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Trial registered on ANZCTR

Registration number

ACTRN12611000506998

Ethics application status

Approved

Date submitted

12/05/2011

Date registered

16/05/2011

Date last updated

23/09/2014

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]

Nil

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

high-risk operable breast cancer

Condition category

Condition code

Cancer

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]

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]

Disease-Free Survival (DFS).
DFS was measured from randomization until local recurrence, distant relapse or death from the disease without relapse.

Timepoint [1]

5 years from study initiation

Secondary outcome [1]

Overall Survival (OS).
OS was measured from the date of randomization until death from any cause.

Timepoint [1]

5 years from study initiation

Secondary outcome [2]

Acute toxicity

Timepoint [2]

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 [3]

Quality of Life. We use the EUroQol (EQ-5D) evaluation questionnaire

Timepoint [3]

Baseline-End of Chemotherapy

Secondary outcome [4]

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 [4]

Results are correlated with outcome at 5 years and 8 years

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

Sex

Females

Can healthy volunteers participate?

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

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

11/06/1997

Actual

11/06/1997

Date of last participant enrolment

Anticipated

Actual

2/11/2000

Date of last data collection

Anticipated

Actual

Sample size

Target

600

Accrual to date

Final

Recruitment outside Australia

Country [1]

Greece

State/province [1]

Funding & Sponsors

Funding source category [1]

Other Collaborative groups

Name [1]

Hellenic Cooperative Oncology Group

Address [1]

Hatzikostandi 18, 11524, Athens

Country [1]

Greece

Primary sponsor type

Other Collaborative groups

Name

Hellenic Cooperative Oncology Group

Address

Hatzikostandi 18, 11524, Athens

Country

Greece

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

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

Prof George Fountzilas, MD

Address

"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki

Country

Greece

Phone

+30 2313323959

Fax

+30 2313683136

fountzil@auth.gr

Contact person for public queries

Name

Eleni Papakostaki

Address

18, Hatzikostandi str, 11524, Athens

Country

Greece

Phone

+30 2106912520

Fax

e_papakostaki@hecog.ondsl.gr

Contact person for scientific queries

Name

Prof. George Fountzilas, MD

Address

"Papageorgiou" Hospital, Nea Efkarpia, 564 29, Thessaloniki

Country

Greece

Phone

+30 2313323959

Fax

fountzil@auth.gr

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	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.	2012	https://dx.doi.org/10.1186/bcr3354
Dimensions AI	Differential Response of Immunohistochemically Defined Breast Cancer Subtypes to Anthracycline-Based Adjuvant Chemotherapy with or without Paclitaxel	2012	https://doi.org/10.1371/journal.pone.0037946
Dimensions AI	HER2 and TOP2A in high-risk early breast cancer patients treated with adjuvant epirubicin-based dose-dense sequential chemotherapy	2012	https://doi.org/10.1186/1479-5876-10-10
Embase	Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: Pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials.	2013	https://dx.doi.org/10.1186/1471-2407-13-163
Dimensions AI	Prognostic Significance of ESR1 Gene Amplification, mRNA/Protein Expression and Functional Profiles in High-Risk Early Breast Cancer: A Translational Study of the Hellenic Cooperative Oncology Group (HeCOG)	2013	https://doi.org/10.1371/journal.pone.0070634
Dimensions AI	alphaB-crystallin is a marker of aggressive breast cancer behavior but does not independently predict for patient outcome: a combined analysis of two randomized studies	2014	https://doi.org/10.1186/1472-6890-14-28
Dimensions AI	Differential Expression of the Insulin-Like Growth Factor Receptor among Early Breast Cancer Subtypes	2014	https://doi.org/10.1371/journal.pone.0091407
Embase	Prognostic significance of VEGFC and VEGFR1 mRNA expression according to HER2 status in breast cancer: A study of primary tumors from patients with high-risk early breast cancer participating in a randomized hellenic cooperative oncology group trial.	2015
Dimensions AI	Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group	2017	https://doi.org/10.1186/s12967-017-1134-7
Dimensions AI	Evaluation of the Prognostic Value of RANK, OPG, and RANKL mRNA Expression in Early Breast Cancer Patients Treated with Anthracycline-Based Adjuvant Chemotherapy	2017	https://doi.org/10.1016/j.tranon.2017.05.006

N.B. These documents automatically identified may not have been verified by the study sponsor.

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