1. Joint Hospital Surgical Grand Round Accelerated partial breast irradiation: where should we go? Dr Ma Kwok Kuen Queen Mary Hospital

2. Background Early Breast Cancer Trialist’s Collaborative Group meta-analysis: Whole breast radiotherapy (WBRT) after breast conserving surgery (BCS) 19% absolute risk reduction of ipsilateral breast recurrence in 5 years 5% absolute reduction in 15-year risk of death Lancet 2005

3. Definitions Conventional WBRT: 50Gy over 25 fractions (5 weeks) Partial breast irradiation (PBI): irradiation of a limited volume of breast tissue around the tumor bed Accelerated partial breast irradiation (APBI): deliver a larger than standard dose of radiation with each treatment, shortening the overall treatment time

4. Rationale of APBI The spatial pattern of relapse after BCS with or without WBRT: 76-90% at “same site” Five prospective randomized trials NSABP B06. Cancer 1986 Uppsala-Orebro. J Clin Oncol 1999 Ontario Clinical Oncology Group. J Natl Cancer Inst 1996 Milan III. Ann Oncol 2001 SweBCG 91-RT. Eur J Cancer 2003

5. Rationale of APBI WBRT may not protect against the development of new primary cancer in the irradiated breast Milan I trial: comparing mastectomy with quadrantectomy and WBRT Similar rate of other quadrant breast recurrence and contralateral breast cancers (CLB) Yale group: at 15 years after BCT in 1152 patients, 13% incidence of other quadrant breast tumor compared with 10% incidence of CLB New Engl Med 2002 Int J Radiation Oncology Biol Phys 2000

6. Potential advantages of APBI Reduction of treatment time Convenient to patient Increase the use of BCS Shorten the waiting time Treatment costs Reduce normal tissue toxicity Cosmesis

7. Questions to be answered 1. Which patients are best served by APBI? 2. What is the best technique? 3. What is the long term result?

8. 1. Which patients are best served by accelerated partial breast irradiation?

9. Patient selection Patient with low risk of recurrence and multicentric foci ABSASBSASTRO Age (years)>=45 >=60 HistologyIDCIDC or DCISIDC/ favourable subtype Size<=3cm <=2cm Resection margin No tumor at inked margin Negative microscopic surgical margins Negative by at least 2mm Axillary LN status Negative

10. 2. What is the optimal technique of administration of APBI?

11. Methods of APBI Interstitial brachytherapy Balloon brachytherapy Intraoperative radiotherapy External beam radiotherapy Promising Phase I/II trials

12. Interstitial brachytherapy 10-20 catheters Requires high level of expertise

13. Balloon brachytherapy MammoSite Contura SAVI Inflatable balloon placed in lumpectomy cavity 34Gy/10 in 5 days

14. Intraoperative radiotherapy Energy source (Electrons/Photons) Single dose 21Gy

15. External beam radiotherapy 3D conformal Other methods (Intensity modulated radiotherapy (IMRT), tomotherapy)

16. 3. What are the long-term effects on local control, survival and toxcity?

17. APBI vs WBRT (RCT) YearArm 1Arm 2Conclusion Christie1982- 1987 WBRT 40 Gy/15 Electrons 42.5 Gy/8 WBRT superior Yorkshire1986- 1990 WBRT 40Gy/15 EBRT 55Gy/20 WBRT superior Hungary1998- 2004 WBRT 50Gy/25 HDR 36.4 Gy/7 Similar control, better cosmesis with HDR TARGIT A2000- 2009 WBRT 40- 56Gy IORT 20 Gy/1 IORT non-inferior

18. Hungary WBRT (130) vs PBI (128) using HDR multicatheter brachytherapy (69%) or EB (31%) No statistically significant difference in 5 year local recurrence rate: 3.4% in WBRT vs 4.7% in PBI Overall survival: 91.8% vs 96.4% Cancer specific survival: 96% vs 98.3% Disease free survival: 90.3% vs 88.3% Better cosmesis with HDR APBI Int. J. Radiation Oncology Biol. Phys. 2007

19. TARGIT A trial Year 2000-2009: 1113 IORT vs 1119 WBRT Conclusion: IORT should be considered as an alternative to WBRT after BCS Lancet 2010 Local recurrence at 4 years: 1.2% in IORT 0.95% in WBRT

20. Ongoing RCT (APBI vs WBRT) TrialAPBI technique NSABP B39 Multicatheter brachytherapy, MammoSite balloon catheter, 3D conformal radiotherapy ELIOT Intraoperative radiotherapy (Electron) GEC-ESTRO Interstitial brachytherapy RAPID 3D conformal radiotherapy IRMA 3D conformal radiotherapy IMPORT Low Intensity-modulated radiotherapy (IMRT) Arm 1: primary tumor region + low risk region Arm 2: primary tumor region

21. Is it a perfect solution?

22. Counterpoints The spatial pattern of ipsilateral breast tumor relapse is not accurately defined Definition of “same site”: no generally accepted criteria (?index quadrant ?tumor bed ?surgical field ?scar area) Does not correspond closely to pathological findings Pathological studies suggest multifocal/multicentric foci are relatively common (~45%) in patients with clinically unifocal tumors Holland R et al. Cancer 1985 Vaidya JS et al. Br J Cancer 1996

23. Counterpoints The distinction between true recurrence and new primary tumor may not be reliable Vicini FA et al. Cancer 2007: Clinical and the clonality classifications only show 65% concordance 7 randomized breast conservation trials suggests that other quadrant ipsilateral breast relapse is reduced by whole breast radiotherapy

24. What is the likely impact of APBI trials?

25. Conclusions ~16000 women Level I evidence for or against APBI in early breast cancer Identification of patient subgroups with the most and least to benefit from APBI APBI technique comparison (NSABP B39) Increase the understanding of ipsilateral breast tumor relapse and the impact of radiotherapy (IMPORT Low)

26. Supplementary

27. ELIOT trial ELIOT (Electron Intraoperative Therapy) 2000 4-12MeV external beam electron applicator 21 Gy single dose to 10-30mm around the applicator Milan III trial – testing the effect of WBRT after quadrantectomy, in which in the absence of radiotherapy, 85% of IBTR presented “in the scar area” Milan I trial – comparing quadrantectomy and mastectomy, in which patients treated with quadrantectomy suffered comparable rates of other quadrant IBTR and contralateral breast cancer Hypothesis – WBRT is not necessary, since most IBTRs occur in the vicinity of the primary tumor, and radiotherapy does not prevent other quadrant relapses which are mostly new primaries

28. TARGIT trial TARGIT (TARGeted Intraoperative radioTherapy) 2000 Low energy photons (50kV maximum) 20Gy single dose to 2mm beyond the surface of applicator Clinical and pathological observation IBTR occurs in >90% of the patients at the site of the original primary tumor regardless of surgical excision margin and WBRT A pathological study of 30 mastectomy specimens from women eligible for BCS revealed multiple tumor foci in 19 specimens, and in 15 of these, foci were located outside the index quadrant Hypothesis – Multicentric cancer foci remain dormant and are not generally responsible for IBTR

29. GEC-ESTRO trial European Brachytherapy Breast Cancer GEC-ESTRO Working Group trial 2004 High dose rate (HDR) [32 Gy/8 or 30.3Gy/7 BD] or pulsed dose rate (PDR) [50 Gy hourly fractions of 0.6-0.8Gy] brachytherapy Majority of IBTRs occur in close proximity to the tumor bed, and that other quadrant IBTR risk is low and unaffected by radiotherapy

30. NSABP B39/RTOG 0413 trial 2005 Three APBI technique Multicatheter brachytherapy MammoSite balloon catheter 3D conformal radiotherapy Rationals similar to ELIOT trial

31. RAPID and IRMA trials RAPID (Randomised Trial of Accelerated Partial Breast Irradiation) 2006 IRMA (Innovazioni nella Radioterapia della MAmmella) 2007 Compare WBRT and 3D conformal radiotherapy Rationals similar to ELIOT trial

32. IMPORT Low trial IMPORT (Intensity Modulated and Partial Organ Radiotherapy) Low trial 2006 Fixed multisegmented tangential beams in all three arms Whole breast (40Gy/15) Partial breast (40Gy/15) Partial breast (40Gy/15) + remainder of the whole breast (36Gy/15) Testing WBRT vs PBI Direct measure of RT effect against other quadrant relapses