Radiotherapy Implications of ACOSOG Z-11 for Clinical Practice. Julia White, MD Professor of Radiation Oncology Medical College of Wisconsin

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1 1 Radiotherapy Implications of ACOSOG Z-11 for Clinical Practice Julia White, MD Professor of Radiation Oncology Medical College of Wisconsin

2 Disclosures: none

3 Agenda 1. ACOSOG Z-11: Another perspective outcomes 2. Potential influence of breast radiation? 3. Should there be a modification of radiation when completion axillary node dissection (calnd) is omitted?

4 ACOSOG Z-11 T1-2, 1 or 2 SN + Targeted Accrual: Accrued R A N D O M I Z E SLN only SLN + calnd Primary Endpoints: Overall Survival Morbidity

5 ACOSOG Z11 Eligibility: cn0 no palpable nodes T1-T2 Lumpectomy with negative margins 1-2 SN metastases Ineligibility: > 3 SN with metastases Matted notes Gross extra nodal extension Neoadjuvant chemotherapy, hormone therapy

6 ACOSOG Z11 Phase III multi center randomized trial Accrual , 115 institutions Stratification: Age: < 50, > 50 ER: negative, positive T size: < 1 cm, 1-2 cm, > 2 cm Adjuvant Systemic Therapy: 96 % calnd and 97% SNB alone Whole breast RT: 88.9% calnd and 89.6% SNB alone

7 ACOSOG Z11 Outcomes Outcome calnd SLN only n = 420 n = 436 Overall Survival 91.8 % 92.5% Disease Free Survival 82.2.% 83.9% Local Regional Recurrence 4.1% 2.8% Local Recurrence 3.6% 1.8% Axillary Recurrence 0.5% 0.9% Giuliano et. al., JAMA, 305:2011 Giuliano et. al., Ann. of Surg., 252: 2010

8 AGE ACOSOG Z11: Population median (yrs) % > 50 years TUMOR SIZE (% ) T-1 T-2 ALND SLN only ER + or PR + (%) GRADE (%) LVI (%) YES NODES + (%) > 3 Giuliano et. al., JAMA, 305:2011 Giuliano et. al., Ann. of Surg., 252:

9 ACOSOG Z11 Typical profile of patients: > 50: ~ 67 % T-1: ~ 67 % E+ or P+: ~ 80 % Grade 1-2: ~ 71% No LVI ~ 62 %

10 ACOSOG Z11: Lower rate of additional positive nodes at calnd Study n Population cn0 % SN+ % calnd+ %SN +only SNAC 1088 T < 3cm NSABP B T < 4 cm ACOSOG Z T1/T ACOSOG Z T1/T SN mic - 10% had additional positive nodes

11 Meta-analysis: SNB in Early Stage Breast Cancer 69 trials, patients studied Average patient age 56.6 years SNB: Average positive: 42% (median 40%, range 17-74%) Average number 1.92 (median 2, range 1-4) calnd: Additional positive nodes: 53% SN only positvie: 47% Average number: 15.9 (range 11-23) Kim et al, Cancer, 106:2006

12 Meta-analysis: Non-SN Metastases Associated with Micrometastatic SN 25 studies, patients studied calnd: Non- SN + SN Micromets 20% ( CI 16-25%) SN by IHC only 9% (CI 6-13%) Cserni, et al, Br. J. Surg. 91:2004

13 Observation/RT for SLN Metastases Without calnd MSKCC, Naik, 2004 Northwestern, Jeruss, 2004 Baylor, Fant 2003 Kaiser Geuntehr, 2003 MDACC Hwang, 2007 Yale, Pejavar, 2006 n Follow-up (months) Axillary RT Axillary Recurrence % No No No N Yes (60%) Yes 0

14 IBCSG T1-2, Micromet SN + Targeted Accrual: 1960 Opened: 2001 R A N D O M I Z E SNB only SNB + calnd Primary Endpoints: Disease free Survival Secondary Endpoints: Overall survival, Regional recurrence, Morbidity, Pathology correlation

15 Summary: Z-11 Perspective ACOSOG Z-ll outcomes reflect the population of breast cancer accrued Supported by lower-rates of additional axillary node metastases at calnd For most patients SLN was both diagnostic and therapeutic Corroborates single institution reports but needs confirmation by other RCT

16 Are the outcomes on ACOSOG Z-11 influenced by the breast radiation?

17 Measure of Axillary Node inclusion by Standard Breast Tangents: 2D Fluoroscopy Simulation Films Institution MSCKK McCormick 2002 MDACC Schlembach, 2001 Brown U. Chung, 2002 Perugia U. Aristei, 2001 n Measure on tangent simulation film Inclusion % 45 > 5 AND clips SN clips ALL AND clips SN clips clips: L-1, L-2, L-3 L-1: 65 L-2: 50

18 Standard Tangent AND clips: ~ 38-50% SN clips: ~ 84-90%

19 Measure of Axillary Node inclusion by Standard Breast Tangents: 3- dimensional conformal radiation Institution n Dose-volume Measure Inclusion % U. Cordoba Zunino, 2007 European Inst. Onc. Orecchia, 2005 U. Of Washington Reed, 2005 U. Of Mass. Renzik, Gy to 95% SN volume: SN clip + 10mm 15 Level 1 axilla- 80% prescription dose 100% prescription dose 50 Combined L1-2 Axilla- 95% prescription dose 35 L-1, L-2, L-3 Axilla 95% prescription dose L-1: 51 L-2: 26 L-3: 15

20 Standard Tangent Inclusion of the axilla contoured on CT and measured with DVA: L-1: ~ 30-50% L-2: ~ 25% Dose-Volume Analysis 45 Gy Axilla: 38% Level 1 0% Level 2 0% Level 3 V-20 Left Lung 9.5%

21 Recurrences in cn0 BCT Patients without Specific Therapy for the Axilla Institution n. Design National Cancer Institute, Milan Martelli 2005 Italian Oncology Senology Group Veronesi 2005 Harvard Medical School Wong 2008 National Cancer Institute, Milan Greco 2000 National Cancer Institute, Milan Martelli F/U yrs Ave. age Breast RT % HT % CT Axilla RCT 5 70 Y 100 N AND OBS RCT Y 90 9 AxRT OBS % Axilla failure 74 Prosp Y 92 1 OBS Prosp % 34.4 N OBS Prosp N 100 N OBS 4.2

22 IBCSG T1-2, cn0 > 60 yo Tamoxifen n=473 Primary Endpoints: QOL, morbidity Secondary Endpoints: Overall survival, DFS, Regional recurrence, R A N D O M I Z E Breast surgery only Breast surgery + ALND IBCSG, JCO 24:2006

23 IBCSG 1093 Variable % AGE > 60 yo 100 TUMOR SIZE T-1 T ER + or PR + 80 Local Treatment Mastectomy BCS + RT BCS Recurrence (%) S S + ALND Local 4 2 Regional 1 2 Medan follow-up 6.6 years IBCSG, JCO 24:2006

24 Summary: Breast RT Standard breast radiation includes ~ 30-50% level 1, and ~ 25% level 2 axilla Supportive data in clinical trials of BCT with breast radiation only in cn0 patients Very low rates of axillary, regional and local recurrence reinforce that standard breast RT sufficient

25 Which patients with +SN benefit from a modified or more comprehensive radiation plan?

26 Radiation is as Effective as ALND in cn0 Early Stage Breast Cancer Years Accrued NSABP B-04 F/U Yrs. Treatment Arms n LRR p OS p Clinical N-0: Radical Mast. Total Mast. + RT Total Mast. ALND % 5% 13% % 19% 26% ns 40 % of women path. N+ in the Radical Mastectomy arm 19 % develop path. N+ in the Total Mastectomy arm Fisher, NEJM, 347:2002, Fisher, NEJM, 13:1989.

27 EORTC 10981/22023: After Mapping of the Axilla, Radiotherapy or Surgery (AMAROS) T1-2, cn0 Targeted Accrual: 3485 Activated: 2001 R A N D O M I Z E SNB + Axillary RT SNB + calnd Primary Endpoints: Local- regional Control Secondary Endpoints: Morbidity, QOL, Disease free, Overall Survival

28 Comprehensive Radiation Therapy Field for Undissected Axilla SCL L-3 L-2 L-1 Dose-Volume Analysis 45 Gy Axilla: 95 % Level % Level % Level 3 95% SCL V-20 Left Lung 20%

29 Modified Breast Tangents Include level 1-2 axilla that is typically part of the calnd High tangents Customized tangents Consider for intermediate risk patients

30 Dose-Volume Analysis 45 Gy Axilla: 78% Level 1 21% Level 2 V-20 Left Lung 9.75% High Tangent

31 Customized Tangent Dose-Volume Analysis 45 Gy Axilla: 100% Level 1 95% Level 2 V-20 Left Lung 13.2%

32 JS: 63 yo 2.3 cm G2, IDC, +LVI E+P+, H-, ORS- 14

33 ACOSOG Z11: NODES + (%) > 3 ALND SLN only (21%) of patients who underwent calnd had additional mestastases in > 3 positive nonsn nodes Benefit from more comprehensive regional nodal RT

34 Predictors of > 4 Axillary Node Metastases from calnd Massachusetts General Hospital 402 patients with +SNB and calnd Multivariate Analysis: 7 pathology features indentified increasing tumor size Invasive lobular histology LVI in the tumor ENE of the SN Increasing number of positive nodes Macroscopic size of +SN Decreasing number of uninvolved SN Nomogram developed: Predicted probability of > 4 axillary node metastases in 97.5% Katz, JCO, 26:2008

35 Likelihood of N1 vs. N2, N3 from calnd University of Kentucky 126 patients with +SNB and calnd 3 factors predictive for > 3 positive nodes LVI primary tumor ENE of SN > 5 mm SN tumor deposit Samoilova, Ann Surg Onc, 14:2007

36 One Radiation Oncologists Approach to + SNB without calnd Standard Breast Tangents: fit the Z-11 profile Customized Tangents ( Axilla level 1-2): 2 worrisome features.. Associated with risk, e.g. LVI Not as well represented in population, e.g. ER ALND and/or Comprehensive nodal radiation: (Axilla, SCL): - 3+ worrisome features - MGH Nomogram