SUPREMO Selective Use of Postoperative Radiotherapy aftEr MastectOmy

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 SUPREMO   Selective Use of Postoperative
Radiotherapy aftEr MastectOmy  
                

• MRC SUPREMO(BIG 2-04)   Selective Use of
  Postoperative Radiotherapy aftEr MastectOmy
• Phase III randomised trial of chest wall RT in
  intermediate- risk breast cancerKunkler I,
  Canney P, Price A,Prescott R, Hophood P,Dixon J,
  Sainsbury R,Aird E, Thomas G,Bowman A,Thomas J,
  Bartlett J,Dunlop J, Denvir M,McDonagh T,Russell
  N
•  

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BackgroundTrials of postmastectomy RT

• Danish and Canadian trials 9-10 survival benefit
  at 10 yrs from addition of RT to systemic therapy
  (Overgaard 97,99Ragaz 97)
• PMRT standard for T3 and /gt 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

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Trials of PMRT in premen1-3 N adjuvant
CMFchemo (Fowble,1999)
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Whelan Levine,JNCI Jan 2005

• Level I evidence needed to assess PMRT in 1-3 N
• Currently limited to subgroup analysis
• New RCTs needed to address the issue

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Effects of RT on breast cancer mortality and all
cause mortality after breast conserving /
mastectomy and axillary clearance (EBCTCG Lancet
20053662087-2106
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Oxford overview 2006 RT trials and breast
cancer mortality at 20 yr, mastectomy axillary
clearance by nodal status
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Interpretation of Overview of RT trials

• Older radiotherapy techniques
• Loco-regional rather than local RT
• CMF rather than anthracycline systemic therapy
• Improved survival of EPI-CMF vs CMF
• Absolute risk of LRR after Mx and systemic
  therapy may be lower
• Surgery, radiotherapy and systemic therapy not
  quality assured

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PMRT 1-3 N with 8 or more nodes DBCG 82b,c
trial Overgaard et al,Radiother Oncol,2007
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Whelan et al JCO 2000 2000181220-29
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Overall and relapse free survival NEAT trial
(Poole et al,NEJM,2006
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Eligibility criteria

• pT1, pN1, M0 or pT2, pN0-1 M0 histologically
  confirmed invasive breast cancer.
• Unifocal invasive breast cancer or multifocal
  breast cancer if at least a 2cm focus of invasive
  breast cancer
• Fit for adjuvant chemotherapy (if indicated),
  adjuvant endocrine therapy (if indicated) and
  postoperative irradiation
• Undergone simple mastectomy (with minimum of 1mm
  clear margin) and an axillary staging procedure
• If axillary node clearance node positive (1-3
  positive nodes) then an axillary node clearance
  (minimum of 10 nodes removed) should have been
  performed.
• Axillary node negative status can be determined
  on the basis of either axillary node clearance,
  or axillary node sampling or sentinel node biopsy
  T2NO tumours are eligible with grade III
  histology and/or lymphovascular invasion
• Written informed consent

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Exclusion criteria

• Any pT0, pN0-1, or pT1, pN0 or pT3 or pT4
• Patients who have undergone neoadjuvant systemic
  therapy.
• Previous or concurrent malignant other than non
  melanomatous skin cancer and cancer in situ of
  the cervix
• Male sex
• Pregnancy
• Bilateral breast cancer
• Known BRCA1 and BRCA2 carriers
• Not fit for surgery, radiotherapy or adjuvant
  systemic therapy
• Internal mammary nodes positive on sentinel node
  scintigraphy
• Unable or unwilling to give informed consent 

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Randomisation in SUPREMO

• Chest wall irradiation
• Vs
• No chest wall irradiation

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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

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Powering of the trial

• 3500 patients (1750 per arm) for 80 power to
  detect a statistically significant difference at
  the 5 level if the true rates of survival at 5
  years are 75 and 79
• (ie 4 difference)
• Need 794 events (deaths)

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Biological,cardiac, QL and health economic
substudies
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TRANS-SUPREMO

• Archiving of tumour for future analysis for
  molecular markers of radiation sensitivity

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Proteins which may affect local relapse

• Proteins involved in
• Signal
• Transduction
• Adhesion and invasiveness
• Apoptotic pathways

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Late cardiac morbidity (EBCTCG,Lancet
20003551757-1770)
field

• Breast cancer mortality reduced by 13
• Increase in annual mortality rate from other
  causes by 21
• Increase primarily due to excess deaths from
  cardiovascular causes
• Cardiac effects may not emerge until 15 yrs after
  treatment

Breast contour
Heart contour
Maximum Heart Distance (MHD)
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SUPREMO collaboration 136 centres in 24 countries
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Acknowledgements

• ISD Clinical Trials Team, NHS Scotland