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

3. I have no relevant disclosures

4. 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.

5. 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

6. 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?

7. 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 : 569

8. 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 : 569

9. 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.  (3):426-32
Giuliano A et al, JAMA (6):569-75
All comparisons non-significant

10. 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

11. 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 : 569

12. 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

13. 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
Median F/U of 5 years
Noninferiority trial
Galimberti et al Lancet Oncol 2013;14:297

14. 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

15. 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

16. 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

17. 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

18. AMAROS: Patient Characteristics
Axillary Dissection (n=744)
Axillary RT (n=681)
Age 56 55
Tumor size: 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%)

19. 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

20. 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

21. 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

22. 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?

23. 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:

24. 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:

25. MA.20 RT Details Whole breast: 50 Gy/25 fx
Cone down: 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:

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:
in 39% 26

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:
in 39% 27

28. 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:
in 39% 28

29. 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:

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

31. 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:
*NCI – Common toxicity criteria v2 1998

32. 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:

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

34. 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:

35. 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:

36. 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

37. 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

38. 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

39. Thorsen LBJ et al, J Clin Oncol, epub 2015
The Danish Experience
Prospective cohort study,
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

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

41. 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

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

43. 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?

44. 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