxel- based chemotherapy regimen (docetaxel plus cisplatin and 5-fluorouracil, TCF) experienced a significant 23 percent reduction in the risk of death compared to patients who received a current standard treatment of cisplatin and 5-fluorouracil (CF), (median follow-up: 23 months). The median overall survival was significantly longer with the docetaxel-containing regimen (9.2 vs 8.6 months, p=<0.02) with a hazard ratio of 1.29 (95% CI: 1.04-1.61). Time to disease progression was nearly two months longer in the docetaxel - containing arm (5.6 vs 3.7 months, p=0.0004), hazard ratio 1.47 (CF/TCF 95% CI/ 1.19 -1.83). Other secondary objectives included response rate, time to treatment failure, duration of response, safety profiles, quality of life and disease related symptoms.
In total, 81.4 percent of the patients experienced at least one Grade 3-4 (severe) side effect with the docetaxel- based regimen versus 75.4 percent in the control arm, with neutropenia being the most common Grade 3-4 side effect in the docetaxel- based regimen. The most common side effects (all grade) associated with the docetaxel- based regimen were anemia, neutropenia, diarrhea, and nausea. The most common side effects (all grade) associated with the cisplatin and 5-fluorouracil arm were anemia, neutropenia, nausea and vomiting. Primary prophylactic use of growth factor support (granulocyte-colony stimulating factor, G-CSF) was not allowed per the study protocol. G-CSF is a bone marrow growth factor that may be administered to reduce febrile neutropenia in patients receiving myelosuppressive chemotherapy. In the docetaxel arm, febrile neutropenia and/or neutropenic infection occurred in 12 percent of patients receiving secondary prophylactic G-CSF compared to 28 percent who did not, which represents a 57 percent reduction.
Head and Neck Cancer
The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was evaluated in a multicenter, open-label, randomized trial (TAX323). In this study, 358 patients with inoperable locally advanced SCCHN, and WHO performance status 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m
2followed by cisplatin (P) 75 mg/m
2on Day 1, followed by fluorouracil (F) 750 mg/m2 per day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin (P) 100 mg/m
2on Day 1, followed by fluorouracil (F) 1000 mg/m
2/day as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of 4 weeks and a maximal interval of 7 weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines. Locoregional therapy with radiation was delivered either with a conventional fraction regimen (1.8 Gy-2.0 Gy once a day, 5 days per week for a total dose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen (twice a day, with a minimum interfraction interval of 6 hours, 5 days per week, for a total dose of 70 to 74 Gy, respectively). Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively).
The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m
2by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m
2administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m
2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m
2as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m
2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles. All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70-72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT. The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p = 0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 – 0.90].
Hormone Refractory Prostate Cancer
The safety and efficacy of docetaxel in combination with prednisone in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups: docetaxel 75 mg/m
2every 3 weeks for 10 cycles; docetaxel 30 mg/m
2administered weekly for the first 5 weeks in a 6-week cycle for 5 cycles; Mitoxantrone 12 mg/m
2every 3 weeks for 10 cycles. All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously. In the docetaxel every three-week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone (median survival was 18.9 months in the docetaxel+prednisone group compared with 16.5 months in the mitoxantrone+prednisone; p= 0.0094). In the docetaxel weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm.
Non-Small Cell Lung Cancer (NSCLC)
The efficacy and safety of docetaxel has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve. Monotherapy with docetaxel for NSCLC Previously Treated with Platinum-Based Chemotherapy Two randomized, controlled trials established that a docetaxel dose of 75 mg/m
2was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy. Docetaxel at a dose of 100 mg/m
2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used. One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to docetaxel or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to docetaxel 100 mg/m
2or best supportive care, but early toxic deaths at this dose led to a dose reduction to docetaxel 75 mg/m
2. A total of 104 patients were randomized in this amended study to either docetaxel 75 mg/m
2or best supportive care. In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic nonsmall cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to docetaxel 75 mg/m
2, docetaxel 100 mg/m
2and a treatment in which the investigator chose either vinorelbine 30 mg/m
2days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m
2days 1-3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored docetaxel 75 mg/m
2. Patients treated with docetaxel at a dose of 75 mg/m
2experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: docetaxel 75 mg/m
2as a 1 hour infusion immediately followed by cisplatin 75 mg/m
2over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m
2administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m
2administered on day 1 of cycles repeated every 4 weeks; or a combination of docetaxel and carboplatin. The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin.. Median survival was 10.9 months in the docetaxel+cisplatin compared with 10.0 months in the vinorelbine+cisplatin group (p=0.122; 95% CI: 0.74, 1.06). The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of docetaxel to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival) was maintained.
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the docetaxel arm (Kaplan-Meier estimate of median survival was 9.1 months for docetaxel+carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression.
Docetaxel and Bevacizumab with or without Trastuzumab as First-Line Treatment for Metastatic Breast Cancer
Sun et al (2021) noted that although bevacizumab and trastuzumab have been widely added to the standard regimen for metastatic breast cancer (MBC), the clinical outcomes remain controversial. In a meta-analysis, these investigators examined the safety and effectiveness of docetaxel and bevacizumab with or without trastuzumab as 1st-line treatment for patients with MBC. All available literature of clinical studies regarding docetaxel, bevacizumab, trastuzumab and MBC was pooled from PubMed, Embase and Cochrane library database. The meta-analysis combined the PFS, ORR and incidence of all grades adverse events (AEs) in MBC patients. A total of 7 clinical studies were included by 2 reviewers. Docetaxel and bevacizumab with trastuzumab had a pooled PFS of 16.53 months (95 % CI: 13.95 to 19.11 months), the pooled ORR was 0.75 (95 % CI: 0.69 to 0.80) in HER2-positive MBC patients. Docetaxel and bevacizumab showed that the pooled PFS was 8.49 months (95 % CI: 7.80 to 9.18 months), the pooled ORR was 0.51 (95 % CI: 0.47 to 0.55) in HER2-negative MBC patients. The authors concluded this meta-analysis found that trastuzumab combined with bevacizumab and docetaxel led to long PFS and high response rates in patients with HER2-positive MBC, while bevacizumab combined with docetaxel had a reliable effectiveness and lower incidence of AEs in patients with HER2-negative MBC. Moreover, these researchers stated that as a consequence of the limitations of the quality of the included studies, more high-quality, large-sample studies are needed to verify the findings of this study.
The authors stated that this meta-analysis had several drawbacks. First, more multi-center RCTs were needed for a meta-analysis. Second, since the differences of AEs existed in the included studies, only 12 AEs were pooled in the HER2-positive MBC, and only 6 AEs were pooled in the HER2-negative MBC, while 2 studies were included on safety profile in the majority of including studies. These researchers only pooled the incidence of AEs of all grades but did not pool the AEs of grade 3 and 4. Third, due to the lack of relevant data, this meta-analysis could not effectively examine if patients had a longer OS; therefore, further investigation is needed to determine the OS rate of patients with MBC.
Black Box Warnings
Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m
2. Docetaxel should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. LFTs should be obtained before each treatment cycle. Docetaxel should not be given if neutrophil counts are < 1500 cells/mm
3. Frequent blood counts should be obtained to monitor for neutropenia. Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of docetaxel Injection and administration of appropriate therapy. Docetaxel is contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80. Severe fluid retention may occur despite dexamethasone.
Criteria for Initial Approval
Aetna considers docetaxel (Taxotere) medically necessary for the following indications:
Bladder Cancer, Primary Carcinoma of the Urethra, Upper Genitourinary Tract Tumors, and Urothelial Carcinoma of the Prostate:
Bone Cancer:
Aetna considers all other indications as experimental and investigational.
Continuation of Therapy
Aetna considers continuation of docetaxel (Taxotere) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
Dosage and Administration
Docetaxel (Taxotere) is supplied as follows:
Administer in a facility equipped to manage possible complications (e.g., anaphylaxis). Administer intravenously (IV) over 1 hr every 3 weeks. PVC equipment is not recommended. Use only a 21 gauge needle to withdraw Docetaxel Injection from the vial.
The recommended dosing is as follows:
Breast cancer (BC)
Non-small cell lung cancer (NSCLC)
Castration-resistant prostate cancer (CRPC):
Gastric adenocarcinoma (GC)
Squamous cell carcinoma of the heand and neck (SCCHN)
Source: sanofi-aventis, 2021; Sun Pharmaceutical Ind., 2021
Walk through this policy with us
Review how this policy can be converted into cited criteria, prior authorization checks, and operational automation.