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

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Presentation on theme: "+ Best of SABCS 2012 Radiation Oncology Catherine Park, M.D. UCSF Department of 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: *Hypofractionated  larger dose per fraction *Same time vs. shorter time 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 TreatmentLRR at 10 yrs95% CI 50 Gy/ 2Gy7.4% Gy/ 3Gy6.3% Gy/ 3.2Gy8.8%

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 TreatmentLRR at 10 yrs95% 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

17 +

18 + Discussion

19 + 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 Distance Surface PE probe (Gy)Conventional EBRT Physical Dose BEDPhysical Dose BED 0.1 cm cm cm BED= Physical Dose x [1+ (dose/fx) /  )]  = 10 (early effects conventional EBRT)  = 1.5 (assumed for TARGiT device) Physical Dose Profile 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 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 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 +

35 +

36 +

37 +

38 + Results

39 +

40 + 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 EL ectron I ntraoperative R adio T herapy= ELIOT

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 pts with ELIOT from Jan 2000 to Dec 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 Factornumber% Age < Lobular Ca Size 2-5 cm Positive nodes Grade Peritumoral vascular invasion ER negative HER Lum A Lum B Her Basal1377.5

44 + ELIOT results 2010 Factornumber%Annual % True local recurrence Ipsilateral breast ca Regional metastasis Contralateral ca Distant metastasis Other cancer Death as first event Any first event Deaths from br ca Deaths from other Unspecificed death Any death

45 + ELIOT results 2010 Factornumber% Mild fibrosis321.8 Severe fibrosis20.1 Lyponecrosis784.2 Hematoma Edema241.3 Pain130.7 Wound infection241.3 Seroma No side effects side effect side effects side effects160.9

46 + ELIOT Multivariate Model for LR FactorHRP value Age < (1.18–3.74)0.01 Size > (1.02–5.15)0.04 Lobular histology1.89 ( )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 +

49 +

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 SubtypeLR at 5 yrs 1 LR at 5 yrs 2 LR at 5 yrs 3 LR at 8 yrs 4 LR at 10 yrs 5 LR at 10 yrs 6 Lum A0.8%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 Basal7.1%21%3.2%5.8%14%22% 1 Nguyen et al, JCO 26:2373, 2008 Harvard 2 Millar et al, JCO 27: 4701, 2009 Australian 3 Freedman et al, Cancer 115: 946, 2009 FCCC 4 Albert et al, IJROBP 77:1296, 2010: Stage T1a,b N0 BCT 62% MDAH 5 Voduc et al, JCO 28: 1684, 2010 British Columbia and UNC; ^Lum Her2 6 Haffty et al, JCO 24:5652, 2006 Yale * Pre-Herceptin era

51 IJROBP 2009

52 + ASTRO “Suitable Group” FactorALL of the following must be present Age>=60 years Tumour size<=2cm MarginsNegative by at least 2mm GradeAny ER statusPositive MulticentricitySingle tumour MultifocalityClinically unifocal <2.0 cm HistologyInvasive Ductal or favourable subtype Extensive Intraductal Component (>25% DCIS)Absent Lymphovascular invasionAbsent Lymph nodesNode Negative 52

53 + ASTRO “Cautionary Group” FactorAny of these should invoke caution Age50-59 years Tumour size2.1 – 3cm MarginsClose < 2mm ER statusNegative MultifocalityClinically Unifocal, total size cm LVSILimited/focal HistologyInvasive Lobular Pure DCIS<3 cm Extensive Intraductal Component (>25% DCIS)<3 cm Lymphovascular invasionLimited or Focal

54 + ASTRO “Unsuitable Group” FactorAny of the following must be present Age<50 years Tumour size> 3 cm MarginsPositive ER statusNegative MulticentricityMore than 1 tumour HistologyInvasive Lobular Extensive Intraductal Component (>25% DCIS)Present Lymphovascular invasionExtensive Lymph nodesPositive

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 +

60 + Results:

61 + 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 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

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76 + The End


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