Clinical trial NCT00129935: EC Followed Docetaxel Versus ET Followed Capecitabine as Adjuvant Chemotherapy for Node Positive Operable Breast Cancer
Official title: Phase III Trial to Compare Epirubicin and Cyclophosphamide (EC) Followed by Docetaxel (T) to Epirubicin and Docetaxel (ET) Followed by Capecitabine (X) as Adjuvant Treatment, Node Positive Breast Cancer Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: HER2 negative breast cancer
Node positive breast cancer
Adjuvant treatment
Oral chemotherapy
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: Sanofi
name: Hoffmann-La Roche
name: Pfizer
First posted: 2005-08-12
Enrollment: 1384
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: This is a prospective, randomised phase III trial, to compare the efficacy and safety profiles of two types of adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2) negative, node positive breast cancer patients.

Control Arm: This includes 4 cycles of EC 90/600 mg/m2 day 1 every 3 weeks, followed by 4 cycles of T 100 mg/m2 day 1 every 3 weeks.

Experimental Arm: This includes 4 cycles of ET 90/75 mg/m2, day 1 every 3 weeks, followed by 4 cycles of capecitabine 1250 mg/m2, twice a day, via oral intake, for 14 days, and then a one-week rest period.

Premenopausal women with hormone receptor positive tumours must receive 5 years of tamoxifen after the end of chemotherapy.

Postmenopausal women with hormone receptor positive tumours can receive tamoxifen or aromatase inhibitors (or both) after the end of chemotherapy.

Patients may receive radiotherapy when clinically indicated.

Detailed description: Estimation of the 5-year disease-free survival in the control arm is 72%. The experimental arm is expected to increase the 5-year disease-free survival by 7% (up to 79%). With an alpha error of 0.05 and 80% power, 592 patients per arm are needed. Assuming a 17% post-randomization drop-out, 691 patients per arm are needed.

Eligibility criteria: Inclusion Criteria:

* Written informed consent.
* Histological diagnosis of operable invasive adenocarcinoma of the breast (T1-T3). Tumours must be HER2 negative. Time window between surgery and study randomization must be less than 60 days.
* Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinomas in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
* Positive axillary lymph nodes defined as at least 1 out of 10 nodes with presence of disease. If sentinel node technique is used, sentinel node can be the only node affected. Patients belonging to the following classifications are eligible: TNM pathologic stage N1a, TNM pathologic stage N2a, TNM pathologic stage N3a.
* Status of hormone receptors in primary tumour. Results must be available before the end of adjuvant chemotherapy.
* Patients must not present evidence of metastatic disease. Status of HER2 in primary tumour, known before randomization. Patients with immune histochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescence in situ hybridization (FISH) is mandatory and result must be negative.
* Age \>= 18 and \<= 70 years old.
* Performance status (Karnofsky index) \>= 80.
* Normal electrocardiogram (EKG) in the 12 weeks prior to randomization. If needed, normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF).
* Laboratory results (within 14 days prior to randomization):

  * Hematology: neutrophils \>= 1.5 x 10\^9/l; platelets \>= 100 x 10\^9/l; hemoglobin \>= 10 mg/dl;
  * Hepatic function: total bilirubin \<= 1 upper normal limit (UNL); serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) \<= 2.5 UNL; alkaline phosphatase \<= 2.5 UNL. If values of SGOT and SGPT \> 1.5 UNL are associated to alkaline phosphatase \> 2.5 UNL, patient is not eligible;
  * Renal function: creatinine \<= 175 mmol/l (2 mg/dl); creatinine clearance \>= 60 ml/min;
  * Pharmacogenetics: one blood sample is needed for single nucleotide polymorphism (SNP) assessment.
* Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week window). All patients must have a bilateral mammogram, thorax x-ray, abdominal echography and/or computed tomography (CT)-scan. If bone pain, and/or alkaline phosphatase elevation, a bone scintigraphy is mandatory. This test is recommended for all patients. Other tests: as clinically indicated.
* Patients able to comply with treatment and study follow-up.
* Negative pregnancy test done in the 14 prior days to randomization.

Exclusion Criteria:

* Prior systemic therapy for breast cancer.
* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
* Prior radiotherapy for breast cancer.
* Bilateral invasive breast cancer.
* Pregnant or lactating women. Adequate contraceptive methods must be used during chemotherapy and hormone therapy treatments.
* Any T4 or M1 tumour.
* Axillary lymph nodes: patients belonging to the following classifications are excluded: TNM pathologic stage N1b, TNM pathologic stage N1c, TNM pathologic stage N2b, TNM pathologic stage N3b, TNM pathologic stage N3c.
* HER2 positive breast cancer (IHC 3+ or positive FISH result).
* Pre-existing grade \>= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria version 2.0 \[NCICTC v-2.0\]).
* Any other serious medical pathology, such as congestive heart failure; unstable angina; history of myocardial infarction during the previous year; uncontrolled hypertension or high risk arrhythmias.
* History of neurological or psychiatric disorders, which could preclude the patients from free informed consent.
* Active uncontrolled infection.
* Active peptic ulcer; unstable diabetes mellitus.
* Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
* Chronic treatment with corticosteroids.
* Contraindications for corticosteroid administration.
* Concomitant treatment with raloxifene, tamoxifen or other selective estrogen receptor modulators (SERMs), either for osteoporosis treatment or for prevention. These treatments must stop before randomisation.
* Concomitant treatment with other investigational products; participation in other clinical trials with a non-marketed drug in the 20 previous days before randomization.
* Concomitant treatment with another therapy for cancer.
* Males.

Primary outcomes:
measure: Number of Participants With Disease-free Survival (DFS) Event
timeFrame: 5 years
Secondary outcomes:
measure: Number of Participants With Overall Survival (OS) Event
timeFrame: Up to 5 years
measure: The Number of Participants Who Experienced Adverse Events (AE)
timeFrame: 5 years
measure: Quality of Life Questionnaire: Number of Participants With Hair Loss
timeFrame: Up to 24 months
measure: Quality of Life Questionnaire: Number of Participants With Hair Loss Recovery
timeFrame: Up to 30 months
measure: Quality of Life Questionnaire: Time to Taking Off the Wig
timeFrame: Up to 30 months
Other outcomes:
Locations:
city: Ferrol
country: Spain
facility: Hospital Arquitecto Marcide
state: A Coruña
city: Elche
country: Spain
facility: Hospital General Universitario de Elche
state: Alicante
city: Elda
country: Spain
facility: Hospital General Universitario de Elda
state: Alicante
city: Badalona
country: Spain
facility: Hospital Municipal de Badalona
state: Barcelona
city: Badalona
country: Spain
facility: Hospital Universitario Germans Trias i Pujol
state: Barcelona
city: Sabadell
country: Spain
facility: Corporació Sanitaria Parc Taulí
state: Barcelona
city: Santa Coloma De Gramenet
country: Spain
facility: Hospital del Espíritu Santo
state: Barcelona
city: Terrassa
country: Spain
facility: Hospital Mutua de Terrassa
state: Barcelona
city: Terrassa
country: Spain
facility: Consorci Sanitari de Terrassa
state: Barcelona
city: Vic
country: Spain
facility: Hospital General Universitario de Vic
state: Barcelona
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Castellón De La Plana
country: Spain
facility: Hospital Provincial de Castellón
state: Castellón
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
state: Cordoba
city: Jerez De La Frontera
country: Spain
facility: Hospital de Jerez de la Frontera
state: Cádiz
city: Donostia-San Sebastián
country: Spain
facility: Onkologikoa
state: Guipúzcoa
city: Donostia-San Sebastián
country: Spain
facility: Hosptial Donostia
state: Guipúzcoa
city: Barbastro
country: Spain
facility: Hospital de Barbastro
state: Huesca
city: Alcorcón
country: Spain
facility: Hospital Universitario Fundación Alcorcón
state: Madrid
city: Leganés
country: Spain
facility: Hospital Universitario Severo Ochoa
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro
state: Madrid
city: Reus
country: Spain
facility: Hospital Universitario San Joan de Reus
state: Tarragona
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña
city: A Coruña
country: Spain
facility: Centro Oncológico de Galicia
city: Albacete
country: Spain
facility: Hospital General Universitario de Albacete
city: Alicante
country: Spain
facility: Hospital General Universitario de Alicante
city: Alicante
country: Spain
facility: Hospital Universitario Virgen de los Lirios
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital Universitario Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Cádiz
country: Spain
facility: Hospital Universitario Puerta del Mar
city: Girona
country: Spain
facility: Instituto Catalán de Oncología de Girona
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: Guadalajara
country: Spain
facility: Hospital General Universitario de Guadalajara
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaén
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Lleida
city: Lugo
country: Spain
facility: Hospital Universitario Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Fundación Jiménez Díaz
city: Madrid
country: Spain
facility: Hospital Clínico Universitario San Carlos
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer
city: Murcia
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Málaga
country: Spain
facility: Hospital Clínico Universitario Virgen de la Victoria
city: Málaga
country: Spain
facility: Hospital Regional Universitario Carlos Haya
city: Ourense
country: Spain
facility: Complejo Hospitalario Unviersitario de Ourense
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santa Cruz De Tenerife
country: Spain
facility: Hospital Universitario de Canarias
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Sevilla
country: Spain
facility: Hospital Universitario de Valme
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Valencia
country: Spain
facility: Instituto Valenciano de Oncología
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: Valencia
country: Spain
facility: Hospial General Universitario de Valencia
city: Valencia
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Valencia
city: Zamora
country: Spain
facility: Hospital Provincial Rodríguez Chamorro de Zamora
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario de Zaragoza "Lozano Blesa"
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
Study officials:
affiliation: Hospital Clínico Universitario San Carlos
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Martin M, Ruiz Simon A, Ruiz Borrego M, Ribelles N, Rodriguez-Lescure A, Munoz-Mateu M, Gonzalez S, Margeli Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martinez-Janez N, Mendiola Fernandez C, Rodriguez CA, Martinez de Duenas E, Andres R, Plazaola A, de la Haba-Rodriguez J, Lopez-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sanchez-Rovira P, Baena-Canada JM, Casas M, del Carmen Camara M, Carrasco EM, Lluch A. Epirubicin Plus Cyclophosphamide Followed by Docetaxel Versus Epirubicin Plus Docetaxel Followed by Capecitabine As Adjuvant Therapy for Node-Positive Early Breast Cancer: Results From the GEICAM/2003-10 Study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. doi: 10.1200/JCO.2015.61.9510. Epub 2015 Sep 28.
citation: van Mackelenbergh MT, Seither F, Mobus V, O'Shaughnessy J, Martin M, Joensuu H, Untch M, Nitz U, Steger GG, Miralles JJ, Barrios CH, Toi M, Bear HD, Muss H, Reimer T, Nekljudova V, Loibl S. Effects of capecitabine as part of neo-/adjuvant chemotherapy - A meta-analysis of individual breast cancer patient data from 13 randomised trials including 15,993 patients. Eur J Cancer. 2022 May;166:185-201. doi: 10.1016/j.ejca.2022.02.003. Epub 2022 Mar 16.
citation: Hoon SN, Lau PK, White AM, Bulsara MK, Banks PD, Redfern AD. Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer. Cochrane Database Syst Rev. 2021 May 26;5(5):CD011220. doi: 10.1002/14651858.CD011220.pub2.