Clinical trial NCT00003013: Chemotherapy Plus Surgery in Treating Women With Breast Cancer
Official title: European Cooperative Study of Chemotherapy and Surgery Comparing Adjuvant Doxorubicin Followed by CMF vs. Adjuvant Doxorubicin/Paclitaxel Followed by CMF vs. Primary Doxorubicin/Paclitaxel Followed by CMF in Women With Operable Breast Cancer and T>2 cm
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 450
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining surgery with chemotherapy may kill more tumor cells. It is not yet known which treatment regimen is more effective for breast cancer.

PURPOSE: Randomized phase III trial to study the effectiveness of chemotherapy plus surgery in treating women who have breast cancer.

Detailed description: OBJECTIVES:

* Evaluate whether 8 courses of primary chemotherapy before adequate surgery of breast tumor and locoregional radiotherapy plus tamoxifen for 5 years improves the disease-free and overall survival in women with operable breast carcinoma and tumor at diagnosis greater than 2 cm in diameter.
* Assess whether, in the postoperative arms, the addition of paclitaxel to doxorubicin before CMF (cyclophosphamide, methotrexate, and fluorouracil) improves disease-free and overall survival in these patients.
* Define the incidence of pathologic complete response (CR) induced by 8 courses of primary chemotherapy containing paclitaxel.
* Assess whether a pathologic CR is an independent predictor of disease-free and overall survival.
* Evaluate the effects of primary chemotherapy on the rate and quality of breast conserving surgery.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by center, tumor diameter at mammography, nuclear or histological grade, and estrogen/progesterone receptor status. Patients are randomized to one of three treatment arms.

* Arm I: Patients receive doxorubicin IV over 15 minutes once every 3 weeks for 4 courses. Beginning 21 days after the last administration of doxorubicin, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
* Arms II and III: Patients receive doxorubicin IV over 15 minutes and paclitaxel IV over 3 hours once every 3 weeks for 4 courses. Beginning 21 days after the last administration of doxorubicin and paclitaxel, patients receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

All patients have either mastectomy or breast conserving surgery; patients with unclear surgical margins may have second surgery (re-resection or total mastectomy) or radiotherapy. Lymph node axillary dissection is performed up to at least the second level. For patients in the 2 adjuvant arms (arms I and II), adjuvant chemotherapy starts by day 21 after surgery. For patients in the primary chemotherapy arm (arm III), surgery is performed by day 28 after the last course of chemotherapy or at resolution of all possible hematological or infective complications.

At the end of the combined surgery plus chemotherapy approach (i.e., after the last course of CMF (arms I and II) or after surgery (arm III)), patients enrolled after June 30, 2000 with estrogen or progesterone receptor positive disease receive oral tamoxifen daily for 5 years.

All patients who have breast conserving surgery receive postoperative irradiation within 4 weeks after completing chemotherapy and surgery (i.e., within 4 weeks from last dose of adjuvant chemotherapy (arms I and II) or from surgery (arm III)). All patients who have mastectomy and have pT4 disease must receive irradiation to the chest wall.

Patients are followed at 6, 12, 18, and 24 months, and then annually thereafter.

PROJECTED ACCRUAL: A total of 450 patients per arm will be accrued for this study within 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Unilateral carcinoma of the breast that has not been previously treated with standard therapies
* Tumor greater than 2 cm in its maximum diameter as assessed by mammography, except:

  * No locally advanced disease, i.e., no tumor with direct extension to the chest wall or skin
  * No metastatic disease
* Hormone receptor status:

  * Not specified

PATIENT CHARACTERISTICS:

Age:

* 18 to 70

Sex:

* Female

Menopausal status:

* Not specified

Performance status:

* Karnofsky 80-100%

Hematopoietic:

* Granulocyte count at least 2,000/mm\^3
* Platelet count at least 150,000/mm\^3

Hepatic:

* Bilirubin within upper limits of normal (ULN)
* Alkaline phosphatase no greater than 1.5 times ULN
* AST no greater than 1.5 times ULN
* No chronic active hepatitis

Renal:

* Creatinine within ULN

Cardiovascular:

* No prior atrial or ventricular arrhythmias
* No history of congestive heart failure
* No myocardial infarction within the past 6 months
* No uncontrolled hypertension

Neurologic:

* No pre-existing motor or sensory neuropathy greater than grade 1

Other:

* Not pregnant or nursing
* Fertile patients must use effective contraception
* No active infection
* No history of second malignancy except adequately treated basal cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior biologic therapy

Chemotherapy:

* No prior chemotherapy

Endocrine therapy:

* No prior endocrine therapy

Radiotherapy:

* No prior radiotherapy

Surgery:

* No prior surgery
* No prior surgical biopsy of breast nodule

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Kaiser Franz Josef Hospital
city: Ostrava-Poruba
country: Czech Republic
facility: Radiotherapy Institute
city: Tartu
country: Estonia
facility: University of Tartu
city: Munich
country: Germany
facility: Frauenklinik Vom Roten Kreuz
city: Budapest
country: Hungary
facility: Semmelweis University
city: Budapest
country: Hungary
facility: Uzsoki Hospital
city: Perugia
country: Italy
facility: Policlinico Monteluce
city: Pisa
country: Italy
facility: Ospedale St. Santa Chiara
city: Trento
country: Italy
facility: Centro di Riferimento Oncologico - Aviano
city: Udine
country: Italy
facility: Universita Degli Studi di Udine
city: Vicenza
country: Italy
facility: Ospedale San Bortolo
city: Riga
country: Latvia
facility: Latvian Cancer Center
city: Bydgoszcz
country: Poland
facility: Regional Center of Oncology
city: Krakow (Cracow)
country: Poland
facility: Jagiellonian University
city: Poznan
country: Poland
facility: Szpital Kliniczny NR 1
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: Moscow
country: Russian Federation
facility: Russian Academy of Medical Sciences Cancer Research Center
city: Moscow
country: Russian Federation
facility: Moscow Clinical Dispenser
city: Moscow
country: Russian Federation
facility: N. A. Semashko Central Clinical Hospital
city: Murmansk
country: Russian Federation
facility: Regional Oncology Clinic
city: Saint Petersburg
country: Russian Federation
facility: Petrov Research Institute of Oncology
city: Bratislava
country: Slovakia
facility: St. Elizabeth Cancer Institute Hospital
city: Barcelona
country: Spain
facility: Hospital de la Santa Cruz I Sant Pau
city: Barcelona
country: Spain
facility: Hospital General Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Malaga
country: Spain
facility: Hospital Clinico Universitario - Malaga
city: Valencia
country: Spain
facility: Instituto Valenciano De Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Gianni Bonadonna, MD
role: STUDY_CHAIR
References:
citation: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agullo A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. doi: 10.1200/JCO.2008.19.2567. Epub 2009 Mar 30.