1. Best of SABCS 2012 Radiation Oncology
Catherine Park, M.D.
UCSF Department of Radiation Oncology

2. Content Hypofractionation APBI IORT
Local Treatment in Stage IV disease

3. Content
[S4-1] The UK START (Standardisation of Breast Radiotherapy) Trials: 10-Year Follow-Up Results
[S4-2] Targeted Intraoperative Radiotherapy for Early Breast Cancer: TARGIT-A Trial- Updated Analysis of Local Recurrence and First Analysis of Survival
[P ] Intraoperative Electron Radiotherapy in Early Stage Breast Cancer. A Single-Institution Experience
[P ] Patterns of Failure after Accelerated Partial Breast Irradiation by Consensus Panel Group: A Pooled Analysis of William Beaumont Hospital and the American Society of Breast Surgeons Trial Data
[P ] Radiotherapy To the Primary Tumor Is Associated with Improved Survival in Stage IV Breast Cancer

4. Hypofractionated Breast RT
Change in DOSE:
*Hypofractionatedlarger dose per fraction
*Same time vs. shorter time
versus
versus

5. S4-1: The UK START (Standardisation of Breast Radiotherapy) Trials: 10-Year Follow-Up Results
JS Haviland, RK Agrawal, E Aird, J Barrett, P Barrett-Lee, J Brown, J Dewar, J Dobbs, P Hopwood, P Hoskin, P Lawton, B Magee, J Mills, D Morgan,JR Owen, S Simmons, MA Sydenham, K Venables, JM Bliss, JR Yarnold on behalf of the START Trialists

6. Background
International standard adjuvant radiotherapy regimens following primary surgery for early breast cancer have historically delivered a high total dose (50Gy) in 25 small daily doses (fractions)over 5 weeks.
However, randomised trials, including START, indicate that a lower total dose delivered in fewer, larger fractions (Fr) is likely to be at least as safe and effective (START Trialists’ Group, Lancet 2008 & Lancet Oncol 2008).
Here, we report 10-year follow-up of the UK START Trials testing 13- and 15-Fr regimens in terms of local cancer control and late adverse effects.

7. Methods
Between 1999 and 2002, 4451 women with completely excised invasive breast cancer (T1-3, N0-1, M0) were randomised after primary surgery to comparisons of:
50Gy in 25Fr over 5 weeks vs 41·6Gy or 39Gy in 13Fr over 5 weeks (START A)
or 50Gy in 25Fr over 5 weeks vs 40Gy in 15Fr over 3 weeks (START B)
Women were eligible if aged over 18 years and did not have an immediate surgical reconstruction. ~85% START A and >90% START B had lumpectomy.
Protocol-specified principal endpoints were local-regional (LR) tumour relapse and late normal tissue effects.

8. Methods T1-3, N0-1 M0 breast cancer Primary endpoint:
Local-regional relapse
Secondary:
Normal tissue effects
Disease-free and OS
35 UK centers
Median F/U:
START A- 9.3 yrs
START B- 9.9 yrs

9. Findings: START A
Median F/U in survivors is now 9.3 years in START A and 139 LRs
In START A, the 10-year rate of LR relapse was
Treatment
LRR at 10 yrs
95% CI
50 Gy/ 2Gy
7.4%
41.6 Gy/ 3Gy
6.3%
39 Gy/ 3.2Gy
8.8%

10. Findings: START B
Median F/U in survivors is now 9.9 years in START B and 95 LR’s
In START A, the 10-year rate of LR relapse was
Treatment
LRR at 10 yrs
95% CI
50 Gy/ 2Gy
5.5%
(95%CI )
40 Gy/ 2.67Gy
4.3%
(95%CI )

11. Findings
START A

12. Findings
START B

13. Findings: Cosmesis
Clinician assessments suggested lower 10-year rates of any moderate/marked late normal tissue effects after 39Gy (43.9%; 95%CI ) and similar rates after 41.6Gy (49.5%;95%CI ) compared with 50Gy (50.4%; 95%CI ) in START A
and lower rates after 40Gy in START B (37.9%; 95%CI ) compared with 50Gy (45.3%; 95%CI ).
From a planned meta-analysis of START A and the START pilot trial (Owen et al, Lancet Oncol 2006), the adjusted estimate of α/β value for tumour control was 3.5Gy (95% CI ) and for late change inphotographic breast appearance was 3.1Gy (95% CI ).

14. Findings
START A: Physicians’ assessment of cosmesis

15. Findings
START B: Physicians’ assessment of cosmesis

16. Conclusions

18. Discussion

19. Discussion Node-negative clear margins after lumpectomy
exclusion of very large breast size
no boost
10% chemo

20. Accelerated Partial Breast RT
Change in DOSE:
*Hypofractionatedlarger dose per fraction
*Shorter timeless time
versus
Change in VOLUME:
*limited volume less tissue treated

21. Intraoperative Radiotherapy Trials

22. [S4-2] Targeted Intraoperative Radiotherapy for Early Breast Cancer: TARGIT-A Trial- Updated Analysis of Local Recurrence and First Analysis of Survival
Lancet 2010

23. Intrabeam™ for Targeted Intraoperative Radiotherapy

24. Intraoperative Technique
Physical Dose Profile
BED= Physical Dose x [1+ (dose/fx) / a/b)]
a/b = 10 (early effects conventional EBRT)
a/b= 1.5 (assumed for TARGiT device)
Distance Surface
PE probe (Gy)
Conventional EBRT
Physical Dose
BED
0.1 cm 15
165 50 60
0.5 cm
8.75 59
1.0 cm
5.0
21.7
Vaidya et al, Annals of Oncol, 2001; 12:

25. Trial schema

26. Findings

27. Update: Methods
3451 women aged 45 years or older with invasive ductal carcinoma were enrolled from 33 centres in 10 countries between 2000 and 2012.
Randomisation to TARGIT or EBRT arm was done either before lumpectomy (pre-pathology) or after lumpectomy (postpathology).
The primary outcome was ipsilateral within breast recurrence (IBR) with an absolute non-inferiority margin of 2.5% at 5 years and secondary outcome was survival.

28. Updated Results
1721 patients were randomly allocated to receive TARGIT and 1730 to EBRT.
1010 patients have a minimum 4 years follow up and 611 patients have minimum 5 years follow up patients with median F/U of 5 years. Primary events have increased from 13 to 34 since 2010.

29. Updated Results
For the primary outcome of ipsilateral breast recurrence, the absolute difference at 5-years was 2.0%, which was higher with TARGIT and reached the conventional levels of statistical significance (p=0.042), but was within the pre-specified non-inferiority margin;
in prepathology the absolute difference in 5-year IBR was 1%; in postpathology it was 3.7%.

30. Updated Results
For the secondary outcome, there was a non-significant trend for improved overall survival with TARGIT (HR = 0.70( )) due to fewer non-breast cancer deaths (17 vs. 35, HR 0.47 ( )). Cardiovascular deaths were 1 vs. 10 and deaths from cancers other than breast were 7 vs.16.

31. [P ] Intraoperative Electron Radiotherapy in Early Stage Breast Cancer. A Single-Institution Experience
Dall'Oglio S, Maluta S, Marciai N, Gabbani M, Franchini Z, Pietrarota P, Meliadò G, Guariglia S, Cavedon C. University Hospital, Verona, Italy

32. Methods
From July 2006 to December 2009, 226 patients suitable for BCT were enrolled in a phase II trial with IOERT as radical treatment immediately after surgical resection.
After the surgeon temporarily re-approximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed with a margin of 2 cm laterally.

33. Methods

34. Methods

35. Methods

36. Methods

37. Methods

38. Results

39. Results

40. ELectron Intraoperative Radio Therapy= ELIOT
Fig 1. After the upper-outer quadrantectomy of left
breast, a medial glandular flap is performed. The breast
is separated, superficially by the skin, and deeply by the
pectoralis muscle.
Fig 2. The mobilization of the breast target is concluded preparing the lateral glandular flap.
Fig 3. The gland is reconstructed over the aluminum
and lead disks to expose the correct portion of the breast
to be irradiated. The disks (outlined) appear between
the restored breast and the pectoralis muscle.
Intra…Veronesi et al Surgery September 2006

41. Electrons Intraoperative Therapy: ELIOT Trial
Fig 4. Sagittal plane of the breast. The sterile collimator
of the linear accelerator is introduced through the skin
incision and placed directly in contact with the breast
target. The aluminum and lead disks are located between
gland and pectoralis muscle, exactly on the line of the
collimator. The disk size must be at least equal or superior
to the breast target size.
Veronesi et al, Ann Surg 2005;242: 101–106

42. ELIOT results 2010 1822 pts with ELIOT from Jan 2000 to Dec 2008
1800 pts received 21 Gy rx to 90% isodose
1381 received endocrine therapy
176 chemotherapy alone
198 chemotherapy and endocrine therapy
67 had no adjuvant treatment
58 women since 2005 received Herceptin
Mean f/u 36.1 months
Veronesi, Br Can Res Tr 2010

43. ELIOT results 2010 Factor number % Age <50 368 20.2 Lobular Ca 202
11.1
Size 2-5 cm
261
14.3
Positive nodes
517
28.4
Grade 3
459
25.2
Peritumoral vascular invasion
294
16.1
ER negative
194
10.6
HER2 +
173
9.5
Lum A
648
35.6
Lum B
977
53.6
Her2+ 53
2.9
Basal
137
7.5

44. ELIOT results 2010 Factor number % Annual % True local recurrence 42
2.3
0.77
Ipsilateral breast ca 24
1.3
0.44
Regional metastasis 18
1.0
0.33
Contralateral ca 19
0.35
Distant metastasis 26
1.4
0.47
Other cancer 33
1.8
0.60
Death as first event 11
0.6
0.20
Any first event
171
9.4
3.12
Deaths from br ca 28
1.5
0.45
Deaths from other 12
0.7
Unspecificed death 6
0.3
0.10
Any death 46
2.5
0.76

45. ELIOT results 2010 Factor number % Mild fibrosis 32 1.8
Severe fibrosis 2
0.1
Lyponecrosis 78
4.2
Hematoma
101
5.5
Edema 24
1.3
Pain 13
0.7
Wound infection
Seroma
235
12.9
No side effects
1434
78.7
1 side effect
292
16.0
2 side effects 76
3 side effects 16
0.9

46. ELIOT Multivariate Model for LR
Factor HR
P value
Age <50
2.10 (1.18–3.74)
0.01
Size >2.0
2.29 (1.02–5.15)
0.04
Lobular histology
1.89 ( )
0.09
Lum A (ER+ or PR+,KI-67<14%, Her2-)
1.00
Lum B (ER+ or PR+, KI-67>14% or Her2+)
3.46 (1.52–7.90)
0.003
Her2+ (ER- and PR-, Her2+) (n=53)
5.68 (1.72–18.8)
0.004
Basal (ER-, PR-, Her2-)
5.26 (1.84–15.0)
0.002

47. ELIOT trial results 2010

48. ELIOT trial results 2010

50. How much is tumor biology driving local recurrence risk?
1.2 cm, grade 1, ER/PR +, Her2+ “luminal” type
1.2 cm, grade 3, ER/PR-,Her2- “basal” type
Subtype
LR at 5 yrs1
LR at 5 yrs2
LR at 5 yrs3
LR at 8 yrs4
LR at 10 yrs5
LR at 10 yrs6
Lum A
0.8% 2%
2.3%
3.5% 8% ns
Lum B*
1.5% 3% --
13.4%
^8%
HER 2*
8.4%
13%
4.6%
29.2%
21%
Basal
7.1%
3.2%
5.8%
14%
22%
1Nguyen et al, JCO 26:2373, 2008 Harvard
2Millar et al, JCO 27: 4701, 2009 Australian
3Freedman et al, Cancer 115: 946, 2009 FCCC
4Albert et al, IJROBP 77:1296, 2010: Stage T1a,b N0 BCT 62% MDAH
5Voduc et al, JCO 28: 1684, 2010 British Columbia and UNC; ^Lum Her2
6Haffty et al, JCO 24:5652, 2006 Yale
* Pre-Herceptin era

51. IJROBP 2009

52. ASTRO “Suitable Group”
Factor
ALL of the following must be present
Age
>=60 years
Tumour size
<=2cm
Margins
Negative by at least 2mm
Grade
Any
ER status
Positive
Multicentricity
Single tumour
Multifocality
Clinically unifocal <2.0 cm
Histology
Invasive Ductal or favourable subtype
Extensive Intraductal Component (>25% DCIS)
Absent
Lymphovascular invasion
Lymph nodes
Node Negative

53. ASTRO “Cautionary Group”
Factor
Any of these should invoke caution
Age
50-59 years
Tumour size
2.1 – 3cm
Margins
Close < 2mm
ER status
Negative
Multifocality
Clinically Unifocal, total size cm
LVSI
Limited/focal
Histology
Invasive Lobular
Pure DCIS
<3 cm
Extensive Intraductal Component (>25% DCIS)
Lymphovascular invasion
Limited or Focal

54. ASTRO “Unsuitable Group”
Factor
Any of the following must be present
Age
<50 years
Tumour size
> 3 cm
Margins
Positive
ER status
Negative
Multicentricity
More than 1 tumour
Histology
Invasive Lobular
Extensive Intraductal Component (>25% DCIS)
Present
Lymphovascular invasion
Extensive
Lymph nodes

55. [P ] Patterns of Failure after Accelerated Partial Breast Irradiation by Consensus Panel Group: A Pooled Analysis of William Beaumont Hospital and the American Society of Breast Surgeons Trial Data
Wilkinson JB, Beitsch PD, Arthur D, Shah C, Haffty BG, Wazer D, Keisch M, Shaitelman SF, Lyden M, Chen PY, Vicini FA. Oakland University William Beaumont School of Medicine, Royal Oak, MI; Dallas Surgical Group, Dallas, TX; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; Washington University School of Medicine, St. Louis, MO; Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Camden, NJ; Tufts Medical Center and Rhode Island Hospital/Brown University, Boston, MA; Cancer Healthcare Associates, Miami, FL; University of Texas M.D. Anderson Cancer Center, Houston, TX; Biostat International, Inc., Tampa, FL; Michigan Healthcare Professionals/21st Century Oncology, Farmington Hills, MI

56. Background:
To determine six-year outcomes and patterns of failure following accelerated partial breast irradiation (APBI) within a pooled patient population from William Beaumont Hospital (WBH) and the American Society of Breast Surgeons (ASBrS) MammoSite® Registry Trial.

57. Methods:
2,127 cases of early-stage breast cancer were treated using APBI (WBH: n=678; ASBrS: n=1,449).
Three forms of APBI were used at WBH (interstitial, n=221; balloon-based, n=255; or 3D-CRT, n=206) while all Registry Trial patients received balloon-based brachytherapy.
Patients with complete coding necessary for ASTRO Consensus Panel (CP) group assignment (n=1,813) were divided into suitable (n=661, 36.5%), cautionary (n=850, 46.9%), and unsuitable (n=302, 16.7%) categories.
Tumor characteristics, clinical outcomes, and patterns of failure were analyzed according to CP group.

58. Methods:

59. Methods:

60. Results:

61. Results: Median follow up was 59.4 months.
Six-year rates of ipsilateral breast tumor recurrence (IBTR), regional nodal failure (RNF), and distant metastasis (DM) for the whole cohort were 3.2%, 0.7%, and 1.1%, respectively.
Elsewhere failures (EF) were the predominant mode of in- breast recurrence for each CP group (suitable: 2.3%, cautionary: 2.5%, unsuitable: 4.9%, p=0.16) as compared to true recurrences (TR) near the lumpectomy bed (suitable 0.9%, cautionary: 1.5%, unsuitable: 0.8%).
No statistical difference in combined rates of ipsilateral recurrence (TR+EF) were observed between the three consensus panel groups (suitable: 3.2%, cautionary: 4.1%, unsuitable: 5.7%, p=0.25).

62. Results:
On multivariate analysis, no factor was associated with risk of true recurrence while ER negative status (OR: 4.13, p<0.01) and a positive/close margin (OR: 2.70, p=0.02) were associated with increased rates of elsewhere failure.

63. Conclusions
Factors specifically associated with IBTR following breast conserving therapy include young age at diagnosis,
involved or close surgical margins, increased tumor size,
ER negative receptor status, high grade histology, lymph
node involvement, extensive intraductal disease, and
lymphovascular space invasion.
These factors have not necessarily been shown, however, to be specific predictors of elsewhere failure only for women treated with limited-field radiotherapy.

64. Conclusions
The risk factors identified in the ASTRO CS groups may portend for an increased risk for treatment failure following breast conservation, regardless of method of adjuvant radiotherapy. As a result, clinicians and patients are forced to rely on recommendations based upon extrapolated data from risk factors associated with
IBTR following whole breast irradiation and not the
underlying scientific concept of localizing radiation only to the tumor bed region (i.e., APBI).

65. [P ] Radiotherapy To the Primary Tumor Is Associated with Improved Survival in Stage IV Breast Cancer
Morgan SC, Caudrelier J-M, Clemons MJ. University of Ottawa, ON, Canada; The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada

66. Background:
In patients found to have metastatic disease at the time of breast cancer diagnosis, the role of local therapy is undefined. Numerous retrospective analyses have suggested that surgery and/or external beam radiotherapy (EBRT) directed at the primary tumor may improve overall survival (OS). All these analyses, however, are subject to significant selection bias. The current retrospective analysis of a large registry dataset attempts to limit the effect of this bias.

67. Methods:
The study population consisted of women in the Surveillance, Epidemiology, and End Results (SEER) program database diagnosed with stage IV breast cancer between 1988 and 2009.
Only those patients for whom surgery to the primary tumor was recommended but was not undertaken (due to patient refusal or other uncategorized reasons) were included.
In this population of patients deemed candidates for surgery, the association between receipt of primary tumor-directed EBRT and overall survival was studied. Descriptive statistics were used to characterize the study population. OS was estimated using the Kaplan-Meier (KM) method. Univariate and multivariate Cox regression were used to identify factors associated with OS.

68. Results:
A total of 3,529 cases were analyzed. EBRT was received in 768 cases. Median age at diagnosis was 68 years (IQR, years). Median follow-up by reverse KM estimate was 98 months (range, months).
On univariate analysis, EBRT was associated with improved OS (hazard ratio 0.80, 95% CI , p<0.001). 1-year, 3- year, and 5-year OS was 56.9%, 24.2%, and 10.7% respectively in those receiving EBRT and 44.3%, 16.6%, and 7.2% respectively in those not receiving EBRT.
Median OS in those receiving EBRT was 15 months compared to 7 months in those not receiving EBRT.

69. Results:
In a multivariate Cox model taking into account receipt of EBRT, age at diagnosis, year of diagnosis, ethnicity, number of primary cancers, estrogen and progesterone receptor status, histologic grade, and size of primary tumor, EBRT remained significantly associated with improved survival (hazard ratio 0.86, 95% CI , p=0.011).

70. Conclusions:
In a population of women presenting with metastatic breast cancer, all of whom were deemed candidates for surgery to the primary tumor but who did not undergo surgery, receipt of EBRT was associated with improved OS. The observed 8- month absolute difference in median OS is clinically significant. This analysis could not account for performance status, extent of metastatic disease, co-morbidities, use of systemic therapies, and other potentially confounding factors. Only randomized studies, such as the Eastern Cooperative Oncology Group E2108 trial currently underway, will be able to definitively assess the value of local therapy directed at the primary tumor in this setting.

71. ECOG 2108

76. The End