Regional Nodal Radiation Therapy Julia S. Wong MD Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women's Hospital

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Axillary nodes IM nodes This slide shows the lymphatic drainage from the breast. Drainage can be either laterally to the axilla, with an orderly progression into the infraclavicular and supraclavicular area or medially to the internal mammary nodes. From lymphoscintigraphy studies, the first three intercostal interspaces are most at risk.

Negative Sentinel Node: NSABP B32: 10 Year Update SN +ALND (N=1975) SN Alone* (N=2011) OS 85.4% 87.5% DFS 77.0% 76.4% LRR 4.3% (84) 4.0% (81) Axillary recurrence 0.2% 0.4% No difference in OS, DFS, or regional control with SN alone vs. SN + ALND Julian, ASCO 2013 *Dissection only if SN positive

Sentinel Node Positive Patients: Questions In whom can axillary dissection be safely omitted? Can RT substitute for completion dissection? What nodal volume should be irradiated?

ACOSOG Z11 Patient characteristics: Treatment: Clinical T1-2 N0 1 or 2 positive SN No gross ECE Treatment: Lumpectomy with whole breast irradiation Dose/precise fields not specified Adjuvant systemic therapy by choice (97%) Giuliano A et al JAMA 2011 305: 569

ACOSOG Z11: Patient Characteristics cALND SNB Alone # Patients 420 436 Age, median 56 yrs 54 yrs T size, median 1.7 cm 1.6 cm ER/PR+ 82% Grade 3 29% 28% Giuliano A et al JAMA 2011 305: 569

Outcomes of Z11 (Median f/u: 6.3 years) Recurrence Type ALND (420) SLNB only (436) Locoregional (%) 4.1 2.8 Local 3.6 1.8 Axillary 0.5 0.9 DFS (%) 91.8 92.5 OS (%) 83.9 82.2 Giuliano A et al, Ann Surg. 2010 252(3):426-32 Giuliano A et al, JAMA. 2011 305(6):569-75 All comparisons non-significant

Giuliano AE et al Annals of Surg, epub 2016 Ten-Year Results SN Alone (%) SN + Ax Dissection (%) p LRR 5.3 6.2 0.36 DFS 80.3 78.3 0.30 OS 86.3 83.6 0.40 Median follow-up 9.25 years Giuliano AE et al Annals of Surg, epub 2016

Findings on cALND in Z11 46% of positive sentinel nodes were micromets Only 106 (27.4%) of patients treated with cALND had additional positive nodes beyond the SN This is a highly select group Giuliano A et al JAMA 2011 305: 569

Radiation Fields in ACOSOG Z0011 High vs Standard Tangent Fields 11% did not receive RT 228 patients (28.5%) had evaluable RT records: 50% received high tangents 19% had a separate nodal field No difference between arms Axillary Vein Standard Superior Border Axillary LN I think we are typically getting most of level I/II so I wonder about ‘low axilla’ ? Lower axilla. On these, I am now putting in a corner block to spare the upper inner arm. Lumpectomy Cavity Jagsi R, J Clin Oncol 32(32), 2014

IBCSG 23-01: ALND vs SN Only for Micrometastases cT1-T2, micrometastases in 1-2 SNs (H+E or IHC) Accrued: 934 (target 1950) between 2001-2010 Median F/U of 5 years Noninferiority trial Galimberti et al Lancet Oncol 2013;14:297

IBCSG 23-01: Characteristics ALND (n=464) SLNB (n=467) Median Age 53 yrs (23-81) 54 yrs (26-81) T <3 cm 91% 93% ER + 88% Systemic Rx 95% 97% Mastectomy 9% Median # SN 2 (1-9) 1 (1-8) Additional positive nodes 59 (13%) 12 (3%) RT after BCS: 70% External Beam 19% Intraop 9% Combination 98% 13% of pts in ALND had additional positive nodes removed beyond the SLN; 98% of the 91% BCS or 9% mastectomy 96% adjuvant STx, by choice 98% of BCS pts got RT; 70% got EBRT, 19% got IORT, 9% a combination THIS IS A HIGHLY SELECT GROUP

IBCSG 23-01: Characteristics ALND (n=464) SLNB (n=467) Median Age 53 yrs (23-81) 54 yrs (26-81) T <3 cm 91% 93% ER + 88% Systemic Rx 95% 97% Mastectomy 9% Median # SN 2 (1-9) 1 (1-8) Additional positive nodes 59 (13%) 12 (3%) RT after BCS: 70% External Beam 19% Intraop 9% Combination 98% 13% of pts in ALND had additional positive nodes removed beyond the SLN; 98% of the 91% BCS or 9% mastectomy 96% adjuvant STx, by choice 98% of BCS pts got RT; 70% got EBRT, 19% got IORT, 9% a combination THIS IS A HIGHLY SELECT GROUP

Galimberti et al Lancet Oncol 2013;14:297 IBCSG 23-01: Results Recurrence ALND (n=464) SLNB (n=467) Local 10 (2%) 8 (2%) Regional 1 (<1%) 5 (1%) Distant 34 (7%) 25 (5%) 5Y DFS 85%* 88%* 5Y OS 96% *Log rank p=0.16 non-inferiority p=0.004 Galimberti et al Lancet Oncol 2013;14:297

Donker M, Lancet Oncology 2014; 15:303-10 AMAROS: Study Design CT1-2, N0 3381 SN negative 1425 SN positive (n=681) axRT (n=744) cALND ® Donker M, Lancet Oncology 2014; 15:303-10

AMAROS: Patient Characteristics Axillary Dissection (n=744) Axillary RT (n=681) Age 56 55 Tumor size: 0-2 cm 612 (82%) 533 (78%) 2-5 cm 132 (18%) 143 (21%) >5 cm 1 (<1%) Grade: I 179 (24%) 154 (23%) II 356 (48%) 311 (46%) III 192 (26%) 200 (29%) Mastectomy 127 (17%) 121 (18%) Any systemic therapy 666 (90%) 612 (90%) # positive nodes: 1 581 (78%) 512 (75%) 2 134 (20%) 3 29 (4%) 27 (4%) >3 7 (1%) 8 (1%)

Donker M, Lancet Oncology 2014; 15:303-10 Axillary RT in AMAROS Started <12 wks after SNB 25 x 2Gy or equivalent Level I, II, III and medial supraclav Additional axillary RT: >4 positive nodes (in dissection arm) I think we are typically getting most of level I/II so I wonder about ‘low axilla’ ? Lower axilla. On these, I am now putting in a corner block to spare the upper inner arm. Figure adapted from Harris, J Donker M, Lancet Oncology 2014; 15:303-10

AMAROS Results (Median f/u 6.1 years) cALND n=744 AxRT n=681 5-yr Axillary recurrence 0.54% (n=4) 1.03% (n=7) 5Y DFS 87% 83% 5Y OS 94% 5 yr Clinical Lymphedema 23% 11% P<0.0001 Donker M, Lancet Oncology 2014; 15:303-10

AMAROS & Z0011: Similar Characteristics Z0011 (n=856) AMAROS (n=1,425) Median Age 55 yrs Median T-size 16 mm 17 mm ER+ 83% Grade 3 29% 28% Median # SN removed 2 +LN on cALND 27% 33% Micromets 46% 40% Systemic Tx 97% 91% Add intent-to-treat

Substituting RT for Surgery All of these trials indicate RT can substitute for cALND At least in fairly select patients But what volume to irradiate? Tangents alone? High tangents? Supraclav? IMN?

MA.20 Randomization Node positive, or high risk node-negative, s/p breast conservation Whole breast radiation VS Whole breast and regional nodal radiation Anthracylinc, other one hormone; yes, no Whelan TJ et al, NEJM 2015; 373:307-316

Eligibility Node positive High risk node negative >5 cm or >2 cm and <10 nodes removed And grade 3 or LVI positive or ER negative Chemotherapy and/or endocrine therapy required Whelan TJ et al, NEJM 2015; 373:307-316

MA.20 RT Details Whole breast: 50 Gy/25 fx Cone down: 10-16 Gy (e- or brachy) IMNs treated with either partially wide tangents or anterior field (electron and photon combination) 50 Gy/25 fx SCV/axilla (AP or AP/PA) Full axilla for >3 positive nodes or <10 dissected 45 Gy (for AP/PA), 50 Gy (AP) Whelan TJ et al, NEJM 2015; 373:307-316

Baseline Characteristics WBI N=916 WBI + RNI Age (mean) 52.7 53.9 Axillary nodes removed (mean) 12.3 12.4 Node –ve 89 (10) 89(10) Node +ve (1-3) 780 (85) 776 (85) Tumor size > 2 cm 416 (45) 457 (50) Grade III 387 (42) 390(43) ER –ve 235 (26) 232 (25) Adj chemotherapy 829 (91) 830 (91) Adj endocrine therapy 705 (77) 700 (76) Boost irradiation 221 (24) 206 (22) Whelan TJ et al, NEJM 2015; 373:307-316 in 39% 26

Baseline Characteristics WBI N=916 WBI + RNI Age (mean) 52.7 53.9 Axillary nodes removed (mean) 12.3 12.4 Node –ve 89 (10) 89(10) Node +ve (1-3) 780 (85) 776 (85) Tumor size > 2 cm 416 (45) 457 (50) Grade III 387 (42) 390(43) ER –ve 235 (26) 232 (25) Adj chemotherapy 829 (91) 830 (91) Adj endocrine therapy 705 (77) 700 (76) Boost irradiation 221 (24) 206 (22) Whelan TJ et al, NEJM 2015; 373:307-316 in 39% 27

Baseline Characteristics WBI N=916 WBI + RNI Age (mean) 52.7 53.9 Axillary nodes removed (mean) 12.3 12.4 Node –ve 89 (10) 89(10) Node +ve (1-3) 780 (85) 776 (85) Tumor size > 2 cm 416 (45) 457 (50) Grade III 387 (42) 390(43) ER –ve 235 (26) 232 (25) Adj chemotherapy 829 (91) 830 (91) Adj endocrine therapy 705 (77) 700 (76) Boost irradiation 221 (24) 206 (22) Whelan TJ et al, NEJM 2015; 373:307-316 in 39% 28

Ten-year Results (n=1832) 10-Yr No Nodal RT Nodal HR P- value LRR* 6.8% 4.3% 0.59 .009 DFS 77.0% 82.0% 0.76 .01 OS 81.8% 82.8% 0.91 .38 *isolated Whelan TJ et al, NEJM 2015; 373:307-316

MA.20: Hazard Ratios for Overall Survival Whelan et al, NEJM, 2015; 373:307-316

Adverse Events Any lymphedema increased from 4.5% to 8.4%; p = 0.001 Radiation pneumonitis increased from 0.2% to 1.2%; p = 0.01 All grade 2 Major cardiac event 0.4 vs 0.9, p= 0.26 Whelan TJ et al, NEJM 2015; 373:307-316 *NCI – Common toxicity criteria v2 1998

EORTC Phase III Trial 22922/10925 n= 4004 Stage I-III, pN+ or pN- w/ central/medial ARM 1: No nodal RT ® ARM 2: IM and supraclav RT Poortmans PM et al. N Engl J Med 2015;373:317-327

Poortmans PM et al. N Engl J Med 2015;373:317-327

Poortmans PM et al. N Engl J Med 2015;373:317-327 Many node-negatives Poortmans PM et al. N Engl J Med 2015;373:317-327

Poortmans PM et al. N Engl J Med 2015;373:317-327 Distant Disease-free and Overall Survival P=0.02 Figure 2. Distant Disease-free and Overall Survival. Kaplan–Meier curves for survival free from distant disease (Panel A) and overall survival (Panel B) are shown. P=0.06 Median follow-up: 10.9 years Poortmans PM et al. N Engl J Med 2015;373:317-327

Multicenter French Randomized Trial Randomization: CW, SCV +/- IM N=1407 Eligibility: Mastectomy, larger than 1.0 cm Any node positive Medial/central with or without positive nodes Technique: First 5 intercostal spaces included, 2/3rds of the dose with electrons The only randomized trial with mature follow-up to specificlaly address IM radiation is from France. Hennequin et al IJROBP 86(5), 2013

Hennequin et al IJROBP 86(5), 2013 Hennequin: Methods Powered for a 10% difference in the primary endpoint (OS) Stratification factors: Tumor location (medial/central vs lateral) Axillary lymph node status (pN0 vs pN+) Adjuvant systemic therapy (chemotherapy vs no chemotherapy) Hennequin et al IJROBP 86(5), 2013

Hennequin: 10 Year Results Outcome No IM RT (%) IM RT (%) p OS 59.3 62.6 0.8 DFS 53.2 49.9 0.35 LR as first event 9.8 9.2 NS Cardiac Events 2.2 1.7 Hennequin et al IJROBP 86(5), 2013

Thorsen LBJ et al, J Clin Oncol, epub 2015 The Danish Experience Prospective cohort study, 2003-2007 Node positive (macroscopic), younger than age 70 All received periclavicular and chest or breast RT LT-sided: RT without IMN (n=1586) RT-sided: RT with IMN (n=1486) Thorsen LBJ et al, J Clin Oncol, epub 2015

Key Patient/Treatment Characteristics (median follow-up 8.9 years) Median age 56 Mastectomy 65%; BCT 35% ER Positive 80% Positive axillary nodes: 1-3 59% 4-9 26% >10 15% High grade 28% Thorsen LBJ et al, J Clin Oncol, epub 2015

Thorsen LBJ et al, J Clin Oncol, epub 2015 75.9% 72.2% Overall Survival, HR 0.82; p=0.005 Breast Cancer Mortality, HR 0.85; p=0.03 Kaplan-Meier estimates and associated hazard ratios (HRs) of (A) overall survival, (B) cumulated incidence of breast cancer mortality, and (C) distant recurrence in patients with and without internal mammary node irradiation (IMNI). Distant Recurrence, HR 0.89; p=0.07 Thorsen LBJ et al, J Clin Oncol, epub 2015

Overall Survival by IMN RT Thorsen LBJ et al, J Clin Oncol, epub 2015

More Questions (few answers) What is the relative benefit of IM vs supraclav RT Does it make sense to treat supraclav alone in patients with “difficult” anatomy? IM alone in patients with medial tumors and negative axillary nodes? Which subgroups are most likely to benefit Biologic subtypes? Limited nodal involvement? What is the long-term risk of increased lung V20 and low-dose cardiac RT?

Summary Nodal RT reasonable alternative to ALND in patients with limited SN involvement Benefit to regional nodal irradiation (comprehensive?) Optimal extent of nodal RT fields remains unclear (inclusion of IMNs at what toxicity cost?) Implications for selection of patients for PMRT Evolving role of RT with improved systemic therapy Mention neoadjuvant settings