Clinical trial NCT01222052: 6xFU/Epirubicin/Cyclophosphamide (FEC) Compared to 3xFEC-3xDocetaxel in High-risk Node-negative Breast Cancer Patients
Official title: Randomized Multicenter Study Comparing 6xFEC With 3xFEC-3xDoc in High-risk Node-negative Patients With Operable Breast Cancer: Comparison of Efficacy and Evaluation of Clinico-pathological and Biochemical Markers as Risk Selection Criteria
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Keywords: high risk breast cancer
low risk breast cancer
uPA
urokinase-type plasminogen activator
PAI
plasminogen activator inhibitor-type
Lead sponsor: Martin-Luther-Universität Halle-Wittenberg
Sponsor class: OTHER
Collaborators: name: GBG Forschungs GmbH
First posted: 2010-10-18
Enrollment: 4150
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In low-risk node-negative breast cancer patients adjuvant chemotherapy should be spared. The identification of this subgroup can be based either on clinical and pathological or on tumour-biological criteria. Due to their high prognostic impact, the tumour-biological invasion markers uPA/PAI-1 (urokinase-type plasminogen activator and its inhibitor PAI-1) are potential candidates to effectively assess the risk of relapse in node-negative breast cancer. This study is aimed to compare the risk assessment by the traditional clinico-pathological factors and by tumour-biological factors. The second study question refers to the comparison between an adjuvant combination treatment with FE100C\*6 and a sequential treatment with FE100C\*3 and Docetaxel\*3.

Detailed description: 1. To compare FEC\*6 with FEC\*3 followed by DOC\*3 with regard to:

   * the primary endpoint of the study: Disease-Free Survival (DFS)
   * the secondary endpoints: Overall Survival (OS), compliance, and toxicity of chemotherapy in each patient group
2. To compare patients with low risk according to clinico-pathological versus those according to biological risk criteria with regard to:

   * the proportion of low risk versus high risk patients
   * DFS
   * OS (secondary endpoint)

Eligibility criteria: Inclusion Criteria:

* Histological proven primary breast cancer
* Tumour size \>0.5 cm and \<5 cm (pT1b-pT2, pN0, M0)
* Axillary lymph nodes tumour free (node-negative disease)
* Adequate surgical procedure: R0-resection and axillary dissection with more than 10 lymph nodes examined or adequate sentinel procedure in a qualified centre
* Frozen tumour tissue available (for analysis of biological markers and microarrays, centres with biological risk assessment only). The material has to be stored in liquid nitrogen immediately after excision.
* Paraffin blocks or (at least) pathology slides of primary tumour (stained and unstained) and axillary nodes (stained) available for central review.
* HER-2/neu determination by immunohistochemistry. Patients will be stratified to be HER-2/neu-negative or HER-2/neu-positive (HER-2/neu Score 3+, or HER-2/neu Score 2+ and FISH positive).
* No distant metastasis
* Age \>18 years, \<70 years
* Performance status ECOG \<2 (WHO Performance Status 0-1)
* Adequate cardiac function (echocardiographically measured left ventricular ejection fraction (LVEF) or shortening fraction (SF) within the normal limits, i.e. ≥55%)
* Adequate bone function (neutrophil count \>1.5 x109 /l and platelet count \>100 x109 /l)
* Adequate renal function (serum creatinine \<120 µmol/l or 1.35 mg/dl) and hepatic function (serum bilirubin \<1 x UNL, ASAT or ALAT (SGOT or SGPT) \<2,5 x UNL)
* Before patient registration/randomization, written informed consent must be obtained according to ICH/EU GCP, and national/local regulations

Exclusion Criteria:

* Chemotherapy contraindicated
* Inflammatory breast cancer, tumour infiltrated axillary lymph nodes including the sentinel node.
* Other concomitant pathology compromising survival (at entry), or preventing the administration of chemotherapy with either FEC or Docetaxel
* Other serious illness or medical condition that may interfere with the understanding and giving of informed consent and the conduct of the study
* Estimated life-expectancy \<10 years (irrespective of breast cancer diagnosis)
* Patient not accessible for treatment and follow up
* Endocrine treatment not according to the latest standard recommendations of the AGO Kommission "Mamma"
* Pregnancy, lactation (sufficient non-hormonal contraception in fertile women required)
* Surgery more than six weeks ago at the start of chemotherapy
* Pre-existing polyneuropathy
* Previous or concomitant other malignancy (including contralateral breast cancer) except adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix
* Prior chemotherapy or radiotherapy or endocrine therapy

Primary outcomes:
measure: Disease-Free Survival
timeFrame: after 10 years follow up
Secondary outcomes:
measure: Overall Survival
timeFrame: after 10 years follow up
Other outcomes:
Locations:
city: Neu-Isenburg
country: Germany
facility: GBG Forschungs GmbH
Study officials:
affiliation: Dpt. Gynecology University Halle Germany
name: Christoph Thomssen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Breast Center University Cologne
name: Nadia Harbeck, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kantelhardt EJ, Vetter M, Schmidt M, Veyret C, Augustin D, Hanf V, Meisner C, Paepke D, Schmitt M, Sweep F, von Minckwitz G, Martin PM, Jaenicke F, Thomssen C, Harbeck N. Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6xFEC versus 3xFEC/3xDocetaxel. BMC Cancer. 2011 Apr 16;11:140. doi: 10.1186/1471-2407-11-140.