+

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

+Content

Hypofractionation

APBI

IORT

Local Treatment in Stage IV disease

+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

[P4-16-08] Intraoperative Electron Radiotherapy in Early Stage Breast Cancer. A Single-Institution Experience

[P4-16-03] 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

[P4-16-06] Radiotherapy To the Primary Tumor Is Associated with Improved Survival in Stage IV Breast Cancer

+Hypofractionated Breast RT

Change in DOSE:

*Hypofractionatedlarger dose per fraction

*Same time vs. shorter time

versus

versus

+ 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

+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.

+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.

+Methods

T1-3, N0-1 M0 breast cancer

Primary endpoint:Local-regional relapse

Secondary:Normal tissue effectsDisease-free and OS

35 UK centers 1999-2002

Median F/U:START A- 9.3 yrsSTART B- 9.9 yrs

+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% 5.5-10.0

41.6 Gy/ 3Gy 6.3% 4.7-8.5

39 Gy/ 3.2Gy 8.8% 6.7-11.4

+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 4.2-7.2)

40 Gy/ 2.67Gy 4.3% (95%CI 3.2-5.9)

+Findings

START A

+Findings

START B

+Findings: Cosmesis

Clinician assessments suggested lower 10-year rates of any moderate/marked late normal tissue effects after 39Gy (43.9%; 95%CI 39.3-48.7) and similar rates after 41.6Gy (49.5%;95%CI 44.9-54.3) compared with 50Gy (50.4%; 95%CI 45.8-55.3) in START A

and lower rates after 40Gy in START B (37.9%; 95%CI 34.5-41.5) compared with 50Gy (45.3%; 95%CI 41.7-49.0).

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 1.2-5.7) and for late change inphotographic breast appearance was 3.1Gy (95% CI 2.0-4.2).

+Findings

START A: Physicians’ assessment of cosmesis

+Findings

START B: Physicians’ assessment of cosmesis

+Conclusions

+

+Discussion

+Discussion

Node-negativeclear margins after lumpectomy exclusion of very large breast sizeno boost10% chemo

+Accelerated Partial Breast RT

Change in DOSE:

*Hypofractionatedlarger dose per fraction

*Shorter timeless time

versus

Change in VOLUME:

*limited volume less tissue treated

+

Intraoperative Radiotherapy Trials

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

Lancet 2010

Intrabeam™ for Targeted Intraoperative Radiotherapy

Intraoperative Technique

Distance Surface

PE probe (Gy) Conventional EBRT

Physical Dose

BED Physical Dose

BED

0.1 cm 15 165 50 60

0.5 cm 8.75 59 50 60

1.0 cm 5.0 21.7 50 60

BED= Physical Dose x [1+ (dose/fx) / /a b)]

/a b = 10 (early effects conventional EBRT)

/a b= 1.5 (assumed for TARGiT device)

Physical Dose Profile

Vaidya et al, Annals of Oncol, 2001; 12: 1075-1080

+Trial schema

+Findings

+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.

+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. 1222 patients with median F/U of 5 years. Primary events have increased from 13 to 34 since 2010.

+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%.

+Updated Results

For the secondary outcome, there was a non-significant trend for improved overall survival with TARGIT (HR = 0.70(0.46-1.07)) due to fewer non-breast cancer deaths (17 vs. 35, HR 0.47 (0.26-0.84)). Cardiovascular deaths were 1 vs. 10 and deaths from cancers other than breast were 7 vs.16.

+[P4-16-08] 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

+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.

+Methods

+Methods

+Methods

+Methods

+Methods

+Results

+Results

+

Fig 1. After the upper-outer quadrantectomy of leftbreast, a medial glandular flap is performed. The breastis separated, superficially by the skin, and deeply by thepectoralis muscle.

Fig 2. The mobilization of the breast target is concluded preparing the lateral glandular flap.

Fig 3. The gland is reconstructed over the aluminumand lead disks to expose the correct portion of the breastto be irradiated. The disks (outlined) appear betweenthe restored breast and the pectoralis muscle.

Intra…Veronesi et al Surgery September 2006

ELectron Intraoperative Radio Therapy= ELIOT

+Electrons Intraoperative Therapy: ELIOT Trial

Fig 4. Sagittal plane of the breast. The sterile collimatorof the linear accelerator is introduced through the skinincision and placed directly in contact with the breasttarget. The aluminum and lead disks are located betweengland and pectoralis muscle, exactly on the line of thecollimator. The disk size must be at least equal or superiorto the breast target size.

Veronesi et al, Ann Surg 2005;242: 101–106

+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

+ELIOT results 2010Factor 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

+ELIOT results 2010Factor 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 1.0 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 0.20

Unspecificed death 6 0.3 0.10

Any death 46 2.5 0.76

+ELIOT results 2010Factor 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 24 1.3

Seroma 235 12.9

No side effects 1434 78.7

1 side effect 292 16.0

2 side effects 76 4.2

3 side effects 16 0.9

+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 (0.90-3.95)

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

+ELIOT trial results 2010

+ELIOT trial results 2010

+

+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% ns

HER 2* 8.4% 13% 4.6% 29.2% 21% ns

Basal 7.1% 21% 3.2% 5.8% 14% 22%1Nguyen et al, JCO 26:2373, 2008 Harvard2Millar et al, JCO 27: 4701, 2009 Australian3Freedman et al, Cancer 115: 946, 2009 FCCC4Albert et al, IJROBP 77:1296, 2010: Stage T1a,b N0 BCT 62% MDAH5Voduc et al, JCO 28: 1684, 2010 British Columbia and UNC; ^Lum Her26Haffty et al, JCO 24:5652, 2006 Yale

* Pre-Herceptin era

IJROBP 2009

+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 Absent

Lymph nodes Node Negative

52

+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 2.1-3.0cm

LVSI Limited/focal

Histology Invasive Lobular

Pure DCIS <3 cm

Extensive Intraductal Component (>25% DCIS) <3 cm

Lymphovascular invasion Limited or Focal

+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 Positive

+ [P4-16-03] 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

+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.

+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.

+Methods:

+Methods:

+Results:

+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).

+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.

+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, lymphnode involvement, extensive intraductal disease, andlymphovascular 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.

+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 withIBTR following whole breast irradiation and not theunderlying scientific concept of localizing radiation only to the tumor bed region (i.e., APBI).

+[P4-16-06] 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

+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.

+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.

+Results:

A total of 3,529 cases were analyzed. EBRT was received in 768 cases. Median age at diagnosis was 68 years (IQR, 56-79 years). Median follow-up by reverse KM estimate was 98 months (range, 0-252 months).

On univariate analysis, EBRT was associated with improved OS (hazard ratio 0.80, 95% CI 0.74-0.87, 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.

+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 0.76-0.97, p=0.011).

+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.

+ECOG 2108

+

+

+

+

+The End