Trial registered on ANZCTR


Trial ID
ACTRN12611000506998
Ethics application status
Approved
Date submitted
12/05/2011
Date registered
16/05/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
Epirubicin-Paclitaxel-Cyclophosphamide Methotrexate Fluorouracil (E-T-CMF) versus Epirubicin-Cyclophosphamide Methotrexate Fluorouracil (E-CMF) as adjuvant chemotherapy in high risk patients with operable breast cancer. A phase III study conducted by the Hellenic Cooperative Oncology Group (HE10/97)
Scientific title
High-risk patients with operable breast cancer treated with Epirubicin followed by Paclitaxel followed by Cyclophosphamide-Methotrexate-Fluorouracil (E-T-CMF) or Epirubicin followed by Cyclophosphamide-Methotrexate-Fluorouracil (E-CMF) as adjuvant chemotherapy to investigate the effect of the treatment on disease-free survival and overall survival.
Secondary ID [1] 262142 0
Nil
Universal Trial Number (UTN)
Trial acronym

Health condition
Health condition(s) or problem(s) studied:
high-risk operable breast cancer 265820 0
Condition category
Condition code
Cancer 265974 265974 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
epirubicin [110 milligram/square meter (mg/m2) intravenously infused over 30 minutes] every 2 weeks for 3 cycles followed by 3 cycles of paclitaxel (250 mg/m2, intravenously infused over 3 hours) every 2 weeks and 3 cycles of CMF (cyclophosphamide; 840 mg/m2, methotrexate; 57 mg/m2 and fluorouracil; 840 mg/m2 intravenously infused over 30 minutes) every 2 weeks
Intervention code [1] 264560 0
Treatment: drugs
Comparator / control treatment
epirubicin (110 mg/m2, intravenously infused over 30 minutes) every 2 weeks for 4 cycles followed by 4 cycles of CMF (cyclophosphamide; 840 mg/m2, methotrexate; 57 mg/m2 and fluorouracil; 840 mg/m2, intravenously infused over 30 minutes) every 2 weeks.
Control group
Active

Outcomes
Primary outcome [1] 266728 0
Disease-Free Survival (DFS).
DFS was measured from randomization until local recurrence, distant relapse or death from the disease without relapse.
Timepoint [1] 266728 0
5 years from study initiation
Secondary outcome [1] 276269 0
Translational Research of Human Epidermal growth factor Receptor 2 (HER2) status and other biomarkers like: basal marker, angiogenesis, BRCA1 etc.
We collect paraffin embedded tumor tissue at baseline.
The samples are assessed by immunohistochemistry, Fluorescent in situ hybridization (FISH), Chromogenic In Situ Hybridization (CISH), polymerase chain reaction (PCR).
Timepoint [1] 276269 0
Results are correlated with outcome at 5 years and 8 years
Secondary outcome [2] 276313 0
Overall Survival (OS).
OS was measured from the date of randomization until death from any cause.
Timepoint [2] 276313 0
5 years from study initiation
Secondary outcome [3] 276314 0
Acute toxicity
Timepoint [3] 276314 0
Toxicity is assessed by laboratory evaluation of hematology and biochemistry, physical examination etc.
1 month since the last administration of chemotherapy for acute toxicity
Secondary outcome [4] 276315 0
Quality of Life. We use the EUroQol (EQ-5D) evaluation questionnaire
Timepoint [4] 276315 0
Baseline-End of Chemotherapy

Eligibility
Key inclusion criteria
-Histologically-confirmed epithelial cancer of the mammary gland. -Premenopausal patients with T1 to T2 classification with histologically-confirmed invasion of axillary lymph nodes (N1 classification) or T3 and N0 or N1 classification. -Postmenopausal patients with T1 to T2 classification and > 4 positive axillary nodes or T3 and N0 or N1 classification. - White Blood Cells (WBC) >4x10^9/litre, platelets >100 x10^9 /litre. -Serum creatinine, Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), gamma-glutamyltranspeptidase (gamma-GT), serum bilirubin < = 1.3 milligram/milliliter (mg/ml) or inside the normal range of the participating hospital. -Performance status (World Health Organization) 0 or 1. -Age >= 18 years. -Previous surgical treatment: Either radical surgery (i.e. total, radical or modified radical mastectomy), or, for a partial mastectomy, a histologically confirmed sane margin of 2 cm or more and the results of the axillary node dissection available. -Time from surgery 2 to 4 weeks -Informed consent of the patient according to the dispositions of the Helsinki convention and its Tokyo and Venice amendments and to individual institutional policy.
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
- Previous antitumor chemotherapy or radiation
- History of myocardial infarction within the previous 12 months or heart failure (including cardiac insufficiency controlled by digitalis and diuretics) or arrhythmias requiring medication or uncontrolled arterial hypertension (Blood Pressure>= 200/110 millimetres of mercury (mmHg). In high risk patients a normal baseline left ventricular ejection fraction (LVEF) should be demonstrated by Multi Gated Acquisition Scan (MUGA) scan or echocardiogram (ECHO).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint(s)

Recruitment
Anticipated date of first participant enrolment
11/06/1997
Actual date of first participant enrolment
11/06/1997
Anticipated date last participant enrolled
Actual date last participant enrolled
2/11/2000
Anticipated date of last data collection
Actual date of last data collection
Target sample size
600
Actual sample size
Recruitment status
Completed
Recruitment outside Australia
Country [1] 3583 0
Greece
State/province [1] 3583 0

Funding & Sponsors
Funding source category [1] 265042 0
Other Collaborative groups
Name [1] 265042 0
Hellenic Cooperative Oncology Group
Address [1] 265042 0
Hatzikostandi 18, 11524, Athens
Country [1] 265042 0
Greece
Primary sponsor type
Other Collaborative groups
Name
Hellenic Cooperative Oncology Group
Address
Hatzikostandi 18, 11524, Athens
Country
Greece
Secondary sponsor category [1] 264143 0
None
Name [1] 264143 0
Address [1] 264143 0
Country [1] 264143 0

Ethics approval
Ethics application status
Approved

Summary
Brief summary
The aim of this phase III, randomized study was to explore the effect of dose-dense sequential chemotherapy with or without paclitaxel primarily on disease-free survival (DFS) and secondarily on overall survival (OS) in patients with high-risk operable breast cancer. Acute toxicity and quality of life were also investigated. Translational research studies were also performed.
Trial website
Trial related presentations / publications
Postoperative dose-dense sequential chemotherapy with epirubicin, followed byCMFwith or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III
study conducted by the Hellenic Cooperative Oncology Group
G. Fountzilas, D. Skarlos, U. Dafni, H. Gogas, E. Briasoulis, D. Pectasides, C. Papadimitriou, C. Markopoulos, A. Polychronis, H. P. Kalofonos, V. Siafaka, P. Kosmidis, E. Timotheadou, D. Tsavdaridis, D. Bafaloukos, P. Papakostas, E. Razis, P. Makrantonakis, G. Aravantinos, C. Christodoulou and A.M. Dimopoulos
Annals of Oncology 16: 1762–1771, 2005

Evaluation of the prognostic and predictive value of p53 and Bcl-2 in breast cancer patients participating in a randomized study with dose-dense sequential adjuvant chemotherapy
V. Malamou-Mitsi, H. Gogas, U. Dafni, A. Bourli, T. Fillipidis, M. Sotiropoulou, D. Vlachodimitropoulos, S. Papadopoulos, O. Tzaida, G. Kafiri, V. Kyriakou, S. Markaki, I. Papaspyrou, E. Karagianni, K. Pavlakis, T. Toliou, C. D. Scopa, P. Papakostas, D. Bafaloukos, C. Christodoulou and G. Fountzilas
Annals of Oncology 17: 1504–1511, 2006

Evaluation of the prognostic value of HER-2 and VEGF in breast cancer patients participating in a randomized study with dose–dense sequential adjuvant chemotherapy
Ioannis Kostopoulos, Petroula Arapantoni-Dadioti, Helen Gogas, Savvas Papadopoulos, Vasiliki Malamou-Mitsi, Chrisoula D. Scopa, Sofia Markaki, Evangelia Karagianni, Vasiliki Kyriakou, Anastasia Margariti, Elisavet Kyrkou, Kitty Pavlakis, Thomas Zaramboukas, Anna Skordalaki, Antonia Bourli, Christos Markopoulos, Dimitrios Pectasides, Meletios A. Dimopoulos, Dimosthenis Skarlos, and George Fountzilas
Breast Cancer Research and Treatment 96: 251–261, 2006


Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study.
Koutras AK, Kalogeras KT, Dimopoulos MA, Wirtz RM, Dafni U, Briasoulis E, Pectasides D, Gogas H, Christodoulou C, Aravantinos G, Zografos G, Timotheadou E, Papakostas P, Linardou H, Razis E, Economopoulos T, Kalofonos HP, Fountzilas G
British Journal of Cancer 99(11): 1775-85, 2008


Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial.
Pentheroudakis G, Kalogeras KT, Wirtz RM, Grimani I, Zografos G, Gogas H, Stropp U, Pectasides D, Skarlos D, Hennig G, Samantas E, Bafaloukos D, Papakostas P, Kalofonos HP, Pavlidis N, Fountzilas G
Breast Cancer Research and Treatment 116(1):131-43, 2009


Prognostic utility of beta-tubulin isotype III and correlations with other molecular and clinicopathological variables in patients with early breast cancer: a translational Hellenic Cooperative Oncology Group (HeCOG) study.
Pentheroudakis G, Batistatou A, Kalogeras KT, Kronenwett R, Wirtz RM, Bournakis E, Eleftheraki AG, Pectasides D, Bobos M, Papaspirou I, Kamina S, Gogas H, Koutras AK, Pavlidis N, Fountzilas G
Breast Cancer Research and Treatment 127(1):179-93, 2011


Triple-negative phenotype is of adverse prognostic value in patients treated with dose-dense sequential adjuvant chemotherapy: a translational research analysis in the context
of a Hellenic Cooperative Oncology Group (HeCOG) randomized phase III trial
P. Skarlos, C. Christodoulou, K. T. Kalogeras , A. G. Eleftheraki , M. Bobos , A. Batistatou , C. Valavanis, O. Tzaida, E. Timotheadou, R. Kronenwett, R. M. Wirtz, I. Kostopoulos, D. Televantou, E. Koutselini, I. Papaspirou, C. A. Papadimitriou, D. Pectasides, H. Gogas, G. Aravantinos, N. Pavlidis, P. Arapantoni, D. V. Skarlos, G. Fountzilas
Cancer Chemotherapy and Pharmacology 69(2): 533-46, 2012


HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy
George Fountzilas, Christos Valavanis, Vassiliki Kotoula, Anastasia G Eleftheraki, Konstantine T Kalogeras, Olympia Tzaida, Anna Batistatou, Ralf Kronenwett, Ralph M Wirtz, Mattheos Bobos, Eleni Timotheadou, Nikolaos Soupos, George Pentheroudakis, Helen Gogas, Dimitrios Vlachodimitropoulos, Genovefa Polychronidou, Gerasimos Aravantinos, Angelos Koutras, Christos Christodoulou, Dimitrios Pectasides and Petroula Arapantoni
Journal of Translational Medicine 2012, 10:10


Improved Outcome of High-Risk Early HER2 Positive Breast Cancer With High CXCL13-
CXCR5 Messenger RNA Expression
Evangelia Razis, Konstantine T. Kalogeras, Vassiliki Kotoula, Anastasia G. Eleftheraki, Nikitas Nikitas, Ralf Kronenwett, Eleni Timotheadou, Christos Christodoulou, Dimitrios Pectasides,
Helen Gogas, Ralph M. Wirtz, Thomas Makatsoris, Dimitrios Bafaloukos, Gerasimos Aravantinos, Despina Televantou, Nicholas Pavlidis, George Fountzilas
Clinical Breast Cancer 12(3): 183-93, 2012


Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study.
Psyrri A, Kalogeras KT, Kronenwett R, Wirtz RM, Batistatou A, Bournakis E, Timotheadou E, Gogas H, Aravantinos G, Christodoulou C, Makatsoris T, Linardou H, Pectasides D, Pavlidis N, Economopoulos T, Fountzilas G
Annals of Oncology 23(6): 1422-7, 2012


The prognostic and predictive value of mRNA expression of vascular endothelial growth factor family members in breast cancer: a study in primary tumors of high-risk early breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial.
Linardou H, Kalogeras KT, Kronenwett R, Kouvatseas G, Wirtz RM, Zagouri F, Gogas H, Christodoulou C, Koutras AK, Samantas E, Pectasides D, Bafaloukos D, Fountzilas G
Breast Cancer Research 14(6):R145, 2012


Prognostic significance of RACGAP1 mRNA expression in high-risk early breast cancer: a study in primary tumors of breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial.
Pliarchopoulou K, Kalogeras KT, Kronenwett R, Wirtz RM, Eleftheraki AG, Batistatou A, Bobos M, Soupos N, Polychronidou G, Gogas H, Samantas E, Christodoulou C, Makatsoris T, Pavlidis N, Pectasides D, Fountzilas G
Cancer Chemotherapy and Pharmacology 71(1):245-55, 2013
Public notes

Contacts
Principal investigator
Name 32593 0
Prof George Fountzilas, MD
Address 32593 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 32593 0
Greece
Phone 32593 0
+30 2313323959
Fax 32593 0
+30 2313683136
Email 32593 0
fountzil@auth.gr
Contact person for public queries
Name 15840 0
Ms Eleni Papakostaki
Address 15840 0
18, Hatzikostandi str, 11524, Athens
Country 15840 0
Greece
Phone 15840 0
+30 2106912520
Fax 15840 0
Email 15840 0
e_papakostaki@hecog.ondsl.gr
Contact person for scientific queries
Name 6768 0
Prof Prof. George Fountzilas, MD
Address 6768 0
"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki
Country 6768 0
Greece
Phone 6768 0
+30 2313323959
Fax 6768 0
Email 6768 0
fountzil@auth.gr