Sequential vs Upfront Intensified Neoadjuvant Chemotherapy in Patients With Large Resectable or Locally Advanced Breast Cancer.

Study Overview
=================
Brief Summary
-----------------
2 different treatment schedules may be used for neoadjuvant chemotherapy in breast cancer using adriamycin, cyclophosphamide and taxotere. The most optimal sequence- concurrent or sequential- is however unclear. The aim of the study is to compare the efficacy and tolerability of neoadjuvant chemotherapy with AC followed by T(adriamycin, cyclophosphamide, taxotere) versus TAC ( with upfront T) in patient with large resectable or locally advanced breast cancer.

Official Title
-----------------
Sequential vs Upfront Intensified Neoadjuvant Chemotherapy in Patients With Large Resectable and/or Locally Advanced Breast Cancer. The INTENS Study

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Docetaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women presenting with large resectable or locally advanced breast cancer (T2 ≥3 cm, T3, or T4, and/or LN positive) Measurable disease (breast and/or lymph nodes) No prior surgery other than biopsy and no prior chemotherapy or radiation therapy Age ≥18 years and age ≤70 years Karnofsky Performance score ≥70% Estrogen and/or progesterone receptor analysis performed on the primary tumour in the biopsy material In case the tumor is ER/PgR ³ 50% positive, (neo)adjuvant hormonal therapy in stead of chemotherapy should be considered (e.g. in TEAM II study) Her2/neu receptor analysis performed on the primary tumour in the biopsy material Adequate bone marrow function (within 14 days prior to registration): WBC ≥3.0 x 109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l Adequate liver function (within 4 weeks prior to start treatment): bilirubin ≤1.5 x upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL Adequate renal function (within 4 weeks prior to start treatment): the calculated creatinine clearance should be ≥50 mL/min Patients must be accessible for treatment and follow-up Written informed consent according to the local Ethics Committee requirements Exclusion Criteria: Patients with advanced pulmonary disease of any cause (oxygen dependent)- Peripheral neuropathy > grade 2 whatever the cause Serious other diseases as recent myocardial infarction, clinical signs of cardiac failure or clinically significant arrythmias Evidence of distant metastases (M1) Patients with a history of breast cancer Patients with a history of another malignancy (except basal cell skin carcinoma and carcinoma-in-situ of the uterine cervix) within 5 years of study entry- Pregnant or lactating women, or potentially fertile women not using adequate contraception

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A<br>Cycles 1-4 q 3 weeks: doxorubicin plus cyclophosphamide Cycles 5-8 q 3 weeks: docetaxel | Drug: Doxorubicin<br>* doxorubicin (arm A:60 mg/m2) and arm B: 50 mg/m2)<br>* Other names: adriamycin;Drug: Cyclophosphamide<br>* Cyclophosphamide: (arm A; 6000 mg/m2) an (arm B: 500 mg/m2)<br>* Other names: Revimmune;Drug: Docetaxel<br>* Docetaxel: (arm A: 100 mg/m2) and (arm B: 75 mg/m2)<br>* Other names: Taxotere;|
| Experimental: B<br>Cycles 1-6 q 3 weeks: doxorubicin, cyclophosphamide and docetaxel | Drug: Doxorubicin<br>* doxorubicin (arm A:60 mg/m2) and arm B: 50 mg/m2)<br>* Other names: adriamycin;Drug: Cyclophosphamide<br>* Cyclophosphamide: (arm A; 6000 mg/m2) an (arm B: 500 mg/m2)<br>* Other names: Revimmune;Drug: Docetaxel<br>* Docetaxel: (arm A: 100 mg/m2) and (arm B: 75 mg/m2)<br>* Other names: Taxotere;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pathologic complete response rate to neoadjuvant chemotherapy. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The delivered chemotherapy dose and dose-intensity of both chemotherapy regimens |  |  | 
| The tolerability (grade 3/4 CTC toxicities) of both chemotherapy regimens. |  |  | 
| The clinical responses of neoadjuvant chemotherapy correlated to pathological responses after neoadjuvant chemotherapy. |  |  | 
| The value of breast MRI in evaluating response to neoadjuvant chemotherapy as compared to clinical palpation, ultrasound techniques and histo-pathological outcome. |  |  | 
| The false-negative rate of the sentinel node biopsy after neoadjuvant chemotherapy. |  |  | 
| The disease-free and overall survival after 3 and 5 years follow-up. |  |  | 
| The relation between pCR and DFS/OS. |  |  | 
| The feasibility of the criteria for reporting pathological tumour response in surgical breast and axillary node resection specimens. |  |  | 
| The prognostic and predictive value of tumour- and molecular markers, including ER, PgR, c-erbB2, microarray and other tumour characteristic analyses. |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Large resectable breast cancer, Locally advanced breast cancer, Neoadjuvant therapy