Presentation on theme: "Best of SABCS 2012 Radiation Oncology"— Presentation transcript:
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:*Hypofractionatedlarger dose per fraction*Same time vs. shorter timeversusversus
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 BackgroundInternational 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 MethodsBetween 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 relapseSecondary:Normal tissue effectsDisease-free and OS35 UK centersMedian F/U:START A- 9.3 yrsSTART B- 9.9 yrs
9 Findings: START AMedian F/U in survivors is now 9.3 years in START A and 139 LRsIn START A, the 10-year rate of LR relapse wasTreatmentLRR at 10 yrs95% CI50 Gy/ 2Gy7.4%41.6 Gy/ 3Gy6.3%39 Gy/ 3.2Gy8.8%
10 Findings: START BMedian F/U in survivors is now 9.9 years in START B and 95 LR’sIn START A, the 10-year rate of LR relapse wasTreatmentLRR at 10 yrs95% CI50 Gy/ 2Gy5.5%(95%CI )40 Gy/ 2.67Gy4.3%(95%CI )
13 Findings: CosmesisClinician 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 Aand 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 FindingsSTART A: Physicians’ assessment of cosmesis
15 FindingsSTART B: Physicians’ assessment of cosmesis
27 Update: Methods3451 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 Results1721 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 ResultsFor 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 ResultsFor 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 ExperienceDall'Oglio S, Maluta S, Marciai N, Gabbani M, Franchini Z, Pietrarota P, Meliadò G, Guariglia S, Cavedon C. University Hospital, Verona, Italy
32 MethodsFrom 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.
40 ELectron Intraoperative Radio Therapy= ELIOT 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
41 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
42 ELIOT results 2010 1822 pts with ELIOT from Jan 2000 to Dec 2008 1800 pts received 21 Gy rx to 90% isodose1381 received endocrine therapy176 chemotherapy alone198 chemotherapy and endocrine therapy67 had no adjuvant treatment58 women since 2005 received HerceptinMean f/u 36.1 monthsVeronesi, Br Can Res Tr 2010
43 ELIOT results 2010 Factor number % Age <50 368 20.2 Lobular Ca 202 11.1Size 2-5 cm26114.3Positive nodes51728.4Grade 345925.2Peritumoral vascular invasion29416.1ER negative19410.6HER2 +1739.5Lum A64835.6Lum B97753.6Her2+532.9Basal1377.5
44 ELIOT results 2010 Factor number % Annual % True local recurrence 42 2.30.77Ipsilateral breast ca241.30.44Regional metastasis181.00.33Contralateral ca190.35Distant metastasis261.40.47Other cancer331.80.60Death as first event110.60.20Any first event1719.43.12Deaths from br ca281.50.45Deaths from other120.7Unspecificed death60.30.10Any death462.50.76
45 ELIOT results 2010 Factor number % Mild fibrosis 32 1.8 Severe fibrosis20.1Lyponecrosis784.2Hematoma1015.5Edema241.3Pain130.7Wound infectionSeroma23512.9No side effects143478.71 side effect29216.02 side effects763 side effects160.9
46 ELIOT Multivariate Model for LR FactorHRP valueAge <502.10 (1.18–3.74)0.01Size >2.02.29 (1.02–5.15)0.04Lobular histology1.89 ( )0.09Lum A (ER+ or PR+,KI-67<14%, Her2-)1.00Lum B (ER+ or PR+, KI-67>14% or Her2+)3.46 (1.52–7.90)0.003Her2+ (ER- and PR-, Her2+) (n=53)5.68 (1.72–18.8)0.004Basal (ER-, PR-, Her2-)5.26 (1.84–15.0)0.002
50 How much is tumor biology driving local recurrence risk? 1.2 cm, grade 1, ER/PR +, Her2+ “luminal” type1.2 cm, grade 3, ER/PR-,Her2- “basal” typeSubtypeLR at 5 yrs1LR at 5 yrs2LR at 5 yrs3LR at 8 yrs4LR at 10 yrs5LR at 10 yrs6Lum A0.8%2%2.3%3.5%8%nsLum B*1.5%3%--13.4%^8%HER 2*8.4%13%4.6%29.2%21%Basal7.1%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
52 ASTRO “Suitable Group” FactorALL of the following must be presentAge>=60 yearsTumour size<=2cmMarginsNegative by at least 2mmGradeAnyER statusPositiveMulticentricitySingle tumourMultifocalityClinically unifocal <2.0 cmHistologyInvasive Ductal or favourable subtypeExtensive Intraductal Component (>25% DCIS)AbsentLymphovascular invasionLymph nodesNode Negative
53 ASTRO “Cautionary Group” FactorAny of these should invoke cautionAge50-59 yearsTumour size2.1 – 3cmMarginsClose < 2mmER statusNegativeMultifocalityClinically Unifocal, total size cmLVSILimited/focalHistologyInvasive LobularPure DCIS<3 cmExtensive Intraductal Component (>25% DCIS)Lymphovascular invasionLimited or Focal
54 ASTRO “Unsuitable Group” FactorAny of the following must be presentAge<50 yearsTumour size> 3 cmMarginsPositiveER statusNegativeMulticentricityMore than 1 tumourHistologyInvasive LobularExtensive Intraductal Component (>25% DCIS)PresentLymphovascular invasionExtensiveLymph 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 DataWilkinson 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.
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 ConclusionsFactors 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.
64 ConclusionsThe 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).
65 [P ] Radiotherapy To the Primary Tumor Is Associated with Improved Survival in Stage IV Breast CancerMorgan 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.