Additional identifiers
EudraCT number
2013-004307-39
ClinicalTrials.gov number
Protocol/serial number
19069
Study information
Scientific title
Response to Optimal Selection of neo-adjuvant Chemotherapy in Operable breast cancer: A randomised phase III, stratified biomarker trial of neo-adjuvant 5-Fluorouracil, Epirubicin and Cyclophosphamide vs Docetaxel and Cyclophosphamide chemotherapy
Acronym
ROSCO
Study hypothesis
Neoadjuvant chemotherapy (NAC), for early breast cancer reduces the amount of surgical treatment required, often avoiding the need for mastectomy. A pathological complete response (pCR) is generally associated with excellent prognosis and no pCR is associated with poor outcomes. To maximise pCR, patients are treated with both epirubicin and docetaxel containing combinations increasing toxicity due to exposure to both drugs. Retrospective analysis of adjuvant chemotherapy trials strongly suggests that a combination of two genetic markers (CEP17 and TOP2A) predict for epirubicin sensitivity. It may be unnecessary to treat all patients with both epirubicin and docetaxel. Current standard of care in patients with involved axillary nodes before chemotherapy is an axillary dissection. When there is no residual cancer this becomes an unnecessary procedure. The data on the use of sentinel lymph node biopsy post NAC is controversial. In ROSCO, 1056 patients with early breast cancer will be randomised from hospitals around the UK to initial chemotherapy with either epirubicin based or docetaxel based chemotherapy. They will be stratification by CEP17 and TOP2A status. On completion of 4 cycles of chemotherapy patients will undergo surgery and pCR assessment. Where pCR is not achieved, patients will receive the alternative chemotherapy as adjuvant treatment. The aim is to determine if CEP17 and TOP2A status can be used to select the appropriate chemotherapy, resulting in higher pCR rates and a requirement for less chemotherapy. Patients with axillary node involvement prechemotherapy will undergo a post NAC, sentinel node biopsy (SLNB) and axillary clearance as a single procedure to determine if post NAC SLNB is sufficiently accurate to be used as a routine staging tool in this context.
Ethics approval
First MREC approval date 08/12/2014, ref: 14/WM/1213
Study design
Randomised; Interventional; Design type: Treatment
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Topic: Cancer; Subtopic: Breast Cancer; Disease: Breast
Intervention
1. Surgery (combined SLNB and axillary node clearance will be mandatory in all patients with clinically or pathologically involved nodes prior to chemotherapy)
2. All HER2 positive patients will receive Trastuzumab at 8mg/kg with first cycle of chemotherapy followed by 6mg/kg 3 weekly for 6-12 months; TC - surgery - FEC, Docetaxel 75mg/m2, cyclophosphamide 600mg/m2
Follow Up Length: 120 month(s)
Study Entry : Registration and One or More Randomisations
Intervention type
Procedure/Surgery
Phase
Drug names
Primary outcome measure
Complete pathological response (pCR) rate; Timepoint(s): On completion of 4 cycles of NAC
Secondary outcome measures
1. Clinical response in breast alone; Timepoint(s): After 4 cycles of NAC
2. Correlation between SLNB post-surgery and residual tumour burden in axilla; Timepoint(s): On completion of surgery
3. Disease Free Survival (DFS); Timepoint(s): After 5-years follow-up
4. Distant Disease Free Survival; Timepoint(s): After 5-years follow-up
5. Health Economics; Timepoint(s): After 2-years follow-up
6. Overall Survival; Timepoint(s): After 5-years follow-up
7. pCR rate in breast alone; Timepoint(s): After 4 cycles of NAC
8. Pharmacogenetic analysis to identify differences in toxicity and efficacy in individuals with spec; Timepoint(s): After 5-years follow-up
9. Quality of Life; Timepoint(s): After 2-years follow-up
10. Radiological response in breast alone; Timepoint(s): After 4 cycles of NAC
11. Rates of breast conservation; Timepoint(s): On completion of surgery
12. Sensitivity of Sentinal Lymph Node Biopsy (SLNB) following NAC in node positive patients; Timepoint(s): On completion of surgery
13. Time until loco-regional recurrence; Timepoint(s): After 5-years follow-up
14. Tolerability and toxicity of treatment; Timepoint(s): After 4 cycles of NAC
15. Utility of alternative molecular predictors of differential response to treatment; Timepoint(s): After 5 years follow-up
Overall trial start date
01/07/2015
Overall trial end date
01/01/2019
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Patient with histological diagnosis of invasive breast cancer
2. Suitable for neoadjuvant chemotherapy in opinion of investigator
3. Unifocal tumour: - Radiological size greater than or equal to (=) 20 mm by ultrasound (or in some cases Magnetic Resonance Imaging (MRI) is allowed)
4. T4 tumour of any size with direct extension to:
4.1. Chest wall
4.2. Skin
4.3. Both chest wall and skin
5. Inflammatory carcinoma with tumour of any size OR
6. Multifocal tumour: The sum of each tumour’s maximum diameter must be =20 mm (total sum of multifocal deposits =20 mm by ultrasound) OR
7. Other locally advanced disease:
7.1. Biopsy confirmed axillary lymph node involvement or large or fixed axillary lymph nodes (radiological diameter =20 mm or clinical N2), or ipsilateral supraclavicular nodes and primary breast tumour of any diameter
7.2. Involvement of large or fixed axillary lymph nodes (radiological diameter =20 mm or clinical N2), or ipsilateral supraclavicular nodes without a primary breast tumour identified: in this case the presence of breast cancer in a lymph node must be histopathologically confirmed by lymph node biopsy (trucut or whole lymph node)
8. Patients with bilateral disease are eligible to enter the trial, if one of the criteria above is met for disease in at least one breast
9. Any HER2 status
10. Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician. The following recommendations must be taken into account when making this assessment: Patients with HER2 positive disease must not have clinically significant cardiac abnormalities. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of Left Ventricular Ejection Fraction (LVEF) by Multi Gated Acquisition (MUGA) scan or echocardiogram (ECHO). LVEF must be within the normal range as defined locally by the treating hospital. Patients must have adequate bone marrow, hepatic, renal and haematological function
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
12. Women of childbearing potential, or men in a relationship with a woman of childbearing age, prepared to adopt adequate contraceptive measures if sexually active
13. 18 years or older
14. Male or female
15. Written informed consent for the trial
16. Availability of embedded paraffin tumour blocks from prechemotherapy biopsy is required
17. Willing and able to comply with scheduled visits, treatment plan and other study procedures
Sentinel Lymph Node Biopsy Study (in addition to above)
18. Biopsy/fine needle aspiration proven involved ipsilateral axillary lymph nodes at diagnosis
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 1050; UK Sample Size: 1050; Description: 1050 patients gives 90% power, 10% significance, for detecting an interaction. The power to test for an overall treatment effect regardless of CEP17/TOP2A status is >90%. Allowing for 10% loss to follow-up ensures >87% power to test for a treatment effect by CEP17/TOP2A interaction. The stratified approach has power to test for the interaction between CEP17/TOP2A status and treatment effect.
Participant exclusion criteria
1. Tumours of low or intermediate grade (Grade 1 or 2) which are also Oestrogen Receptor (ER) rich and Progesterone Receptor (PgR) rich or PgR unknown, whatever the size or nodal status
2. Previous invasive breast cancer
3. Unequivocal evidence of metastatic disease
4. Previous diagnosis of other malignancy unless:
4.1. Diseasefree for 5 years OR
4.2. Previous basal cell carcinoma, cervical carcinoma in situ, superficial bladder tumour OR
4.3. Contralateral or ipsilateral DCIS of the breast treated by surgery alone
5. Previous chemotherapy
6. Prior extensive radiotherapy (as judged by the investigator) to bone marrow
7. Previous neoadjuvant endocrine therapy (unless less than 6 weeks duration)
8. Concomitant hormonal therapies/chemotherapy or any other medical treatment in relation to treating the breast cancer
9. In HER2 positive patients risk factors precluding coadministration of trastuzumab and FEC75
9.1. Previous myocardial infarction during the 6 months prior to recruitment
9.2 LVEF below institutional lower limit of normal and no echocardiographic evidence of heamodynamically
9.3 Significant valvular heart disease or ventricular contractility
10. Prior diagnosis of cardiac failure
11. Uncontrolled hypertension, coronary heart disease other significant cardiac abnormality
12. Bleeding diathesis
13. Presence of active uncontrolled infection
14. Any evidence of other disease which in the opinion of the investigator places the patient at high risk of treatment related complication
15. Pregnant (female patients of child bearing potential should have a urine or blood Human Chorionic Gonadotropin test performed to rule out pregnancy prior to trial entry)
16. Lactating females
17. Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent completion of treatment or followup
18.Sentinel Lymph Node Biopsy Study (in addition to above)
19. Negative nodes at diagnosis
19.SLNB at diagnosis
20. Allergy to patent blue dye
Recruitment start date
01/07/2015
Recruitment end date
01/01/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Cancer Research UK
Institute for Cancer Studies
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Funders
Funder type
Government
Funder name
Cancer Research UK
Alternative name(s)
CRUK
Funding Body Type
private sector organisation
Funding Body Subtype
other non-profit
Location
United Kingdom
Funder name
Celgene International Sarl (Switzerland)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list