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ISRCTN61145589
, a phase III randomised trial to assess the role of adjuvant chest wall irradiation in ‘intermediate risk’ operable breast cancer following mastectomy
1. pT1, pN1, M0 unilateral histologically confirmed invasive breast cancer.
2. pT2, pN1, M0 unilateral histologically confirmed invasive breast cancer.
3. pT2, pN0 unilateral histologically confirmed invasive breast cancer if grade III histology and/or lymphovascular invasion.
4. Multifocal breast cancer if largest discrete tumour at least 2cm if N0 and grade III histology and/or lymphovascular invasion [see NB (ii)].
5. If the tumour area comprises multiple small adjacent foci of invasive carcinoma then overall maximum dimension taken. This must be greater than 2cm if N0 (see section 7.2) and grade III histology and/or lymphovascular invasion [see NB (iii)].
6. Fit for adjuvant chemotherapy (if indicated), adjuvant endocrine therapy (if indicated) and postoperative irradiation.
7. Undergone total mastectomy (with minimum of 1mm clear margin of invasive cancer and DCIS) and axillary staging procedure.
7.1 If axillary node positive (1-3 positive nodes [including micrometastases >0.2mm-≤2mm]) then an axillary node clearance (minimum of 10 nodes removed) should have been performed. Isolated tumour cells do not count as micrometastases.
7.2 Axillary node negative status can be determined on the basis of either axillary clearance or axillary node sampling or sentinel node biopsy.
8. Written, informed consent.
NB (i) Patients undergoing immediate breast reconstruction are eligible for inclusion.
NB (ii) Multifocal breast cancer if largest focus conforms to the other eligibility criteria. So if NO disease the primary tumour has to have at least one focus size pT2 with grade 3 histology or lymphovascular invasion (criterion 3) or pT1 or pT2 if N1 (criteria 1 and 2).
NB (iii) Criterion 5 is the definition of what is considered pT2 disease for N0 cases (pT1 is also allowed if N1). Please also see section 7.2 of the protocol for more detailed explanation.
1. Any pT0, pN0-1, or pT1, pN0 or pT3, pNO-1 or pT4
2. Patients who have 4 or more pathologically involved axillary nodes
3. Patients who have undergone neoadjuvant systemic therapy.
4. Previous or concurrent malignancy other than non melanomatous skin cancer and carcinoma in situ of the cervix
5. Male
6. Pregnancy
7. Bilateral breast cancer
8. Known BRCA1 and BRCA2 carriers
9. Not fit for surgery, radiotherapy or adjuvant systemic therapy
10. Internal mammary nodes visible on sentinel node scintigraphy in the absence of negative histology.
11. Unable or unwilling to give informed consent
Randomisation to chest wall irradiation or no chest wall irradiation.
Stratification by centre
Overall survival at 5 years
Chest wall recurrence
Regional recurrence
Disease free survival
Metastasis free survival
Cause of death (breast cancer, intercurrent disease [cardiovascular and non-cardiovascular])
Acute and late morbidity
Quality of life
Cost effectiveness
3700 patients over 4 years
: 10 years
50Gy in 25 daily fractions over 5 weeks
45Gy in 20 daily fractions over 4 weeks
40Gy in 15 daily fractions over 3 weeks
(Dr Edwin Aird, Northwood)
The QA programme will build on that developed for the START trial, which has provided a basis for consensus among radiotherapy centres in the UK. In Supremo, the quality assurance programme (QA) will enable confirmation that technical guidelines within the protocol have been understood and implemented correctly by participants and that the dose prescription is delivered according to protocol with appropriate documentation.
according to local practice but specified pre trial
Dr John Bartlett, Edinburgh
To identify molecular factors associated with increased risk of local relapse.
To identify molecular factors contributing to increased radioresistance.
Tissue micro arrays (TMA) represent a significant step forward in our ability to perform translational research focusing on specific molecular pathways and developing multi-factorial models of prognosis, rather than simplistic screening for single candidate genes.
Plasma/serum and whole blood (for tumour and patient DNA) will be obtained from patients and stored for future studies of predictive biochemical markers.
(Dr Peter Canney, Glasgow, Dr Martin Denvir, Edinburgh, Dr Theresa McDonagh, London, Dr David Northridge, Edinburgh)
to assess the role of B type natriuretic peptide in identifying left ventricular dysfunction (LVD) in patients undergoing adjuvant radiotherapy and/or chemotherapy. A subsidiary aim is to store blood for evaluation of potential future markers of cardiac function.
To prospectively assess cardiac toxicity, patients will be divided into the following groups:
1. Anthracycline-containing adjuvant combination chemotherapy + left sided radiotherapy
2. Anthracycline-containing combination chemotherapy + right sided radiotherapy
3. Non-anthracyline-containing combination chemotherapy/ other adjuvant systemic therapy + left sided radiotherapy
4. Non-anthracyline-containing combination chemotherapy/ other adjuvant systemic therapy + right sided radiotherapy
5. Anthracycline-containing chemotherapy and no radiotherapy
6. Non-anthracycline combination chemotherapy/other systemic therapy and no radiotherapy
ECG and blood for B type Natriuretic Peptide to be obtained at various timepoints throughout the trial or at relapse of breast cancer.
(Dr Galina Velikova, Leeds)
There will be a detailed multicentre study of the patients’ quality of life after chemotherapy and after additional radiotherapy in the experimental arm.
(i) EORTC QLQ-C30 – the core, 30-item cancer specific scale
(ii) EORTC BR-23 – the 23-item breast cancer specific module
(iii) Body image: The Body Image Scale - BIS
(iv)Psychological Distress: The Hospital Anxiety and Depression Scale – HADS
Primary QoL endpoints will be:
1. Fatigue (QLQ-C30)
2. Physical functioning subscale (EORTC QLQ-C30)
3. Chest wall, shoulder and arm symptoms (EORTC BR23)
4. Body image (BIS)
5. Anxiety and depression (HADS)
(Prof John Cairns, London)
: the economic study will assess the cost effectiveness of adjuvant irradiation.
Cost-effectiveness will be assessed by calculating the incremental cost per life year gained and the incremental cost per additional quality-adjusted life-year (QALY). The EQ5D (EuroQol) will be used in order to quality-adjust survival.
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