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

Sponsor

Imperial College London (Other)

Overall Status

Completed

CT.gov ID

NCT00963729

Collaborator

(none)

756

Enrollment

Locations

Arms

29.9

Duration (Months)

151.2

Patients Per Site

5.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: cyclophosphamide Drug: docetaxel Drug: epirubicin hydrochloride Drug: fluorouracil Drug: letrozole	Phase 3

Detailed 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

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

756 participants

Allocation:

Randomized

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Neoadjuvant Study of Chemotherapy Versus Endocrine Therapy in Postmenopausal Patients With Primary Breast Cancer

Study Start Date :

Sep 1, 2008

Actual Primary Completion Date :

Mar 1, 2010

Actual Study Completion Date :

Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: cyclophosphamide Given IV Drug: docetaxel Given IV Drug: epirubicin hydrochloride Given IV Drug: fluorouracil Given IV
Experimental: Arm II Patients receive oral letrozole daily for 18-23 weeks until day of surgery.	Drug: letrozole Given orally

Arm

Intervention/Treatment

Experimental: 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.

Drug: cyclophosphamide

Given IV

Drug: docetaxel

Given IV

Drug: epirubicin hydrochloride

Given IV

Drug: fluorouracil

Given IV

Experimental: Arm II

Patients receive oral letrozole daily for 18-23 weeks until day of surgery.

Drug: letrozole

Given orally

Outcome Measures

Primary Outcome Measures

Feasibility of patient recruitment (pilot) []
Feasibility of tissue collection (pilot) []
Ultrasound (or mammogram) response rate []

Secondary Outcome Measures

Clinical response rate []
Radiologic response rate by ultrasound (pilot) []
Quality of life []
Pathological complete response rate (pCR) defined as no residual invasive or pre-invasive carcinoma in breast or axilla (pilot) []
Plasma DNA changes in relation to treatment response []
Rate of conservation surgery []
Degree of pathological response []
Ki-67 changes and its relationship to treatment response []
Length of time to maximum response within the treatment period []
Tolerability of the various treatments []
Disease-free survival []
Overall survival []
MRI response []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Asan Medical Center - University of Ulsan College of Medicine	Seoul		Korea, Republic of	138-736
2	West Middlesex University Hospital	Isleworth	England	United Kingdom	TW7 6AF
3	Guy's Hospital	London	England	United Kingdom	SE1 9RT
4	St. Mary's Hospital	London	England	United Kingdom	W2 1NY
5	Charing Cross Hospital	London	England	United Kingdom	W6 8RF