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Adverse Events: Breast Cancer

Locally Advanced or Metastatic Breast Cancer

Taxotere® (docetaxel) 100 mg/m2

The following table summarizes adverse events from pooled phase III clinical trials including Taxotere® 100 mg/m2 for the treatment of locally advanced or metastatic breast cancer after failure of prior chemotherapy.1


Pooled Trials: Adverse Events With Taxotere® 100 mg/m2
Summary of
adverse events		 Breast cancer normal LFTs*
Taxotere® 100 mg/m2
(n=965)
% of patients
Hematologic
Neutropenia  
     <2000 cells/mm3 98.5
     <500 cells/mm3 85.9
Leukopenia  
     <4000 cells/mm3 98.6
     <1000 cells/mm3 43.7
Thrombocytopenia (<100,000 cells/mm3) 9.2
Anemia  
     <11 g/dL> 93.6
     <8 g/dL 7.7
Febrile neutropenia† 12.3
Septic death‡ 1.4
Nonseptic death‡ 0.6
Non-hematologic
Infection (severe) 6.4
Fever in absence of infection (severe) 2.2
Hypersensitivity reactions (severe) 2.6
Fluid retention (severe) 8.9
Neurosensory (severe) 5.5
Cutaneous (severe) 5.2
Nail changes (severe) 3.7
Gastrointestinal  
     Nausea (any) 42.1
     Vomiting (any) 23.4
     Diarrhea (severe) 5.5
Stomatitis (severe) 7.4
Asthenia (severe) 14.9
Myalgia (severe) 1.8
Arthralgia (any) 8.2
Infusion site reaction (any) 4.0

* Normal baseline liver function test (LFTs): Transaminases < 1.5x upper limit of normal (ULN) or alkaline phosphatase ≤ 2.5 x ULN or Isolated elevations of transaminases or alkaline phosphate up to 5 x ULN.
† Febrile neutropenia: ANC grade 4 with fever >38°C with IV antibiotics and/or hospitalization
‡ A grade 3/4 rating does not apply to toxic death because it is defined as grade 5.


Taxotere® at Various Doses

Adverse events in relation to dose and baseline liver chemistry

As shown in the following tables, hematologic and other toxicities increased in study patients receiving higher doses of Taxotere® and in patients with elevated baseline liver function tests (LFTs).1


Hematologic Adverse Events: Relation to Dose and Baseline Liver Chemistry
Adverse Event Taxotere®
100 mg/m2 		Taxotere®
60 mg/m2
Normal
LFTs*
(n=730)
% 		Elevated
LFTs†
(n=18)
% 		Normal
LFTs*
(n=174)
%
Neutropenia
  Any             <2000 cells/mm3
  Grade 4       <500 cells/mm3
98.4
84.4
100
93.8
95.4
74.9
Thrombocytopenia
  Any             <100,000 cells/mm3
  Grade 4       <20,000 cells/mm3
10.8
0.6
44.4
16.7

14.4
1.1
Anemia         <11 g/dL 94.6 94.4 64.9
Infection
  Any
  Grade 3/4
22.5
7.1
38.9
33.3
1.1
0
Febrile Neutropenia
  By patient
  By course
11.8
2.4
33.3
8.6
0
0
Septic Death 1.5 5.6 1.1
Nonseptic Death 1.1 11.1 0

* Normal baseline liver function tests (LFTs): Transaminases < 1.5 times upper limit of normal (ULN) or alkaline phosphatase < 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN.
† Elevated baseline LFTs: Serum glutamic-oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN.
‡ Incidence of infection requiring hospitalization and/or intravenous (I.V.) antibiotics was 8.5% (n=62) among the 730 patients with normal LFTs at baseline; 7 patients had concurrent grade 3 neutropenia, and 46 patients had grade 4 neutropenia.
§ Febrile neutropenia: For 100 mg/m2, absolute neutrophil count (ANC) grade 4 and fever > 38°C with I.V. antibiotics and/or hospitalization; for 60 mg/m2, ANC grade 3/4 and fever > 38.1°C.

Non-hematologic Adverse Events: Relation to Dose and Baseline Liver Chemistry
Adverse Event Taxotere®
100 mg/m2 		Taxotere®
60 mg/m2
Normal
LFTs*
(n=730)
% 		Elevated
LFTs†
(n=18)
% 		Elevated
Normal
LFTs*
(n=174)
%
Acute Hypersensitivity
Reaction Regardless of Premedication
  Any
  Severe

13.0
1.2

5.6
0

0.6
0
Fluid Retention‡
Regardless of Premedication
  Any
  Severe

56.2
7.9

61.1
16.7

12.6
0
Neurosensory
  Any
  Severe
56.8
5.8
50
0
19.5
0
Myalgia 22.7 33.3 3.4
Cutaneous
  Any
  Severe
44.8
4.8
61.1
16.7
30.5
0
Asthenia
  Any
  Severe
65.2
16.6
44.4
22.2
65.5
0
Diarrhea
  Any
  Severe
42.2
6.3
27.8
11.1
NA
Stomatitis
  Any
  Severe
53.3
7.8
66.7
38.9
19.0
0.6

* Normal baseline liver function tests (LFTs): Transaminases < 1.5 times upper limit of normal (ULN) or alkaline phosphatase < 2.5 times ULN or isolated elevations of transaminases or alkaline phosphatase up to 5 times ULN.
† Elevated baseline liver function: Serum glutamic-oxaloacetic transaminase (SGOT) and/or serum glutamate pyruvate transaminase (SGPT) > 1.5 times ULN concurrent with alkaline phosphatase > 2.5 times ULN.
‡ Fluid retention includes (by COSTART): Edema (peripheral, localized, generalized, lymphedema, pulmonary edema, and edema otherwise not specified) and effusion (pleural, pericardial, and ascites); no premedication given with the 60 mg/m2 dose.
NA = Not available.

Tax 313 dose-response trial

In the three-arm monotherapy trial, TAX 313, which compared Taxotere® 60 mg/m2, 75 mg/m2 and 100 mg/m2 in advanced breast cancer, the overall safety profile was consistent with the safety profile observed in previous Taxotere® trials.1


TAX 313 Dose-Response Trial: Grade 3/4 Events
Grade 3/4
adverse event		 Taxotere®
60 mg/m2
(n=149)
% of patients		 Taxotere®
75 mg/m2
(n=190)
% of patients		 Taxotere®
100 mg/m2
(n=185)
% of patients
Hematologic
Neutropenia* 76.4 83.7 93.4
Anemia 6.0 8.9 13.5
Thrombocytopenia 1.3 4.2 5.4
Non-hematologic
Infection 2.0 3.2 6.5
Fever in absence
of infection		 — 1.1 2.2
Peripheral edema 1.3 2.6 5.9
Neurosensory 1.3 1.6 3.8
Neuromotor — — 1.1
Skin toxicity 0.7 0.5 1.1
Nail disorder 0.7 2.1 3.2
Nausea 2.7 2.1 1.6
Vomiting — 0.5 2.2
Diarrhea 1.3 3.7 4.9
Stomatitis 0.7 2.1 5.4
Pulmonary 0.7 2.1 2.2
Lacrimation disorder — — —
Asthenia 2.7 8.4 14.5
Arthralgia — 0.5 2.2
Myalgia 0.7 1.6 2.7
Allergy — 1.1 1.6
Pain 0.7 1.1 2.2
Anorexia — — 0.5
Weight gain — 1.1 —
Dizziness — — 0.5

*The number of evaluable patients for neutropenia in the 60 mg/m2, 75 mg/m2, and 100 mg/m2 dose was 148, 190, and 182, respectively.

Discontinuation due to adverse events was reported in 5.3% of patients treated with Taxotere® 60 mg/m2 vs. 6.9% and 16.5% for patients treated with Taxotere® 75 mg/m2 and 100 mg/m2, respectively.1
Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m2 compared to 5.3% and 1.6% for patients treated at 75 mg/m2 and 100 mg/m2, respectively.1
The following adverse events were associated with increasing Taxotere® doses of 60 mg/m2, 75 mg/m2 and 100 mg/m2:

  • Fluid retention (26%, 38% and 46%, respectively)
  • Thrombocytopenia (7%, 11% and 12%, respectively)
  • Neutropenia (92%, 94% and 97%, respectively)
  • Febrile neutropenia (5%, 7% and 14%, respectively)
  • Treatment-related grade 3/4 infection (2%, 3% and 7%, respectively)
  • Anemia (87%, 94% and 97%, respectively)

Hematologic

Febrile neutropenia (<500 cells/mm3 with fever > 38°C with I.V. antibiotics and/or hospitalization) occurred in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.1

Severe infectious episodes occurred in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids.1

Thrombocytopenia (<100,000 cells/mm3) associated with fatal gastrointestinal hemorrhage has been reported.1

For more information on hematologic events, refer to the WARNINGS section of Taxotere® prescribing information.

Hypersensitivity Reactions

Severe hypersensitivity reactions to Taxotere® are discussed in the BOXED WARNING, WARNINGS, and PRECAUTIONS sections of the Taxotere® prescribing information.
Minor events, including the following, have been reported and resolved after discontinuing the Taxotere® infusion and receiving appropriate therapy.1

  • Flushing
  • Rash with or without pruritus
  • Chest tightness
  • Back pain
  • Dyspnea
  • Drug fever
  • Chills

Fluid Retention

Fluid retention is discussed in the BOXED WARNING, WARNINGS: Premedication Regimen, and PRECAUTIONS sections of the Taxotere® prescribing information.


Cutaneous

Severe skin toxicities are discussed in the PRECAUTIONS section of the Taxotere® prescribing information.

Reversible cutaneous reactions characterized by a rash, including localized eruptions mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after Taxotere® infusion, recovered before the next infusion, and were not disabling.1

Neurologic

Please refer to the PRECAUTIONS section of the Taxotere® prescribing information for information on neurologic events.

Gastrointestinal

Gastrointestinal reactions (nausea and/or vomiting and/or diarrhea) were generally mild to moderate in metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids.1
Severe stomatitis occurred in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids.1

Cardiovascular

Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely.1
In a randomized trial, 8.1% (7/86) of metastatic breast cancer patients receiving Taxotere® 100 mg/m2 who had serial left ventricular ejection fractions assessed developed deterioration of left ventricular ejection fraction by > 10% associated with a drop below the institutional lower limit of normal.1

Infusion Site Reactions

Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.1

Adjuvant treatment of Operable, Node-Positive Breast Cancer

Taxotere® 75 mg/m2

The following table summarizes adverse events from the BCIRG (Breast Cancer International Research Group) 001 clinical trial comparing Taxotere® 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 (TAC) to 5-fluorouracil 500 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2 (FAC) in the treatment of operable, node-positive breast cancer.1

BCIRG 001 Trial: Summary of Treatment-Emergent Adverse Events
  Taxotere® 75 mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (TAC)
(n=744)
% 		5-Fluorouracil 500 mg/m2 + Doxorubicin 50 mg/m2 + Cyclophosphamide 500 mg/m2 (FAC)
(n=736)
%
Adverse Event Any Grade 3/4 Any Grade 3/4
Anemia 91.5 4.3 71.7 1.6
Neutropenia 71.4 65.5 82.0 49.3
Fever in Absence of Infection 46.5 1.3 17.1 0.0
Infection 39.4 3.9 36.3 2.2
Thrombocytopenia 39.4 2.0 27.7 1.2
Febrile Neutropenia 24.7 N/A 2.5 N/A
Neutropenic Infection 12.1 N/A 6.3 N/A
Hypersensitivity Reactions 13.4 1.3 3.7 0.1
Lymphedema 4.4 0.0 1.2 0.0
Fluid Retention*
Peripheral edema
Weight gain 		35.1
26.9
12.9 		0.9
0.4
0.3 		14.7
7.3
8.6 		0.1
0.0
0.3
Neuropathy Sensory 25.5 0.0 10.2 0.0
Neurocortical 5.1 0.5 6.4 0.7
Neuropathy Motor 3.8 0.1 2.2 0.0
Neurocerebellar 2.4 0.1 2.0 0.0
Syncope 1.6 0.5 1.2 0.3
Alopecia 97.8 N/A 97.1 N/A
Skin Toxicity 26.5 0.8 17.7 0.4
Nail Disorders 18.5 0.4 14.4 0.1
Nausea 80.5 5.1 88.0 9.5
Stomatitis 69.4 7.1 52.9 2.0
Vomiting 44.5 4.3 59.2 7.3
Diarrhea 35.2 3.8 27.9 1.8
Constipation 33.9 1.1 31.8 1.4
Taste Perversion 27.8 0.7 15.1 0.0
Anorexia 21.6 2.2 17.7 1.2
Abdominal Pain 10.9 0.7 5.3 0.0
Amenorrhea 61.7 N/A 52.4 N/A
Cough 13.7 0.0 9.8 0.1
Cardiac Dysrhythmias 7.9 0.3 6.0 0.3
Vasodilatation 27.0 1.1 21.2 0.5
Hypotension 2.6 0.0 1.1 0.1
Phlebitis 1.2 0.0 0.8 0.0
Asthenia 80.8 11.2 71.2 5.6
Myalgia 26.7 0.8 9.9 0.0
Arthralgia 19.4 0.5 9.0 0.3
Lacrimation Disorder 11.3 0.1 7.1 0.0
Conjunctivitis 5.1 0.3 6.9 0.1

* COSTART term and grading system for events related to treatment.
Of the 744 patients treated with TAC, 36.3% experienced severe treatment-emergent adverse events compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm.1
Six percent of patients treated with TAC discontinued treatment due to adverse events, compared to 1.1% treated with FAC; fever in the absence of infection and allergy were the most common reasons for withdrawal among TAC-treated patients.1
Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs.1

Fever and Infection

Fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC-treated and FAC-treated patients, respectively.1
Infection was seen in 39.4% of TAC-treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients, respectively. There were no septic deaths in either treatment arm.1

Gastrointestinal Events

In addition to gastrointestinal events reflected in the above table, seven patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation vs. one patient in the FAC arm. Five of seven TAC-treated patients required treatment discontinuation; no deaths due to these events occurred.1

Cardiovascular Events

More cardiovascular events were reported in the TAC arm than the FAC arm:

  • Dysrhythmias, all grades (7.9% vs. 6.0%, respectively)
  • Hypotension, all grades (2.6% vs. 1.1%, respectively)
  • Congestive heart failure (1.6% vs. 0.5%, respectively)1

One patient in each arm died due to heart failure.1

Acute Myeloid Leukemia

Treatment-related acute myeloid leukemia (AML) is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer.1
AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (BCIRG 001).1

The cumulative risk of developing treatment-related AML at 5 years in BCIRG 001 was 0.4% for TAC-treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other breast cancer therapy regimens containing anthracyclines and/or cyclophosphamide.1

Addressing Adverse Events

The occurrence of side effects or special considerations may require Taxotere® dosing adjustments in certain individuals. Please visit the dosing adjustment guidelines section of this site for more information about dose adjustments.

For more information on Taxotere® adverse events and important safety information, please refer to the Taxotere® full prescribing information.

Reference

  1. Taxotere® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; March 2007.
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US.DOC.06.05.010  Last update:  March 2007
WARNING
  • 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 transaminase (SGOT) and/or serum glutamic-pyruvic transaminase (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.

  • 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

    • 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).