1. MRC SUPREMO (BIG 2-04)    Selective Use of Postoperative Radiotherapy aftEr MastectOmy
Phase III randomised trial of chest wall RT in intermediate- risk breast cancer Kunkler I, Canney P, Price A, Anderson N, Dixon J, Sainsbury R, Aird E, Thomas G, Bowman A, Thomas J, Bartlett J, Devine I, Denvir M, McDonagh T, Russell N, Cairns J, Boon Chua, Karlsson P, Northridge D, Scullion R, van Tienhoven G, Velikova G, Walker A

2. Background: Trials of postmastectomy RT
PMRT standard for T3 and =/> 4 N+
Role of PMRT in 1-3 N+ research priority of NIH (2000)
Weighting of risk factors (N+, grade, LVI) in selecting patients for PMRT unclear

3. Endpoints for SUPREMO:
Primary: overall survival
Secondary:
Disease free survival
Acute and late morbidity
Quality of life
Cost effectiveness (cost per life year)
Molecular markers of local relapse and radiosensivity 3

4. Sub-studies TRANS-SUPREMO Quality of Life (UK only)
Health Economics (UK only)
Cardiac (currently suspended)

5. SUPREMO eligibility criteria
1.1 Stage II histologically confirmed unilateral breast cancer following mastectomy including the following pTNM stages –
pT1N1M0
pT2N1M0
pT2N0M0 if grade III histology and/or lymphovascular invasion
pT3N0M0
1.2 Stage II histologically confirmed unilateral breast cancer following neoadjuvant systemic therapy and mastectomy, if the original clinical stage was cT1-2cN0-1M0 or cT1-2pN1(sn)M0 and with the following (ypTNM) stages after neoadjuvant systemic therapy -
ypT1pN1M0
ypT2pN1M0
ypT2pN0M0 if grade III histology and/or lymphovascular invasion.
ypT0pN0 or ypT1pN0 or ypT0pN1 (pathological complete remission, or near complete remission).
ypT2N0 independent of grade or lymphovascular invasion, if the original clinical stage was cT3N0.
ypT3N0M0, if original clinical staging was cT1-3cN0 M0 or cT1-3pN0 (sn) M0.
1.3 Unilateral invasive breast cancer that conforms to the initial clinical staging of criterion 1, but has been down-staged by neoadjuvant systemic therapy to ypT0 pN0 or ypT1pN0 or ypT0pN1 (pathological complete remission, or near complete remission). If tumour stage cT3 or ypT3, then nodal status must be N0 both before and after neoadjuvant systemic therapy.

6. SUPREMO eligibility criteria (cont.)
2. Undergone total mastectomy (with minimum of 1mm clear margin of invasive cancer and DCIS) and axillary staging procedure.
3.1 If axillary node positive (1-3 positive nodes [including micrometastases >0.2mm-≤2mm]) then an axillary node clearance (minimum of 8 nodes removed) should have been performed. Isolated tumour cells do not count as micrometastases.
3.2 Axillary node negative status can be determined on the basis of either axillary clearance or axillary node sampling or sentinel node biopsy.
3.3 Sentinel nodes identified in the internal mammary chain are considered pN1b or pN1c if histologically proven. Patients can be included in the trial with microscopic metastasis in the internal mammary chain detected by sentinel node biopsy, if not more than 3 tumour positive nodes in axillary lymph nodes.
3.4 Before neoadjuvant systemic therapy, axillary ultrasound is advised. Where axillary ultrasound is normal, negative axillary node status does not require histological confirmation before starting neoadjuvant systemic therapy.  Positive, or negative, nodal status may also be determined by sentinel node biopsy before start of neoadjuvant therapy.
4. Fit for adjuvant or neoadjuvant chemotherapy (if indicated), adjuvant or neoadjuvant endocrine therapy (if indicated) and post-operative irradiation.
5. Written, informed consent.

7. SUPREMO exclusion criteria
1. Any pT0, pN0-1, or pT1, pN0 after primary surgery
2. Any pT3pN1 or pT4 tumours. Initial stage cT3cN1 or pN1(sn) or cT4 in patients receiving neoadjuvant systemic therapy cannot be included, even if downstaging has occurred and the pathological ypT and N stage is lower.
3. Patients who have 4 or more pathologically involved axillary nodes. For the purpose of this study protocol, nodal scarring after neoadjuvant systemic therapy will be considered as evidence of previous pathological nodal involvement and count towards the total number of involved axillary nodes.
4. Past history or concurrent diagnosis of ductal carcinoma in situ (DCIS) of the contralateral breast, unless treated by mastectomy. Previous DCIS of the ipsilateral breast if treated with radiotherapy (i.e. previous DCIS treated by conservation surgery not followed by radiotherapy would be considered eligible).
5. Bilateral breast cancer. However, patients who have undergone a prophylactic contralateral mastectomy can be included, if the breast was pathologically free of invasive tumour.
6. Previous or concurrent malignancy other than non melanomatous skin cancer and carcinoma in situ of the cervix
7. Male
8. Pregnancy, at the time of radiotherapy treatment
9. Not fit for surgery, radiotherapy or adjuvant systemic therapy
10. Unable or unwilling to give informed consent

10. Timepoints for establishing eligibility and entry onto trial
Patient undergoes diagnosis and staging
Patient confirmed as potentially suitable by local research staff at MDTs/MDMs
Surgery
Eligibility confirmed – patient seen by Oncologist and trial discussed (PIS given)
Patient given at least 24 hours time before deciding to take part

11. When to randomise a patient
Usually when radiotherapy would normally be discussed
Can be prior to post-operative chemotherapy or during a patient’s planned course of post-operative chemotherapy or after post-operative chemotherapy (as long as starts radiotherapy within 6 weeks after completing post-operative chemotherapy)

12. ISD Cancer Clinical Trials Team Edinburgh
SUPREMO Team Eve Macdonald Senior Trial Coordinator Julian Lipscombe Trial Coordinator Leigh Fell Trial Coordinator
ISD Cancer Clinical Trials Team Edinburgh

13. Trial Co-ordination Provided by ISD Trials Unit
Randomisation service
Advice on protocol and eligibility
Investigator Site Files (ISFs)
Regular newsflashes, newsletters & website reports (
10% Source data monitoring (UK and Ireland only)

14. Service Provided by ISD – UK Sites*
Randomisation
Service Provided by ISD – UK Sites*
Phone randomisation service on or
Monday-Friday 9.00am-5.00pm
Following randomisation, ISD Trials Unit will fax anonymised confirmation details to centre
Recorded delivery letter with full patient details and pathology request form will follow within 2 weeks
* all other sites should follow their local randomisation procedures. If you have any questions please contact a member of the SUPREMO team.

15. Randomisation in SUPREMO
Chest wall irradiation Vs
No chest wall irradiation

16. Patient Consent Procedures 1
Patient Information
Patients should have a verbal explanation of the trial and be given most recent MREC-approved Patient Information Sheet (PIS) for the main SUPREMO trial and TRANS-SUPREMO.

17. Patient Consent Procedures 2
Consent Form Completion
Consent forms must be printed on hospital headed paper & accompanied by centre’s standard radiotherapy information sheets
All participating patients must sign the most recent version of consent forms.
Patients must initial, not tick boxes
PI to countersign forms, but PI can delegate responsibility as appropriate (must be clearly documented in delegation log).
No trial procedures can be performed prior to the patient giving informed consent.

18. Patient Consent Procedures 3
Consent Form Copies – UK Only*
4 copies of signed consent forms required
Original copy should be kept in site folder
Copy given to patient
Copy sent to ISD CCTT
Copy kept in patient hospital notes
* all other sites should follow their local procedures. If you have any questions please contact a member of the SUPREMO team.

19. TRANS-SUPREMO Sub-Study – UK Only*
Tammy Piper, Endocrine Cancer Group, will supply:
Lab kits and lab manual
Site will need to contact Tammy to arrange collection of frozen blood samples by courier. All transport packaging & dry ice will be provided.
Prompts for the tissue blocks will be sent with the confirmation of randomisation letter
Centres will be reimbursed for sending tissue blocks to the Endocrine Cancer Group, Edinburgh (£15 per block).
* all other participating sites should follow their own local procedures. If you have any questions please contact a member of the SUPREMO team.

20. TRANS-SUPREMO Bloods 1 Rationale Pharmacogenomics
DNA from whole blood.
Proteomic analysis
Recurrence markers
Serum/Plasma stored frozen.

21. TRANS-SUPREMO Bloods 2 Blood Samples
25 ml blood sample to be taken at baseline (1st visit) and at disease recurrence (local and/or distant relapse)
Samples need to be separated within 1 hour & frozen within 30 mins

22. TRANS-SUPREMO Bloods 3 Lab Pack
Laboratory Requisition Form (LRF) (2 copies).
15 colour coded tubes provided, add labels (pre-printed).
Pasteur pipettes (x 4, including 1 spare)
Place 1 LRF (white) with samples, freeze at
-80°C (-20 °C).
Other LRF (blue) in patient file.
Detailed instructions in laboratory manual
Lab kits will be provided by Tammy Piper

23. Equipment Not Provided
TRANS-SUPREMO Bloods 4
Equipment Not Provided
The following equipment is required but not provided:
Venepuncture kit
Plain tube with separator gel; 10 ml (SST Vacutainer or S-Monovette Serum)
EDTA tubes; 3x 5 ml
Centrifuge
Freezer (-80oC or if not available, -20oC acceptable for 4-6 months)

24. Quality of Life Sub-Study (UK sites only)
Summary
Baseline Questionnaire Booklets to be completed in clinic prior to patient being informed of treatment allocation and after given written informed consent
Centre to send completed Booklet with copy of signed QoL consent form to Centre of Population Health Sciences
Subsequent Questionnaire Booklets will be sent out by Centre of Population Health Sciences at 1, 2, 5 and 10 years from randomisation
GP will be contacted prior to subsequent Questionnaires being sent out to ensure patient alive and well enough to receive
Centre of Population Health Sciences will inform GP if patient scores particularly high on HAD scale (within 2 weeks)

25. Health Economics Sub-Study (UK sites only)
Summary
Will assess the cost effectiveness of adjuvant irradiation
Patient diary to be given to patient at site on the date of randomisation to record NHS resource use during and post radiotherapy and equivalent time period in those patients not randomised to receive radiotherapy
Colour of patient diary given to patient will be dependent on whether they are randomised to receive radiotherapy and whether they received post-operative chemotherapy
Patient to send completed patient diary to Centre of Population Health Sciences by freepost envelope or to be given to the Research Nurse or clinic health professional

26. Health Economics Sub-Study (UK sites only)
Patient Diaries and timelines for reporting health professional visits
Red diary: patients randomised to receive radiotherapy following post-operative chemotherapy (after post-operative chemotherapy and up to 8 weeks after radiotherapy)
Orange diary: patients randomised to receive radiotherapy after surgery and hormone therapy alone OR neoadjuvant systemic therapy and surgery +/- post-operative hormonal therapy (after post-operative chemotherapy and up to 8 weeks after radiotherapy)
Blue diary: patients NOT randomised to receive radiotherapy following post-operative chemotherapy (five month period following post-operative chemotherapy)
Green diary: patients NOT randomised to receive radiotherapy after surgery and hormone therapy alone OR neoadjuvant systemic therapy and surgery +/- post-operative hormonal therapy (five month period following date of last definitive surgery)

27. Radiotherapy Quality Assurance (RT QA) Programme
The plans for the first 5 patients in the radiotherapy arm, together with verification images will be collected by the QA team
Subsequently, 1 in 10 plans will be collected by the QA team

28. Case Report Form Completion
Main Trial 1
Randomisation Checklist
Initial Clinical Data
Neoadjuvant Details
Mastectomy Pathology Details
Completion of Chemotherapy (all patients)
Completion of Radiotherapy (all patients)

29. Case Report Form Completion
Main Trial 2
Initial Follow-up
12, 24, 36, 48, 60, 72, 84, 96, 108, 120-month Follow-up (annually from date of mastectomy or last definitive surgery)
Acute and Late Morbidity to be completed for trial patients on both arms of study (if grade 4/5 report as SAE)
Notification of recurrence/ new primary
Death
Termination
Protocol Deviations

30. Serious Adverse Events 1
SAE Definition
A SAE is defined as an untoward occurrence that:
Results in death
Is life threatening
Requires hospitalisation or prolongation of existing hospitalisation
Results in persistent disability or incapacity
Is a congenital anomaly/birth defect
Is otherwise considered medically significant by the investigator

31. Serious Adverse Events 2
Expected Radiotherapy SAEs
For SUPREMO patients receiving radiotherapy the potential expected adverse events/reactions include:
Skin reactions leading to chest wall tenderness and itching
Chest wall pain
Pneumonitis (inflammation of the lung) causing shortness of breath
Osteitis (inflammation of the ribs) causing the ribs to fracture
Late cardiac damage
If any of the above expected reactions fall under the definition of SAE they should be listed on SUPREMO SAE/SUSARs form

32. Serious Adverse Events 3
Chemotherapy SAEs
Chemotherapy related SAEs that require reporting
Chemotherapy related SAEs that do not require reporting on SAE/ SUSAR form (unless they impact on delivery of the randomised treatment)
Wound infections
Necrosis of the mastectomy skin flaps
Any cardiac event
Development of any other serious medical condition between date of consent and planned start of radiotherapy (or equivalent period for those patients randomised to not receive radiotherapy)
Hospitalisation due to:
Neutropenia
Febrile neutropenia
Diarrhoea
Infections, including those to Hickman line, catheter.
Pyrexia
Sore throat
Nausea or vomiting
Cellulitis

33. Serious Adverse Events 4
Reporting – UK Only*
At the centre:
Use SAE/SUSAR form to report all SAEs (even if the SAE is chemotherapy related)
Fax copy to ISD Trials Unit if possible within 24 hours of the event or at least within 24 hours of the PI becoming aware of the event on
Do not delay because of missing information and/or signatures
Local PI to assess whether unexpected, severity and/or related to radiotherapy
Provide missing information (and outcome information) as soon as it is known
* all other sites should follow their own local procedures. If you have any questions please contact a member of the SUPREMO team.

34. Serious Adverse Events 5
Processing
ISD Trials Unit will:
Allocate an SAE number
Forward initial report to CI immediately if local PI assesses event as unexpected
Advise the PI if SAE is evaluated as a SUSAR
Comply with NRES guidelines on reporting of SAEs
Report all SAEs to DMEC/MREC/local ethical authorities on an annual basis (or to comply with local procedures)

35. Accrual *Figures up to 14th December 2011
1277 patients total
920 patients randomised to date in UK
252 patients recruited from EORTC centres
105 patients recruited from non-EORTC international sites (60 China, 13 Australia, 12 Singapore, 11 Ireland, 9 Japan)
Top recruiting sites:
UK: Christie Hospital, Manchester (52)
EORTC: Arnhems Radio. Instituut (45)
International: Chinese Academy of Medical Sciences (24)

36. Accrual *Figures up to 14th December 2011
Main trial
TRANS SUPREMO 1007
Quality of Life 730
Cardiac substudy 53*
Health Economics 157
* Cardiac substudy suspended 13th December 2010

37. SUPREMO participating centres
United Kingdom
119 sites open
914 patients
China
5 sites open
60 patients
Ireland
3 sites open
11 patients
Japan
3 sites open
9 patients
EORTC
26 sites open
251 patients
Singapore
1 site open
12 patients
New Zealand
1 site open
0 patients
Australia
7 sites open
13 patients

38. ISD CANCER CLINICAL TRIALS TEAM