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Taxotere® based Induction Therapy for Head and Neck Cancer

In 2006 Taxotere® (docetaxel) received approval from the U.S. Food and Drug Administration (FDA) for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN).1 Taxotere is approved in combination with cisplatin and fluorouracil (TPF) for the induction treatment of patients with inoperable, locally advanced squamous cell carcinoma of the head and neck (SCCHN)1

This is the first FDA approval of an induction treatment for locally advanced head and neck cancer, offering physicians and their patients an important option for treating this devastating disease.2 Furthermore, TPF is one of the induction regimens recommended by the National Comprehensive Cancer Network's (NCCN) guidelines for locally advanced SCCHN.3

Taxotere® may offer benefits to people living with SCCHN.

The TAX 323 Study:

The TAX 323 clinical trial by Vermorken et al. compared Taxotere® + cisplatin + fluorouracil (TPF) to the standard regimen of cisplatin + fluorouracil (PF) in the treatment of inoperable, locally advanced SCCHN.

Two induction regiments were compared in a multicenter,
open-label, randomized, phase III trial*1,8

All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.
Study Scheme
  • All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy*

Primary endpoint:Progression-free survival(PFS)

Secondary endpoints: Overall survival (OS), overall response rate (RR) before and after radiotherapy, duration of response, time to treatment failure, and quality of life.

  • Selected inclusion criteria
    • 18 to 70 years of age
    • Histologically or cytologically proven SCCHN presenting with locally advanced, inoperable disease at diagnosis
    • Stage ||| |V disease without distant metastases
    • Tumor site inculding hypopharynx, larynx, oropharynx, or oral cavity
    • performance status of 0-1
  • Selected exclusion criteria
    • Tumors of the nasopharynx, nasal and paranasal cavities

Taxotere® based Induction Therapy Provided Significant Improvement In All 3 Major Endpoints

  • Significant increase in overall survival
  • Significantly improved progression-free survival 1,2
  • Significantly greater overall response after completion of all therapy

Proven survival benefits over a PF regimen in patients
with good performance status1,8

Overall Survival Table
All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.

Proven Overall Survival Advantage

The TPF group showed a significant improvement in overall survival with a 29% reduction in the risk of mortality (P=.0055).

Significant increase in overall survival1

All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.
Overall Survival
  • Overall survival was measured after completion of the entire scope of therapy, which included induction with TPF or PF
  • The majority of patients went on to receive radiotherapy per protocol(TPF: 75%, PF: 69%)
    • Only 2 TPF patients and 8 PF patients were unable to receive radiotherapy because of induction toxicity
    • The most common reason for not receiving radiotherapy was progressive disease.

Proven Improved Progression-Free Survival

The TPF group showed a significant improvement in progression-free survival advantage with a 29% reduction in the risk of progression (P=.0077).

Significantly improved progression-free survival1

All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.
Progression free survival

Significant increase in overall survival1

All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.

Proven Overall Response Rate

The TPF group showed a significant higher overall response rate (complete response + partial response) after patients completed radiotherapy compared to the PF group (72.3% vs. 58.6%; P=.0061)

Significantly greater overall response with Taxotere®

All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.
Overall Response
  • Overall response rate (complete response + partial response) after completion of radiotherapy was significantly higher in the TPF group.
  • Complete response after completion of radiotherapy was higher in the TPF group (33.3%) than in the PF group (19.9%; P=.004). Partial response rates were similar in the TPF group (39.0%) and the PF group (38.7%).

The TPF group better tolerated chemotherapy treatment, remained on treatment longer and experienced fewer side effects. 1,2

Well Established Safety Profile

The TAX 323 trial demonstrated a well-established safety profile in Taxotere® + cisplatin + flurorouracil vs. cisplatin + flurorouracil.

TPF patients received lower doses of cisplatin
and fluorouracil1

Grade 3/4 adverse events occuring in >5% of patients during the induction phase.
Taxotere® 75 mg/m2 + cisplatin 75 mg/m2+ fluorouracil 750 mg/m2 (n=174) cisplatin 100 mg/m2+ fluorouracil 1000 mg/m2 (n=181)
% %
Hermatologic    
Neutropenia 76 53
Febrile Neutropenia*(any grade) 5 2
Anemia 9 14
Infection 9 8
Thrombocytopenia 5 18
Non-hematologic    
Alopecia 11 0
Weight loss 7 1
Cancer Pain 5 3
Gastrointestinal (GI)    
Stomatitis 4 11
Nausea 1 1
Vomiting 1 5
All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.

The incidence of less common adverse events was
similar between TPF and PF treatment groups1

Grade 3/4 adverse events occuring in
≥5% of patients during the induction
phase.
Taxotere® 75 mg/m2 +
cisplatin 75 mg/m2+
fluorouracil 750 mg/m2
(n=174)		 cisplatin 100 mg/m2
+fluorouracil 1000 mg/m2

(n=181)
% %
Diarrhea 3 4
Lethargy 3 3
Cardiac dysrhythmia 2 1
Gastrointestinal bleeding 2 0
Ischemia myocardial 2 0
Venous 2 2
Anorexia 1 30
Alopecia 11 0
Constipation 1 1
Desquamation 1 0
Esophagitis/dysphagia/odynophagia 1 3
Fever in the absence of infection 1 0
Gastrointestinal pain/cramping 1 1
Myalgia 1 0
Neurosensory 1 1
Altered hearing 0 3
Dizziness 0 1
Fluid retention 0 1
All patients except those progressing during induction chemotherapy were to receive protocol radiotherapy.

Learn more about Taxotere® side effects.

References

  1. Taxotere® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; November 2007
  2. Data on file. Clinical study report. A randomized phase III multicenter trial of neoadjuvant docetaxel (XRP5976F-323, Taxotere®) plus cisplatin plus 5-fluorouracil versus neoadjuvant cisplatin plus 5-fluorouracil in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. Aventis Pharmaceuticals Inc; January 6, 2005.
  3. Sanofi-aventis Indication Letter, "Taxotere® (docetaxel) Injection Concentrate Receives FDA Approval for the induction Treatment of Locally Advanced Head and Neck Cancer." Bridgewater, NJ.
  4. 06.12.034- Need to fill in information
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US.DOC.07.07.077  Last update:  November 2007
WARNING
  • Taxotere® should be administered only under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available
  • The incidence of treatment-related mortality associated with Taxotere® therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Taxotere® as a single agent at a dose of 100 mg/m2 (see WARNINGS section of the prescribing information)
  • Taxotere® should generally not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with serum glutamic-oxaloacetic transferase (SGOT) and/or serum glutamic-pyruvic transferase (SGPT) > 1.5 X ULN concomitant with alkaline phosphatase > 2.5 X ULN
    • Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death
    • Patients with isolated elevations of transaminase > 1.5 X ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death
    • Bilirubin, SGOT or SGPT, and alkaline phosphatase values should be obtained prior to each cycle of Taxotere® therapy and reviewed by the treating physician
  • Taxotere® therapy should not be given to patients with neutrophil counts of < 1500 cells/mm3
    • In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood-cell counts should be performed on all patients receiving Taxotere®
  • Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients who received the recommended 3-day dexamethasone premedication
    • Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions
  • Taxotere® must not be given to patients who have a history of severe hypersensitivity reactions to Taxotere® or to other drugs formulated with polysorbate 80
    • All patients should be premedicated with oral corticosteroids such as dexamethasone (see DOSAGE AND ADMINISTRATION section of the prescribing information)
  • Severe fluid retention occurred in 6.5% (6/92) of patients despite use of a 3-day dexamethasone premedication regimen. It was characterized by one or more of the following events: poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) (see PRECAUTIONS section of the prescribing information)

Additional Warnings
  • Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use with Taxotere® in adjuvant therapy of breast cancer

  • Taxotere® can cause fetal harm when administered to pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Taxotere®


    • Precautions
  • Localized erythema of the extremities with edema followed by desquamation has been observed

    • — In case of severe skin toxicity, an adjustment in dosage is recommended (see DOSAGE AND ADMINISTRATION section of the prescribing information)
  • Severe neurosensory symptoms (paresthesia, dysesthesia, pain) were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%

    • — When these symptoms occur, dosage must be adjusted; if symptoms persist, treatment should be discontinued (see DOSAGE AND ADMINISTRATION section of the prescribing information)
  • Severe asthenia was reported in 14.9% (144/965) of metastatic breast cancer patients, but led to treatment discontinuation in only 1.8%

    • — Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease
  • In patients treated with TCF for gastric cancer, the incidence of serious adverse events was higher in patients >65 years than in younger patients. Adverse events (all grades) occurring at rates >10% higher in elderly patients included lethargy, stomatitis, diarrhea, dizziness, edema, and febrile neutropenia/neutropenic infection.

    • Please see important safety information and full prescribing information, including boxed WARNING.

    Taxotere Indications

    Breast Cancer
    TAXOTERE® is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy
    TAXOTERE® in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer

    Non-Small Cell Lung Cancer
    TAXOTERE®, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy
    TAXOTERE® in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic NSCLC who have not previously received chemotherapy for this condition.

    Prostate Cancer
    TAXOTERE® in combination with prednisone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

    Gastric Cancer
    TAXOTERE® in combination with cisplatin and flouroucil is indicated for the treatment of patients with advanced gastric adenocercinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.

    Head and neck Cancer
    TAXOTERE® in combination with cisplatin and flourouracil is indicated for the induction treatment of patients with locally advanced squamous cell cercinoma of the head and neck (SCCHN).