Selective Use Of Postoperative Radiotherapy AftEr MastectOmy


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Selective Use Of Postoperative Radiotherapy AftEr MastectOmy

  1. 1.   SUPREMO     S elective U se of P ostoperative R adiotherapy aft E r M astect O my                                     MRC SUPREMO (BIG 2-04)     S elective U se of P ostoperative R adiotherapy aft E r M astect O my Phase III randomised trial of chest wall RT in intermediate- risk breast cancer Kunkler 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  
  2. 2. Background: Trials of postmastectomy RT <ul><li>Danish and Canadian trials 9-10% survival benefit at 10 yrs from addition of RT to systemic therapy ( Overgaard 97,99;Ragaz 97) </li></ul><ul><li>PMRT standard for T3 and =/> 4 N+ </li></ul><ul><li>Role of PMRT in 1-3 N+ research priority of NIH (2000) </li></ul><ul><li>Weighting of risk factors (N+, grade, LVI) in selecting patients for PMRT unclear </li></ul>
  3. 4. Trials of PMRT in premen1-3 N+ + adjuvant CMFchemo (Fowble,1999) Trial No Redn LRR OS % C OS% C+RT P value Int (yr) B.C 183 23% 48 64 0.06 15act Den’k pre 1061 23% 54 62 - 10act Glas pre 141 NS 84 78 .40 5act Dana 83 3% 85 77 >.05 4.4me
  4. 5. Whelan & Levine,JNCI Jan 2005 <ul><li>Level I evidence needed to assess PMRT in 1-3 N+ </li></ul><ul><li>Currently limited to subgroup analysis </li></ul><ul><li>New RCTs needed to address the issue </li></ul>
  5. 6. Effects of RT on breast cancer mortality and all cause mortality after breast conserving / mastectomy and axillary clearance (EBCTCG; Lancet 2005;366:2087-2106
  6. 7. Oxford overview 2006; RT trials and breast cancer mortality at 20 yr, mastectomy & axillary clearance by nodal status Breast ca mortality (%) Breast ca mortality(%) 20 yr gain/loss(%) Path nodal status No RT RT pNO 28.7 30.2 -1.6 NS pN1-3 54.2 47.7 +6.4 2p=0.002 pN =/>4N+ 81.5 70.8 +10.7 2p=0.0008
  7. 8. Interpretation of Overview of RT trials <ul><li>Older radiotherapy techniques </li></ul><ul><li>Loco-regional rather than local RT </li></ul><ul><li>CMF rather than anthracycline systemic therapy </li></ul><ul><li>Improved survival of EPI-CMF vs CMF </li></ul><ul><li>Absolute risk of LRR after Mx and systemic therapy may be lower </li></ul><ul><li>Surgery, radiotherapy and systemic therapy not quality assured </li></ul>
  8. 9. PMRT 1-3 N+ with 8 or more nodes DBCG 82b,c trial Overgaard et al,Radiother Oncol,2007 RT No RT p value LRR 4% 27% <0.001 Overall survival 57% 48% 0.03
  9. 10. Whelan et al JCO 2000 2000;18:1220-29 0.73 - 1.38 1.00 5 YES 0.25 0.70 - 0.89 0.79 13 NO p 95% CI Odds ratio No of studies Anthracycline use
  10. 11. Overall and relapse free survival NEAT trial (Poole et al,NEJM,2006
  11. 12. Eligibility criteria <ul><li>pT1, pN1, M0 or pT2, pN0-1 M0 histologically confirmed invasive breast cancer. </li></ul><ul><li>Unifocal invasive breast cancer or multifocal breast cancer if at least a 2cm focus of invasive breast cancer </li></ul><ul><li>Fit for adjuvant chemotherapy (if indicated), adjuvant endocrine therapy (if indicated) and postoperative irradiation </li></ul><ul><li>Undergone simple mastectomy (with minimum of 1mm clear margin) and an axillary staging procedure </li></ul><ul><ul><li>If axillary node clearance node positive (1-3 positive nodes) then an axillary node clearance (minimum of 10 nodes removed) should have been performed. </li></ul></ul><ul><ul><li>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 </li></ul></ul><ul><li>Written informed consent </li></ul>
  12. 13. Exclusion criteria <ul><li>Any pT0, pN0-1, or pT1, pN0 or pT3 or pT4 </li></ul><ul><li>Patients who have undergone neoadjuvant systemic therapy. </li></ul><ul><li>Previous or concurrent malignant other than non melanomatous skin cancer and cancer in situ of the cervix </li></ul><ul><li>Male sex </li></ul><ul><li>Pregnancy </li></ul><ul><li>Bilateral breast cancer </li></ul><ul><li>Known BRCA1 and BRCA2 carriers </li></ul><ul><li>Not fit for surgery, radiotherapy or adjuvant systemic therapy </li></ul><ul><li>Internal mammary nodes positive on sentinel node scintigraphy </li></ul><ul><li>Unable or unwilling to give informed consent  </li></ul>
  13. 14. Randomisation in SUPREMO Chest wall irradiation Vs No chest wall irradiation
  14. 15. Endpoints for SUPREMO : <ul><li>Primary: overall survival </li></ul><ul><li>Secondary : </li></ul><ul><li>Disease free survival </li></ul><ul><li>Acute and late morbidity </li></ul><ul><li>Quality of life </li></ul><ul><li>Cost effectiveness (cost per life year) </li></ul><ul><li>Molecular markers of local relapse and </li></ul><ul><li>radiosensivity </li></ul>
  15. 16. Powering of the trial <ul><li>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% </li></ul><ul><li>(ie 4% difference) </li></ul><ul><li>Need 794 events (deaths) </li></ul>
  16. 17. Biological,cardiac, QL and health economic substudies
  17. 18. TRANS-SUPREMO <ul><li>Archiving of tumour for future analysis for molecular markers of radiation sensitivity </li></ul>
  18. 19. Proteins which may affect local relapse <ul><li>Proteins involved in: </li></ul><ul><ul><ul><li>Signal </li></ul></ul></ul><ul><ul><ul><li>Transduction </li></ul></ul></ul><ul><ul><ul><li>Adhesion and invasiveness </li></ul></ul></ul><ul><ul><ul><li>Apoptotic pathways </li></ul></ul></ul>
  19. 20. Late cardiac morbidity ( EBCTCG,Lancet 2000;355:1757-1770) <ul><li>Breast cancer mortality reduced by 13% </li></ul><ul><li>Increase in annual mortality rate from other causes by 21% </li></ul><ul><li>Increase primarily due to excess deaths from cardiovascular causes </li></ul><ul><li>Cardiac effects may not emerge until 15 yrs after treatment </li></ul>field Maximum Heart Distance (MHD) Heart contour Breast contour
  20. 21. SUPREMO collaboration 136 centres in 24 countries
  21. 22. Acknowledgements <ul><li>ISD Clinical Trials Team, NHS Scotland </li></ul>