Response to optimal selection of neo-adjuvant chemotherapy in operable breast cancer
| ISRCTN | ISRCTN15094808 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15094808 |
| EudraCT/CTIS number | 2013-004307-39 |
| IRAS number | 129176 |
| Secondary identifying numbers | 19069 |
- Submission date
- 03/06/2015
- Registration date
- 03/06/2015
- Last edited
- 02/07/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English summary of protocol
Contact information
Dr Sarah Bowden
Public
Public
Cancer Research UK
Institute for Cancer Studies
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | 0121 414 8040 |
|---|---|
| S.J.Bowden@BHam.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| 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 |
| Study acronym | ROSCO |
| Study objectives | 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(s) | First MREC approval date 08/12/2014, ref: 14/WM/1213 |
| Health condition(s) or problem(s) studied | Breast cancer |
| 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 8 mg/kg with first cycle of chemotherapy followed by 6 mg/kg 3 weekly for 6-12 months; TC - surgery - FEC, Docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2 Follow Up Length: 120 month(s) Study Entry : Registration and One or More Randomisations |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Cyclophosphamide, docetaxel, epirubicin, 5-fluorouracil, Herceptin (trastuzumab) |
| 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 study start date | 01/07/2015 |
| Completion date | 31/05/2028 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | 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. |
| Total final enrolment | 990 |
| Key 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 |
| Key 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. Disease free 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 haemodynamically 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 childbearing 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 |
| Date of first enrolment | 01/07/2015 |
| Date of final enrolment | 31/05/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Cancer Research UK
Institute for Cancer Studies
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
Sponsor information
University of Birmingham
University/education
University/education
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| no@email.provided | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Government
Cancer Research UK
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, CRUK
- Location
- United Kingdom
Celgene International Sarl (Switzerland)
No information available
Results and Publications
| Intention to publish date | 31/05/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal a year after the last patient has completed their 5-year follow-up. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham. Data will be shared in accordance with the CRCTUs data sharing policy which is available on the CRCTU website (https://www.birmingham.ac.uk/research/crctu/Data-sharing-policy.aspx). Anonymised data will be available 6 months after the publication of the outcome measures. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
02/07/2025: IRAS number and total final enrolment added.
03/05/2023: The following changes were made to the trial record:
1. The overall end date was changed from 31/12/2027 to 31/05/2028.
2. The intention to publish date was changed from 31/12/2028 to 31/05/2029.
12/01/2023: The recruitment end date was changed from 31/12/2022 to 31/05/2023.
16/04/2021: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/04/2021 to 31/12/2022.
2. The overall trial end date was changed from 01/04/2026 to 31/12/2027.
3. The intention to publish date was changed from 01/04/2027 to 31/12/2028.
4. The trial website was added.
09/07/2020: The trial contact details have been made publicly visible.
07/07/2020: Intervention type corrected, phase and drug names added. IPD sharing statement updated.
25/06/2019: Publication and dissemination plan and IPD sharing statement added.
19/06/2019: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/01/2019 to 01/04/2021.
2. The overall trial end date was changed from 01/01/2019 to 01/04/2026.
10/03/2016: Cancer Help UK lay summary link added.
