Controversies in Radiation Therapy for Breast Cancer?

1. Prof. Yazid Belkacemi Controversies in Radiation Therapy for Breast Cancer?

2. Controversies in Radiation Therapy for Breast Cancer? Patients’ selection for APBI out of trial? Patients’ selection for IORT? Hypofractionation RT new standard in BC?

3. Is there a subgroup of patients who may benefit equally from APBI or WBI?

4. Tumor bed Standard RT in Breast Cancer

5. Techniques Intra op procedures Intra or post op implantation Post op irradiation

6. CASE 1 Ms. D. 54y of age Menopausal status confirmed since 50 y No significant co morbidity Regular mammograms since 10 years : no abnormalities Self discovery of a 1 cm mass in the Upper Outer Quadrant of the right breast Mammogram and US: ACR5 Biopsy: ductal ADK grade I, HR+

7. CASE 1 • Lumpectomy + SLNB • Pathology report: • Ductal invasive carcinoma, size: 15 mm • DCIS component 10% • Grade I • Minimal margins size 2mm • ER+ PR-, HER2-, Ki67 5% • No LVI • 2SN -

8. Would you recommend APBI out of clinical trial ? YES NO 54 y pT1 11mm Margins 2mm ER+ HER2- SN-

9. If this patient was 70y Would you recommend APBI out of clinical trial ? 70 y pT1 11mm Margins 2mm ER+ HER- SN- YES NO

10. APBI consensus statement from the ASTRO Sélection des patientes • Based on 645 original research articles • 4 published randomized clinical trials • 38 published prospective single arm studies • “Suitable” group • “Cautionary” group • “Unsuitable” group Smith BD et al. IJROBP, 2009

11. APBI consensus statement from the ASTRO ASTRO consensus statement guidelines regarding patient selection for accelerated partial breast irradiation off clinical trial Smith BD et al. IJROBP, 2009

12. GEC - ESTRO

13. DIFFERENCES SHARE 2800 > 50 et Ménop < 20 pN0 pN0(i+) I, II, III < 2mm RTC 3D 40Gy/10f Hypo 40Gy/3W 42.5Gy/3w 50Gy/25 +16 NON 2 bras 3 bras 3 bras 2 bras 2 bras 2 bras 2 bras

14. If this patient was 70y Would you recommend INTRAOP out of clinical trial ? YES NO 70 y pT1 11mm Margins 2mm ER+ HER2- SN-

15. 120 100 80 Relative dose (%) 60 40 20 0 0 20 40 60 Depth (mm) INTRAOP techniques • Novac-7 4-12 MeV 20 Gy in 3-5 min 650 kgs (Hithesys) • Mobetron 4-12 MeV 20 Gy in 3-5 min 1275 kgs (SRCLinac) • Intrabeam X-Ray 50kV 5 Gy @ 1cm in 25-30 min 1.8 kg 20 Gy @ surface

16. Dose • Uniform spherical radiation field • Steep dose gradient • High dose rate

17. Design (n = 2232, 9 countries – 28 centres) Randomisation 1.1 (pre ou per operative) Patients criteria Age 63 y , pT ≤ 3cm: 86 %, grade I/II: 84 %, N-: 83 %, HR+: 90% Treatment Targit Arm : 86% received the planned RT WBI in 14% FUP > 4 y n = 420 Lancet 2010, 376, 91-102

18. The Lancet 2010

19. Toxicity Intrabeam WBI Seroma 2.1% 0.8% Grade 3-4 0.5% 2.1% Local Control at 4y LR rate 1.20 % 0.95% (p=0.41) Conclusion There is non inferiority with INTRABEAM compared to WRI Lancet 2010, 376, 91-102

20. San Antonio 2012 Vaidya J.S et al., SABCS 2012, S4-2 • Update • Whole population n=3451 • INTRABEAM arm n=1721 • EBRT arm n=1730 • Minimal FUP of 4y n=1010 • Minimal FUP of 5y n=610 • Since 2010 : local recurrence events increased from 13 to 34 • Local recurrence probability at 5 y is in favour of EBRT • Inferiority of INTRABEAM INTRABEAM 23 (3.3%) vs EBRT 11 (1.3%), p=0.042

21. Conclusion Vaidya J.S et al., SABCS 2012, S4-2 • No difference if PgR+ • Suitable group for INTRABEAM (> 60 y, HR+, tumor < 2 cm, SN-)

22. Is there anymore discussion for Hypofractionation RT in BC ?

23. CASE 2 • Ms A-R. 50y of age • Peri menopausal status • No significant morbidity • Large size breast (100 D) • Lumpectomy + SNB • Ductal invasive carcinoma pT1 18 mm; margins: 3mm • Grade III (3,2,3), No LVI, Ki 67: 25% • ER+ 40% PR+ 20% HER2- • 2 SN : 1 micromets. No secondary ALND • Adjuvant CT • 4FEC 100 and 2TXT. Neurotoxicity G3

24. Radiotherapy modality 50y peri menopausal pT1 18mm SN micrometastsis/2 No secondary ALND Would you recommend: 1. Hypofractionated schedule in 3 weeks 2. Standard in 6.5 weeks

25. Radiotherapy modality Would you recommend nodal irradiation ? YES NO 50y peri menopausal pT1 18mm SN micrometastsis/2 No secondary ALND

26. Hypofractionation Canadian trial 50Gy in 25 fractions - 5 w vs 42.5Gy in 16 fractions - 3 w Stratification : age (50); T (< 2cm); adjuvant TRT & centre

27. 0,1 0,08 6,7 % 0,06 Recurrence (%) 6,2 % 0,04 0,02 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Years since randomization SWBI 612 597 578 592 550 553 499 485 470 449 410 317 218 AHWBI 622 609 592 569 548 524 500 472 447 430 406 330 214 Hypofractionation Cancer Care Ontario Regional Cancer Centres; Princess Margaret Hospital; Montreal General Hospital FUP : 144 m Whelan et al. NEJM 2010

28. 50y peri menopausal pT1 18mm SN micrometastsis/2 No secondary ALND Canadian trial Comments: the results could be extrapolated to all pts? Stratification by tumor size < 2cm No boost, no nodal RT No N+ patients included No large breast Small proportion of pts with CT Better cosmetic results Impact of age and T size Whelan et al. NEJM 2010

29. START TRIALS

30. START TRIALS

31. 50y peri menopausal pT1 18mm GIII SN microM/2, No ALND CT+ Fraction size 2.0 Gy Fraction sizes > 2.0 Gy better better No of patients Hazard ratio (95% CI) Age Primary surgery Axillary nodes (pN) Tumour grade Boost RT Adjuvant CT < 50 yrs > 50 yrs 1389 4472 0.84 (0.62, 1.15) 1.07 (0.83, 1.38) Breast conserving Mastectomy 5348 513 0.97 (0.80, 1.19) 0.91 (0.46, 1.81) Negative Positive 4318 1421 1.10 (0.86, 1.40) 0.80 (0.57, 1.11) 1 2 3 1213 2398 1272 0.96 (0.51, 1.82) 1.07 (0.72, 1.59) 0.86 (0.59, 1.25) No Yes 2749 3071 0.99 (0.74, 1.32) 0.99 (0.76, 1.29) No Yes 4346 1480 1.09 (0.86, 1.38) 0.81 (0.57, 1.14) .4 .6 .8 1 1.2 1.4 1.6 1.8 2 Hazard Ratio (95% CI) Meta-analysis of START pilot & START A&BSubgroup analyses of LR relapse (n=5861) Haviland JS et al., SABCS 2012, S4-1

32. 50y peri menopausal pT1 18mm GIII SN microM/2, No ALND CT+ Patients Haviland JS et al., SABCS 2012, S4-1

33. Thank you!