Marched Pair Study Conventional Doxorubicin(DOX) Versus Pegylated Liposomal Doxorubicin(PLD) Neoadjuvant Chemotherapy

Study Overview
=================
Brief Summary
-----------------
The regimen PLD plus cyclophosphamide 4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in phase II CAPRICE) will be used as experimental group. The regimen will be compared to the standard treatment of doxorubicin plus cyclophosphamide(AC) 4 cycles followed by paclitaxel or docetaxel 4 cycles[noted in National Comprehensive Cancer Network (NCCN) guideline].

Detailed Description
-----------------
Purpose :Anthracycline based chemotherapy regimen is the milestone on the treatment of breast cancer . A sequential protocol, using docetaxel or Paclitaxel after an anthracycline-based combination is primary treatment for high-risk breast cancer .Despite its efficient antitumor activity profile, the use of conventional anthracycline in clinical practice is limited due to it's the risk of cardiac toxicity. The meta analysis show that subclinical cardiotoxicity was 17.9% whereas the incidence of clinically overt cardiotoxicity was 6.3%. Overall cardiovascular events occurred in 10.6%(Lotrisone , Am J Cardiol. 2013).Many patients have healed from breast cancer while they are snatched lives because of heart issue from chemotherapy using anthracycline. There are a lot of clinical trials exploring the possibilities of chemotherapy regimen without anthracycline ,however the recent result has shown anthracycline is indispensible for the patients whose axillary nodes are involved or triple negative breast cancer (ASCO 2016 ).So our target is to find a kind of anthracycline which is of equal efficiency with conventional anthracycline while less cardiac toxicity. Pegylated Liposomal Doxorubicin(PLD) is a novel kind of anthracycline. It distributes into cardiac cells lowly and releases Doxorubicin (DOX) slower to avoid peak plasma concentration, so it is of significant less cardiotoxicity compared to free DOX. It also achieve non-inferior efficacy at 50mg/m2 to conventional anthracycline in Metastatic Breast Cancer (MBC).( M. E. R. O'Brien, ,Annals of Oncology,2004;). PLD 35mg/m2 in combination with paclitaxel showed an overall response rate of 71% ,tolerating toxicity of the skin(3% hand-foot syndrome)and rare cardiac event( H. Gogas1, Annals of Oncology, 2002;Gil-Gil , Breast Cancer Res Treat. 2015)However, There are a crucial question is to know if 35mg/m2 PLD has equivalent efficacy with less cardiac toxicity compared with 60 mg/m2 DOX in adjuvant chemotherapy for all patients. The regimen PLD plus cyclophosphamide 4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in phase II CAPRICE)will be used as experimental group. The regimen will be compared to the standard treatment of doxorubicin plus cyclophosphamide (AC)4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in NCCN guideline). Condition Intervention Phase Individualized Chemotherapy Drug: Pegylated Liposomal Doxorubicin(PLD) Drug: Doxorubicin(DOX) Drug: Cyclophosphamide Drug: docetaxel or Paclitaxel Phase 2 Study Type: Interventional Study Design: Allocation: assignment based on patients desire Endpoint Classification: Safety/Efficacy Study Intervention Model: Marched pair Parallel Assignment Masking: Open Label Primary Purpose: Treatment

Official Title
-----------------
Marched Pair Study of the Standard Chemotherapy 4doxorubicin Plus Cyclophosphamide(AC) 60 + 4 Docetaxel Protocol Versus 4 PLD C35+4 Docetaxel in Neoadjuvant Chemotherapy of Breast Cancer

Conditions
-----------------
Antineoplastic Combined Chemotherapy Protocols

Intervention / Treatment
-----------------
* Drug: Pegylated Liposomal Doxorubicin
* Drug: Cyclophosphamide
* Drug: Taxotere
* Drug: Dexrazoxane (DZR)
* Drug: vitamin B
* Drug: Doxorubicin
* Procedure: Breast Conserved Surgery
* Procedure: Modified Radical Mastectomy
* Procedure: Sentinel Lymph Node Biopsy（SLNB）


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient with histological proof of invasive cancer, whose clinical tumor diameter is > 2 cm, or < 2 cm, but Axillary lymphnodes are involved .There is no metastatic Imaging findings. Stage II,III tumor, non-metastatic, grade II - III Performance Status = 0-1 World Health Organization (WHO). Patient non pretreated for breast cancer. Patient without cardiac pathology and without anthracyclines contra-indication (assessed by normal ejection fraction). Normal haematological, renal and hepatic functions : platelets > 100. 109 /l, Hb > 10 g/dl, normal bilirubin serum , Aspartate transaminase(ASAT) and Alanine Aminotransferase(ALAT) < 2,5 Upper Limit of Normal (ULN), alkaline phosphatases < 2,5 ULN, creatinin < 140 µmol/l or creatinin clearance > 60 ml/min Written informed consent dated and signed by the patient Exclusion Criteria: All other breast cancers than those described in inclusion criteria, in particular inflammatory and/or neglected (T4b or T4d) forms. Patient presenting with intraduct cancer in situ.(DCIS) Grade I well differentiated tumor. Non measurable lesion, in the two diameters, whatever radiological methods used. Patient already operated for breast cancer or having had primary axillar node dissection. Patient presenting with cancer in other system. Any psychological, familial, sociological or geographical condition that may potentially hamper compliance with the study protocol and follow up schedule, assessed with the patient prior to registration in the trial

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: conventional Doxorubicin plus C-T<br>AC-T regimen 8 cycles ,60mg/M2 conventional Doxorubicin will be used as active comparator. four cycles of Doxorubicin plus 600mg/m2 Cyclophosphamide every three weeks followed 4 cycles of 100mg/m2 Taxotere, every three weeks for one cycle.Dexrazoxane (DZR)will be used for protecting cardiac toxicity.Patients will undergo Modified Radical Mastectomy or Breast Conserved Surgery or Axillary Lymph Node Dissection(ALND) or Sentinel Lymph Node Biopsy（SLNB） after 8 cycles of chemotherapy | Drug: Cyclophosphamide<br>* 600mg/m2 IV drop during the first 4 cycles every three week<br>* Other names: cytoxan;Drug: Taxotere<br>* 100mg/m2 IV drop during the last 4 cycles every three week<br>* Other names: Docetaxel;Drug: Dexrazoxane (DZR)<br>* DZR will be administrated for protecting Cardiac toxicity in the group of Active comparator.<br>* Other names: DZR;Drug: Doxorubicin<br>* 60mg/m2 Doxorubicin IV drop during the first 4 cycles every three week<br>* Other names: Pirarubicin Hydrochloride for injection;Procedure: Breast Conserved Surgery<br>* Patients will undergo Breast Conserved Surgery if the tumor/breast ratio is proper and she demands to conserve the breast after 8 cycles of chemotherapy<br>* Other names: segmental mastectomy and ALND;Procedure: Modified Radical Mastectomy<br>* Patients will undergo Modified Radical Mastectomy if she does not keep her breast after 8 cycles of chemotherapy<br>* Other names: Mastectomy and ALND;Procedure: Sentinel Lymph Node Biopsy（SLNB）<br>* Patients will undergo Sentinel Lymph Node Biopsy（SLNB） if the evaluation of lymph node are negative after 8 cycles of chemotherapy<br>* Other names: Sentinel Lymph Node(SLN);|
| Experimental: PLD plus C -T<br>Pegylated Liposomal Doxorubicin(PLD) plus Cyclophosphamide followed Taxotere 8 cycles.35mg/M2 PLD will be used as experimental medicine. four cycles of PLD plus 600mg/m2 Cyclophosphamide every three weeks followed 4 cycles of 100mg/m2 Taxotere , every three weeks for one cycle.Vitamin B will be used for protecting hand-foot syndrome(HFS).Patients will undergo Modified Radical Mastectomy or Breast Conserved Surgery or Axillary Lymph Node Dissection(ALND) or Sentinel Lymph Node Biopsy（SLNB） after 8 cycles of chemotherapy | Drug: Pegylated Liposomal Doxorubicin<br>* 35mg/m2 iv drop during the first 4 cycles every three week<br>* Other names: liposome doxorubicin injection;Drug: Cyclophosphamide<br>* 600mg/m2 IV drop during the first 4 cycles every three week<br>* Other names: cytoxan;Drug: Taxotere<br>* 100mg/m2 IV drop during the last 4 cycles every three week<br>* Other names: Docetaxel;Drug: vitamin B<br>* Vitamin B will be administrated for protecting HFS in PLD group<br>* Other names: Compound Vitamin B;Procedure: Breast Conserved Surgery<br>* Patients will undergo Breast Conserved Surgery if the tumor/breast ratio is proper and she demands to conserve the breast after 8 cycles of chemotherapy<br>* Other names: segmental mastectomy and ALND;Procedure: Modified Radical Mastectomy<br>* Patients will undergo Modified Radical Mastectomy if she does not keep her breast after 8 cycles of chemotherapy<br>* Other names: Mastectomy and ALND;Procedure: Sentinel Lymph Node Biopsy（SLNB）<br>* Patients will undergo Sentinel Lymph Node Biopsy（SLNB） if the evaluation of lymph node are negative after 8 cycles of chemotherapy<br>* Other names: Sentinel Lymph Node(SLN);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| improvement of pathological complete response（PCR) | Pathological evaluation after sugary | at th 26th weeks of treatment since recruitment (after 8 cycles of neoadjuvant chemotherapy when the patient will undergo surgery) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance according to Common Terminology Criteria Adverse Events (CTCAE) Version 4.0 | Cardiogram Cardiac sonography, examination of Cardiac Marker if necessary and Questionaire Survey about Side Effect | at 3rd ,6th,9th,12th, 15 ,18,21,24th weeks since recruitment (after each cycle of chemotherapy) ; half year ,1 year , one and half year ,two years since recruitment | 
| Clinical Response Rate | ultrasound of breast and Pathological reports | at 3rd ,6th,9th,12th, 15 ,18,21,24th weeks since recruitment （after each cycle of chemotherapy） | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neoadjuvant chemotherapy, Pegylated liposomal doxorubicin, breast cancer