Chemotherapy or Letrozole Before Surgery in Treating Postmenopausal Women With Breast Cancer That Can Be Removed By Surgery

Imperial College London

Status and phase

Completed

Phase 3

Conditions

Breast Cancer

Treatments

Drug: cyclophosphamide

Drug: fluorouracil

Drug: letrozole

Drug: docetaxel

Drug: epirubicin hydrochloride

Study type

Interventional

Funder types

Other

Identifiers

NCT00963729

EUDRACT-2006-003596-12

ICCRU-NEOcent-C-21-07

CDR0000641383 (Registry Identifier)

EU-20936

ISRCTN77234840

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. It is not yet known whether giving more than one drug (combination chemotherapy) or giving letrozole before surgery is more effective in treating women with breast cancer.

PURPOSE: This randomized phase III trial is studying giving combination chemotherapy before surgery to see how well it works compared with letrozole given before surgery in treating postmenopausal women with breast cancer that can be removed by surgery.

Full description

OBJECTIVES:

To compare the efficacy and tolerability of cytotoxic chemotherapy versus aromatase inhibition for the down-staging of strongly ER+ primary breast cancer in postmenopausal women.
To identify biological predictors of response to these two treatment modalities.

OUTLINE: This is a multicenter pilot, feasibility study followed by a randomized study. In the pilot study, a record of all patients screened and invited to participate in the study is compiled. Reasons for failure to recruit will be recorded. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive fluorouracil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who do not achieve at least partial response after 3 courses receive docetaxel IV on day 1 of 3-week courses for an additional 3 courses.
Arm II: Patients receive oral letrozole daily for 18-23 weeks until day of surgery.

Patients in both arms undergo surgery at week 18-23. Most patients then receive adjuvant therapy.

Quality of life is assessed at baseline, periodically during study treatment, and then during follow up.

Blood is collected pre-treatment, at mid-treatment, and before surgery. Blood is then collected every 6 months for 2 years. Blood samples and preserved tumor samples are used for correlative studies.

After completion of surgery, patients are followed up at least annually for 10 years.

PROJECTED ACCRUAL: A total of 40 patients for the pilot study and 716 patients for the phase III study will be accrued.

Enrollment

756 estimated patients

Sex

Female

Ages

18 to 70 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically proven primary invasive breast cancer that is thought to be suitable for neoadjuvant treatment
- No cytological proof of malignancy only
- T2 tumor or greater (≥ 20 mm by ultrasound) or any T stage with nodal disease ≥ 20 mm diameter on ultrasound assessment
- No evidence of distant metastatic disease as disclosed by bone scan, liver, and chest imaging
Definite indication for neoadjuvant and adjuvant chemotherapy
Primary tumor amenable to biopsy
No inoperable disease that is judged very unlikely to be rendered operable by neoadjuvant treatment
No inflammatory breast cancer
No bilateral invasive breast cancer
HER-2 positivity is NOT an exclusion criterion in the feasibility (pilot) study
Estrogen receptor (ER) positive tumor
- No ER-poor disease as defined locally (e.g., H-score < 100, Allred 3/4/5)
- Allred 6/7/8, H-score H ≥100 allowed

PATIENT CHARACTERISTICS:

Postmenopausal, meeting 1 of the following criteria:
- Over 12 months since last menstrual period
- Postmenopausal gonadotrophin levels (luteinizing hormone or follicle-stimulating hormone levels above local criteria)
- Postmenopausal estradiol levels below local criteria
- Prior bilateral oophorectomy
- Menopause induced by gonadotrophin-releasing hormone not allowed
WHO performance status 0 or 1
WBC ≥ 3.0 × 10^9/L
ANC ≥ 1.5 × 10^9/L
Platelets ≥ 100 × 10^9/L
Hemoglobin > 9 g/dL
AST/ALT ≤ 1.5 times upper limit of normal (ULN)
Serum bilirubin ≤ 1.5 times ULN
Alkaline phosphatase ≤ 1.5 times ULN
Serum creatinine ≤ 1.5 times ULN
No active, uncontrolled infection
No malignancy within the past 10 years except for basal cell carcinoma or cervical carcinoma in situ
- Treatment for previous malignancy confined to resection alone
No concomitant medical, psychiatric, or geographic problems that might prevent completion of treatment or follow-up
No known severe hypersensitivity to aromatase inhibitors
No contraindication to receiving aromatase inhibitors (clinical evidence or recorded history of osteoporosis)
No other serious illness or medical condition including any of the following:
- Congestive heart failure or unstable angina pectoris
- Myocardial infarction within the past year
- Uncontrolled hypertension or high-risk uncontrolled arrhythmias
- History of significant neurologic or psychiatric disorders, including psychotic disorders, dementia, or seizures, that would prohibit the understanding and giving of informed consent
- Active peptic ulcer
- Unstable diabetes mellitus
No definite contraindications for the use of corticosteroids
No contraindication to receiving combination anthracycline/taxane chemotherapy
Willing to undergo repeat biopsies

PRIOR CONCURRENT THERAPY:

No hormone replacement therapy within 4 weeks of starting treatment
No chronic oral treatment with corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 20 mg methylprednisolone or equivalent)
No concurrent warfarin or heparin therapy

Trial design

756 participants in 2 patient groups

Arm I

Experimental group

Description:

Patients receive fluorouracil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Treatment: