1. Radiotherapy of the Axilla in Early Breast Cancer When and How? Marc R. Wygoda M.D. Radiotherapy Unit Department of Oncology Hadassah University Hospital Jerusalem May 1st, 2014

2. Axillary recurrence rate in studies of SLN+ without comple:on Axillary Dissec:on Pepels, Breast cancer res Trt 2010 Giuliano AnnSurg 2010

3. Radiotherapy of the Axilla in Early Breast Cancer

4. ACSOG Z0011 Trial ALND: anatomic level I and II dissection with at least 10 nodes removed Median number of lymph nodes removed: 17 in the ALND group 2 in the SLND group. Did ALND reveal more positive lymph nodes? In the ALND group, 27.3% had additional mets identified by axillary dissection

5. Radiotherapy 2 Opposed Tangeantials Fields No Axillary / Supra-Clavicular Field

6. ACOSOG Z00115-Year Recurrence Rates 3.6% 0.5% 4.1% 1.8% 0.9% 2.8% 0% 2% 4% 6% Local Regional Total Locoregional Recurrence P = .11, ALND vs SLND. Abbreviations: ALND, axillary lymph node dissection; SLND, sentinel lymph node dissection. ALND (n = 420) SLND (n = 436)

7. Overall Survival Non-inferiority P= 0.008 5-year overall survival: - 91.8% in ALND group - 92.5% in SLND group.

8. Disease Free Survival 5-yr DFS: 83.9% for SLND-only 82.2% for ALND (P=.14).

9. Factors Associated with Improved Disease- Free Survival Factors Not Associated with Disease-Free Survival Estrogen receptor status Age (50 years) Adjuvant systemic therapy Treatment arm Progesterone receptor status Tumor size Level 1 lymph nodes Histologic type Number positive lymph nodes Modified Bloom-Richardson ACOSOG Z0011: Predictors of Disease-Free Survival in Multivariate Analysis Giuliano AE, et al. J Clin Oncol. 2010;28:18S

10. ACOSOG Z0011 What are the Conclusions?? 1. No need for completion ALND in selected Sentinel LN positive pts 2. Radiotherapy Fields can be limited to Breast tissue only, without the regional LN

11. Criticism on Z0011 Trial Statistical power Follow up duration still short Less than expected rate of failures Why include only patients with less than 3 positive SLNs? What about patients with palpable lymph nodes?

12. AMAROS Dutch/EORTC Phase III study: After Mapping of the Axilla, Radiotherapy or Surgery? Invasive Breast cancer T1-2 ( 5cm ( 31% ) or Invasion of skin or Pectoralis fascia Phase III Randomized Trial: 2 arms MRM + CMF MRM + CMF + XRT (XRT= 50Gy to chest wall and full lymphatics; Timing: Surgery1CMFXRT5 CMFs) Overgaard et al. NEJM, 1997

29. Danish Trial 82b: Results

30. The British Columbia Trial 318 pts (Entry: 1979-1986) Eligibility: premenopausal Node Positive Post Mod. Rad. Mastectomy All pts given IV CMF Chemo Dose: 600/40/600 mg/m2, Q3w Number of course: 12 6 Randomization: Surgery + CMF XRT Ragaz et al. JNCI Jan 19, 2005

31. The British Columbia Trial Overall Survival

32. Danish Trial 82c: postmenopausal MRM + TAM XRT DFS and Overall Survival p30yrs follow-up: Gustave Roussy data

49. Breast Cancer Evolution: 3 The Spectrum Paradigm 10 2 3

50. The Spectrum Paradigm Breast Cancer is a Heterogeneous Disease Spectrum of Proclivities: From a Local Disease through its entire course To a Systemic Disease when first detectable Implications: Lymph nodes can be the source of distant mets Loco-Regional control is important for Survival

51. Axillary levels: implications on Radiotherapy Extent

52. 3D Delineation of nodal stations

53. Axillary levels: implications on Radiotherapy Extent Axillary Level I Medial Supra-Clav. Axillary Level II Lateral Supra-Clav. Axillary Level III Infraclavicular Parasternal

54. Estimations of % of Axillary nodes treated by Tangential fields Level I Level II Level III Traditional Tangential 50% 20-30% - High Tangential 80% 60% -

55. Lets be a bit provocative

56. Royal Marsden No Surgery after cCR post NACT

57. Royal Marsden No Surgery after cCR post NACT

58. NSABP B04 Difference ALND vs Axillary RT Rnode - Total mastectomy + ALND Total mastectomy + RT Total mastectomy n = 1079 Rnode + Total mastectomy + ALND Total mastectomy + RT n = 586 Regional 4 vs 4% Regional 8 vs 11% Fisher NEJM,347; 657, 2002 NSABP B04

59. morbidity ALND-ART Deutsch, IJROBP, 2008 Rnode - Total mastectomy + ALND Total mastectomy + RT Total mastectomy n = 1079

60. Dutch experience in LABC and cN+ disease If aTer neoadjuvant chemotherapy the axilla is clinically and radiologically nega:ve (yN0).. Treatment without ALND, but only ART. Kol, poster EBCC 2010 N = 138 (median follow-up: 4yr) 7 regional recurrences (5%) axillary 3 (2%) Non axillay 4 (3%)

61. Conclusions 1. Two Randomized trials in early stage SLN+ patients demonstrate that Completion Axillary Clearance is not needed and Radiotherapy is as effective with less side effects than surgery 2. No Consensus on whether Tangeantial fields are enough or whether an extra axillary/supra field is needed 3. Radiotherapy contributes to Overall Survival 4. Avoid Double Axillary Treatment (Surgery + Radiotherapy) 5. Axillary Radiotherapy might replace Surgery in the future, even in clinical N+ or high burden axillary disease patients

62. Less is more: - = + Mastectomy vs Lumpectomy + XRT

63. Less is more: Axillary Dissection vs. Sentinel LNB

64. Merci beaucoup !