Selective Use of Postoperative Radiotherapy aftEr MastectOmy.

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

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. SUPREMO Team
Eve Macdonald (eve.macdonald@nhs.net) Senior Trial Coordinator
Julian Lipscombe (jlipscombe@nhs.net) Trial Coordinator
Leigh Fell (leigh.fell@nhs.net) Trial Coordinator
ISD Cancer Clinical Trials Team
Edinburgh
nss.isdsupremo@nhs.net

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

14. • Phone randomisation service on 0131 275 7276 or 0131 316
4278
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
Randomisation
Service Provided by ISD – UK Sites*
* 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. • 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.
Patient Consent Procedures 1
Patient Information

17. • 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.
Patient Consent Procedures 2
Consent Form Completion

18. 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.
Patient Consent Procedures 3
Consent Form Copies – UK Only*

19. • Tammy Piper, Endocrine Cancer Group, will supply:
– Lab kits and lab manual
• Site will need to contact Tammy (trobson@staffmail.ed.ac.uk) 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.
TRANS-SUPREMO Sub-Study –
UK Only*

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

21. • 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
TRANS-SUPREMO Bloods 2
Blood Samples
CENTRIFUGECENTRIFUGE
BLUE
TOP
GREEN
TOP
RED
TOP
10 mls
GEL
SEPARATOR
tube
SERUM
2 x 5 mls
EDTA
tube
PLASMA
5 mls
EDTA
tube
WHOLE
BLOOD

22. • 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
TRANS-SUPREMO Bloods 3
Lab Pack

23. 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 (-80o
C or if not available, -20o
C acceptable for 4-6
months)
TRANS-SUPREMO Bloods 4
Equipment Not Provided

24. • 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)
Quality of Life Sub-Study (UK sites only)
Summary

25. • 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
Health Economics Sub-Study (UK sites only)
Summary

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. • 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
Radiotherapy Quality Assurance (RT QA)
Programme

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

29. • 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
Case Report Form Completion
Main Trial 2

30. 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
Serious Adverse Events 1
SAE Definition

31. 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
Serious Adverse Events 2
Expected Radiotherapy SAEs

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)
1. Wound infections
2. Necrosis of the mastectomy skin
flaps
3. Any cardiac event
4. 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:
1. Neutropenia
2. Febrile neutropenia
3. Diarrhoea
4. Infections, including those to Hickman
line, catheter.
5. Pyrexia
6. Sore throat
7. Nausea or vomiting
8. Cellulitis

33. 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 0131 275 7512
• 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.
Serious Adverse Events 4
Reporting – UK Only*

34. 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)
Serious Adverse Events 5
Processing

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. • Main trial 1277
• TRANS SUPREMO 1007
• Quality of Life 730
• Cardiac substudy 53*
• Health Economics 157
* Cardiac substudy suspended 13th
December 2010
Accrual
*Figures up to 14th December 2011

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

38. ISD CANCER CLINICAL
TRIALS TEAM