Objectives Intraoperative Radiation Therapy for Early Stage Breast Cancer

Objectives Intraoperative Radiation Therapy for Early Stage Breast Cancer Cristina Lopez-Peñalver, MD, FACS October 11, 2014 Disclosures I have no relevant commercial relationships to disclose. Discuss the rationale for using IORT Identify patient selection criteria Discuss the technique of IORT Determine the benefit of implementing an IORT technique Surgical Management of Surgical Management of Breast Cancer 1895 to mid 1970s 1977-present Earlier Diagnosis Smaller size More options for BCT Breast conserving surgery Partial breast irradiation Lumpectomy + SNB + EBRT + systemic therapy 1

Trial NSABP B-06 Randomized trials for BCT Accrual Years 1976-1984 Randomized Trials Comparing Mastectomy and BCT # of pts Max Tumor size (cm) Min lumpectomy margin Median f/u years OS (%) LR/IBTR (%) Mastectomy BCT BCT Mastectomy 1851 4 No tumor on ink 20 47 Lump, 46 Lump/XRT, 47 Milan 1973-701 2 20 58.8 58.3 8.8 2.3 1980 NCI 1979-1987 237 5 Grossly neg 18.4 58 54 22 0 Institut Gustav Rossy EORTC 1980-868 5 Grossly neg 13.4 66 65 20 12 1986 1970-1982 179 2 10 79 78 4 NR Danish 1983-905 5 Grossly neg 6 82 79 NR NR 1989 39.3 14.3 10.2 Radiation Therapy Delivery Externally High energy X-rays are generated outside the patient No radioactive sources Treats the whole breast Internally Brachytherapy Radioactive isotopes or electronic source Targeted 21% of women don t complete XRT after BCS 1 1 Tuttle et al Cancer. 2012;118:2004-2013 Rationale for PBI: Pattern of Local Recurrence Hypofractionation: dose-dense reduces the length of treatment Partial Breast Irradiation reduces the amount of breast tissue irradiated Whole organ analysis of mastectomy specimens 63% harbor occult cancer 80% of these are in other quadrants Vaidya, 1996 Holland, 1985 Occult cancers Recurrences 4 cm 41% 2 cm 20% 39% 90% of recurrences occur in the index quadrant Vaidya Br J Cancer 1996;74:820-824 2

APBI Techniques External Beam 3D Conformal Brachytherapy Interstitial LR comparable to WBXRT Intracavitary LR (< 5%) comparable to WBXRT Intraoperative Radiation Therapy Boost Primary treatment IORT A Single Dose of Radiation Therapy Given Intraoperatively During BCS as Sole Treatment Photons Xoft Axxent Intrabeam Electrons Mobetron Liac Novac Goals of Partial Breast Irradiation Accelerate the delivery of radiotherapy total dose, treatment time Target the radiotherapy to the tumor site APBI widely adopted Increased by 1600% from 2000-2007 0.4% in 2000 to 6.8% in 2007 (p<.001) No long term randomized trial data NSABP B-39 Abbott, Cancer 2011;117:3305-10 Objectives Discuss the rationale for using IORT Identify patient selection criteria Discuss the technique of IORT Determine the benefit of implementing an IORT technique 3

Effect of radiotherapy after breast-conserving surgery (10 trials of BCS ± RT) on local recurrence and breast cancer mortality 6097 women with node-neg disease 1214 women with node-pos disease Identification of the APBI Candidate Selection Criteria 4:1 ratio ASTRO Guidelines for APBI ASBS Guidelines for APBI By preventing LR, RT improves survival Identify a subset at low risk of clinically occult disease EBCTG Lancet 2005;366:2087-2106 ASTRO Task Force CS Guidelines for use of APBI outside of a clinical trial ASBS Selection Criteria for APBI Suitable (All) Cautionary (Any) Unsuitable (Any) Patient factors Age, years > 60 50-59 < 50 BRCA1/2 mutation Absent Absent Present Pathologic factors Tumor size, cm < 2 2.1-3.0 >3 pt pt1 pt0 or pt2 pt3-pt4 Margins Negative Close Positive Grade Any Any Any LVI No Limited/focal Extensive ER status Positive Negative Any Multicentricity Unicentric Unicentric Present Multifocality < 2cm < 3cm > 3cm Histology Ductal Lobular Any Pure DCIS Not allowed < 3 cm > 3cm EIC Not allowed < 3cm > 3cm Nodal factors Nodal stage pn0 pn0 pn1, pn2, pn3 Nodal surgery SNB or AND SNB or AND Not performed Treatment factors Neoadjuvant therapy Not allowed Not allowed Yes Women > 45 years of age with invasive carcinoma Women > 50 years of age with DCIS Invasive carcinoma or DCIS Total tumor size < 3cm Negative surgical margins Negative sentinel node no data on histology, multicentricity/multifocality, BRCA mutation or LVI 4

ASTRO Criteria Applied to a Pooled Analysis Pooled analysis of WBH & ASBS MammoSiteRegistry Trial, n=2127 WBH, n=678 ASBS, n=1449 Interstitial, n=221 Balloon based, n=255 3D conformal, n= 206 36.5% Suitable (n=661) 46.9% Cautionary (n=850) 16.7% Unsuitable (n=302) Int J Radiat Oncol Biol Phys 2013;85(5):1179-85 ASTRO Criteria Applied to a Pooled Analysis Results median age: 65 years (32-94 years) median tumor size: 10mm (0-45 mm) median f/u time: 60.6 months 5 year actuarial rates of IBTR: 2.8% RNF: 0.6% DM: 1.6% Int J Radiat Oncol Biol Phys 2013;85(5):1179-85 ASTRO Criteria Applied to a Pooled Analysis Results 5 year actuarial rates of IBTR Suitable 2.5% Cautionary 3.3% Unsuitable 4.6% p=0.20 increase in IBTR for cautionary & unsuitable elsewhere failures/new primaries (p=.04) tumor bed recurrence (p=0.93) Int J Radiat Oncol Biol Phys 2013;85(5):1179-85 ASTRO criteria applied to the ASBS Mammosite Registry Trial 1449 patients 1025 (71%) could be classified according to ASTRO categories 419 (41%) Suitable 430 (42%) Cautionary 176 (17%) Unsuitable At median f/u of 53.5 months, the 5 yr actuarial rates of IBTR 2.59% Suitable 5.43% Cautionary p=0.1884 5.28% Unsuitable Negative ER status associated with IBTR (p=.00003) Cancer 2010;116:4677-8 5

Conclusion Excellent outcomes were observed after BCS and APBI ASTRO CS guidelines did not differentiate a subset of patients at an increased risk of IBTR when treated with APBI Clinical Evidence for IORT PBI : 50-kV (IORT) ELIOT Trial: 3-12 MeV (IOERT) Int J Radiat Oncol Biol Phys 2013;85(5):1179-85 Targeted Intraoperative RadioTherapy Alone 3/2000-6/2012 at 33 centers in 11 countries 3,451 women randomized to IORT(n=1721) 20 Gy to surface using 50 KV WBEBRT (n=1730) 40-56 Gy in 15-25 fractions +/- 10-16 Gy boost in 5-8 fractions Eligibility criteria women aged 45 yrs unifocal IDC amenable to BCS (no MRI) clinical T1 or T2(<3.5 cm), N0-N1, M0 2004 amendment prepathology: before lumpectomy postpathology: after lumpectomy (30 days) EBRT was added to TARGIT for high risk factors: Risk Adapted IORT unexpected ILC extensive in situ component margins < 1mm several + nodes extensive LVI Vaidya, Lancet 2014;383:603-13 Vaidya, Lancet 2014;383:603-13 6

Breast Cancer being treated with BCS Randomization TARGIT Technique TARGIT group n=1721 EBRT group n=1730 Single dose of TARGIT (in ~ 85%) + if high risk add EBRT (45-50 Gy) no boost (in ~15%) External Beam Radiotherapy (EBRT) 40-56 Gy in 15-25 fractions +/- Boost 10-16 Gy in 5-8 fractions Non-Inferiority trial: 2.5% difference in LR at 5 years 0.625% difference in mortality at 15 years 1.5-5 cm 20 Gy at the surface that tapers to 5-7 Gy at 1 cm 20-45 minutes TARGIT-A ELIOT: RCT Trial non-inferiority trial: prespecified non-inferiority margin of LR of 2.5% absolute difference in LR at 5 years primary outcome: absolute diff in LR in conserved breast secondary outcomes: OS & toxicity exploratory outcome: any other recurrence median follow-up: 3451 patients: 2 years & 5 months 2020 patients: 4 years 1222 patients: 5 years IORT with TARGIT: 1721 patients EBRT: 1730 patients 2/3 (2298 patients) prepathology 1/3 (1153 patients) postpathology 15% received TARGIT and EBRT 21.6% in prepathology group 3.6% in postpathology group Vaidya, Lancet 2014;383:603-13 7

Patient Characteristics With a median f/u of 29 months Results Mostly good prognosis patients 87% tumors 2 cm 85% were Grade 1 or 2 84% were node negative 93% were ER + 82% were PR+ 69% were detected by screening > 1,200 patients were < 60 yrs 15% tumors > 2 cm 15% were grade 3 16% were node + 66% Hormonal therapy 12% Chemotherapy Vaidya, Lancet 2014;383:603-13 Vaidya, Lancet 2014;383:603-13 Results Silverstein, Ann Surg Oncol 2014 8

Prepathology vs Postpathology Differences Effect of Wound Fluid Wound fluid collected in the first 24 hours after lumpectomy and added to breast cancer cell lines stimulated: Delay in wound fluid suppression of tumor cells Geometric miss when inserting the applicator post surgery Less irradiated tissue volume in postpathology group Change in tumor microenvironment Wound fluid from patients with TARGIT did not stimulate breast cancer cells TARGIT abrogated stimulatory effect of wound fluid on cancer cell motility and invasion Clin Cancer Res 2008;14(5):1325-1332 Overall Survival Results Non-Breast Cancer Deaths 0 10 20 30 40 (n=36) (n=52) Other Cancers 8 16 TARGIT 2.6% EBRT 1.9% TARGIT 1.4% EBRT 3.5% Cardiovascular 2 11 TARGIT EBRT Other causes 7 8 Total 17 35 5 year risk = 1.4% vs 3.5% HR 0.47 (0.26 0.84) Log rank p = 0.009 Vaidya SABCS 2012 9

Non-Breast Cancer Deaths Criticisms stroke & ischemic bowel included median follow up < 5 years no info on cardiac risk factors no information on other cancers latency period for induced cancers is 15-20 years diff in mortality with cardiac deaths and breast cancer deaths is only 2 patients Vaidya, Lancet 2014;383:603-13 Complications Complications 6 months after randomization fibrosis, telangectasias, edema, retraction, ulceration, lymphedema of the arm, hyperpigmentation, and pain Vaidya, Lancet 2014;383:603-13, appendix Late Radiation Toxicity after IORT with TARGIT impact on quality of life University Medical Center Mannheim 2/2002-12/2008, 305 patients were treated within TARGIT-A 109 within Arm A: n=34 IORT, n=20 IORT +EBRT Arm B: EBRT: n=55 196 TARGIT as planned boost followed by EBRT median follow up of 40 months (Arm A) and 42 months (Arm B) Sperk, Breast Cancer Res Treat 2012;135:253-260 Late Radiation Toxicity after IORT with TARGIT toxicity assessed according to the LENT SOMA scales no significant differences between Arm A & Arm B fibrosis breast edema retraction ulceration lymphedema hyperpigmentation pain Arm A had significantly less telangectasias (p=0.049) at 3 years Sperk, Breast Cancer Res Treat 2012;135:253-260 10

Late Radiation Toxicity after IORT with TARGIT Subanalyisis Arm A: IORT Arm A: IORT +EBRT Arm B: EBRT Higher grade toxicity as first event: HR 0.46 for Arm A IORT vs Arm B (p=0.010) IORT boost control group fibrosis 5.9% 37.5% 18.4% 38.2% telangectasias 0% 17.5% 17.7% Exploratory Analyses No difference in 5 year risk of : regional recurrence: 1.1% TARGIT vs 0.9% EBRT distant recurrence: 3.9% TARGIT vs 3.2% EBRT any other recurrence: 4.9% TARGIT vs 4.4% EBRT all recurrence: 8.2% TARGIT vs 5.7% EBRT diff mainly driven by LR prepathology: 6.9% TARGIT vs 5.8% EBRT postpathology: 10.4% TARGIT vs 5.4% EBRT locoregional recurrence: 4.2% TARGIT vs 2.0% EBRT prepathology: 3.1% TARGIT vs 2.0% EBRT postpathology: 6.2% TARGIT vs 2.0% EBRT Vaidya, Lancet 2014;383:603-13 Conclusions Conclusions 5 yr risk of LR was non-inferior to EBRT for all patients only prepathology group was non-inferior breast cancer mortality was the same for both arms although diff not significant, higher LR rates with short f/u suggests that longer f/u is needed significantly fewer non-breast cancer deaths attributable to fewer deaths from cardiovascular causes and other cancers wound related complications were the same for both arms fewer grade 3 or 4 RT related complications with TARGIT prepathology women meeting the TARGIT-A eligibility criteria appear to be the best candidates 15% of women will require EBRT as well 11

ELIOT: Milan Experience ELIOT Technique Electronic IntraOperative RadioTherapy 2,792 patients received IOERT (1/2000-12/2008) 651 patients: RCT 319 patients: not included, previous cancer 1,822 patients treated off protocol 22 patients treated with 16-19 Gy as part of initial dose finding study 1,800 patients:21 Gy prescribed @90% isodose Quadrantectomy Mobilization Veronesi, Breast Cancer Res Treat 2010;124:141-151 Veronesi, Breast Journal 2003;9(2):106-112 ELIOT Technique ELIOT Technique Chest wall protection Reconstruction Placement of collimator tube 5 mm thick 4, 5, 6, 8, or 10 cm tumor size & location Skin protection 12

ELIOT Technique ELIOT ELIOT: Randomized RCT Trial November 2000 December 2007 Ages 48-75 T< 2.5 cm ILC allowed after MRI 1305 patients Randomized portable linear accelerator Liac, Novac 7, Mobetron 3, 5, 7, & 9 MeV 2 minute treatment time 654 patients External radiotherapy 50 Gy + 10 Gy boost 651 patients IORT 21 Gy ELIOT: RCT ELIOT: RCT Results EBRT (n=654) ELIOT (n=651) p value equivalence trial: prespecified equivalence margin was a LR of 7.5% in the IORT group primary endpoint: IBTR secondary endpoint: Overall Survival (OS) median follow-up: 5.8 years # 5 yr rate # 5 yr rate IBTR 4 0.4% 35 4.4% <.0001 Local (true) 4 0.4% 21 2.5% 0.0003 Elsewhere 0 0 14 1.9% 0.0001 Axillary/Regional 2 0.3% 9 1.0% 0.03 Contralateral BC 13 1.7% 8 1.1% 0.34 Distant metastases 35 4.8% 33 5.1% 0.94 Other primary ca 22 3.2% 20 2.5% 0.88 Deaths (total) 31 3.1% 34 3.2% 0.59 Breast cancer 20 2.0% 23 2.1% 0.56 Other 11 1.1% 11 1.1% 0.94 Veronesi, Lancet Oncol 2013; 14:1269-77 13

ELIOT: RCT Results 5 year event rate Primary endpoint: IBTR (p<0.0001) HR 9.3 IORT: 4.4% (95% CI 2.7-6.1) EBRT: 0.4% (95% CI 0.0-1.0) Secondary endpoint: OS (p=0.59) IORT: 96.8% (95% CI 95.3-98.3) EBRT: 96.9% (95% CI 95.5-98.3) ELIOT: RCT Overall Survival 10 yr survival: ELIOT 89% vs EBRT 92% Veronesi, Lancet Oncol 2013; 14:1269-77 Veronesi, Lancet Oncol 2013; 14:1269-77 Factors Associated with IBTR 5 yribtr rates > 10% large (>2 cm) tumors (10 of 83, 10.9%) 4 or more + lymph nodes (4 of 31, 15%) Grade 3 tumors (15 of 129, 11.9%) ER negative tumors (8 of 63, 14.9%) triple negative tumors (7 of 43, 18.9%) Ki-67 > 20% trended to a high IBTR (22 of 244, 9.1%) but did not reach 10% threshold. Factors Associated with IBTR tumors > 2 cm (HR 2.24) Multivariate Analysis 4 or more + lymph nodes (HR 2.61) poorly differentiated tumors (HR 2.18) triple negative subtype (HR 2.40) Doubled the risk! Veronesi, Lancet Oncol 2013; 14:1269-77 14

IBTR 11.3% 199 women (30.6%) who had at least one unfavorable characteristics IBTR 1.5% ELIOT Low Risk 452 women (69.4%) without any factors IORT: 4.4% IBTR ELIOT Low Risk: 1.5% IBTR EBRT: 0.4% IBTR 5 year rate of IBTR p<0.0001 less skin damage(p=.0002) erythema hyperpigmentation dryness itching no difference fibrosis retraction more fat necrosis 5% vs 2% less pulmonary toxicity (p<.0001) 9.5% vs 90.5% ELIOT: RCT IORT Complications IOERT: n=464 vs EBRT: n=412 (p=.04) pain burning Radiographic changes post BCS & IORT A.12 months after IORT B.2 years after IORT C.4 years after IORT Fat necrosis manifesting as a spiculated mass, 1yr after IORT A Radiolucent lesion surrounded by a smooth rim B Coarse calcifications in the periphery of the mass 2 yrs out Mammographic Findings after IORT 59 C 15

ELIOT Conclusions Current guidelines for ELIOT Higher rate of IBTR after 5 years of f/u (4.4% vs 0.4%) both true LR & new ipsilateral breast cancers Improved selection of patients rate of IBTR ELIOT Low Risk (1.5% vs 11.3%) T < 2 cm, grade 1/2, ER+, Ki-67 <20%, luminal A biology OS did not differ between the two groups fewer side effects involving the skin Age 60 years tumor size < 2 cm applicator size 6 cm minimum, 5 cm occasionally grade 1/2 ER + ki-67 <20% luminal A biology lobular carcinomas with MRI assessment Summary of IORT Trial Results Both included unfavorable patients, but have contributed to our knowledge ELIOT:median follow up of 5.8 years recurrence rates (p=0.0001) ELIOT: 4.4% low risk ELIOT group: 1.5% EBRT: 0.4% TARGIT-A: median follow up of 29 months recurrence rates (p=0.042) TARGIT-A: 3.3% prepathology patients: 2.1% EBRT: 1.3% A Safety & Efficacy Study of IORT Using the Xoft Axxent ebx System at the Time of BCS for Early Stage Breast Cancer 16

A Safety & Efficacy Study of IORT Using the Xoft Axxent ebx System at the Time of BCS for Early Stage Breast Cancer Accrual goal: 1000 patients Participating centers: 22 (21 US, 1 Portugal) Number enrolled: 446 patients as of 9/15/2014 Hypothesis: IORT using the Xoft Axxent ebx System is noninferior to whole breast irradiation (WBI) when used as a stand-alone radiation treatment immediately following breast conserving surgery in women with early stage breast cancer. Outcome Measures Primary Outcome IBTR at 5 years Assessed at 6 months, 12 months, 18 months, year 2, and then annually through year 10 A non-inferiority comparison to WBI will be made at 5 years Secondary Outcome Regional Recurrence Safety (AE: device related, procedure related, radiation related) Disease Free Survival Overall Survival Cosmetic Outcome Quality of Life IBTR at 10 years Informed consent Eligibility Criteria: Eligibility Criteria: Inclusion Criteria Biopsy proven invasive ductal carcinoma or DCIS Female 40 years of age Tumors < 3 cm by preop assessment Clinical Staging: Tis, T1 or T2 (< 3cm), N0, M0 Bilateral cancers ok if both meet inclusion criteria Women of childbearing age need neg preg test within 1 week Women of childbearing age must use adequate contraception from time of neg preg test to IORT Pregnant or nursing patient Significant auto-immune disease Pacemaker in field of IORT Multifocal cancer > 3 cm Multicentric cancer Known LVI Invasive lobular carcinoma Neoadjuvant systemic therapy Recurrent breast cancer in the ipsilateral breast Prior radiation exposure of the involved breast BRCA 1 or 2 mutation (testing required for bilateral cancers) Contraindication to XRT Eligibility Criteria: Eligibility Criteria: Exclusion Criteria Patient considered high risk for BCS &/or IORT Patient part of another study that likely to confound study results or affect outcome at time of IORT or for 3 months prior to IORT 17

Eligibility Criteria: Intra-operative Criteria Tumor Removal and Cavity Evaluation Inclusion: Balloon surface-to-skin distance > 1cm by US Satisfactory balloon conformance Exclusion: + sentinel node + surgical margin Insertion of Balloon Applicator, Wound Closure & US Verification Delivery of the Radiation 5-20 minutes treatment time 18

IORT Single Fraction Treatment Planning Pre-op Right Breast 6-month follow-up 33 Treatment Plans at 5 cc increments provide 20 Gy to the balloon applicator surface 12-month follow-up 18-month follow-up Pre-op 6-month follow-up Left Breast Pre-Op Left 18-month Follow-up 12-month follow-up 18-month follow-up Right Breast Pre-op Right 18-month Follow-up 19

Preop 6-month follow-up 12-month follow-up Pre-Op Left breast 6-Month Follow-up Pre-Op Right Breast 6-Month Follow-up Pre-Op Left Breast 6-Month Follow-up 20

Eligibility Criteria: IORT: Summary Rationale for IORT: Target the site at highest risk of recurrence Selection criteria: Cautiously (early stage, low risk of IBTR) ASTRO guidelines TARGIT/ELIOT eligibility criteria Concurrent IORT Add EBRT if adverse prognostic factors are present RT Dose Optimized Dose is precisely delivered to the area at greatest risk of tumor recurrence: avoids geographical miss Dose is delivered at the time of surgery and avoids delay when chemotherapy is used: temporal miss Minimizes radiation exposure to healthy tissues Shorter treatment time: increases compliance More convenient for working women and the elderly Less side effects Less cost Eligibility Criteria: IORT Summary: Advantages to IORT? Reduced mortality from less CV events Breast Cancer: Evolution of Radiation Therapy 1950 - Present 1992 - Present 2000 - Future 6-7 weeks of treatment 5 days twice a day As little as 8 min. during surgery WBRT APBI IORT RT has also progressed towards more tissue-sparing and shorter treatment times 21

Nowadays Future Direction of IORT? Is radiotherapy necessary in low risk patients treated with BCS? Is de-escalation of radiotherapy possible in selected patients? APBI is such a treatment option (LR, toxicity, feasibility) IORT is increasingly becoming an option TARGIT-A & ELIOT results patient selection with equal OS, identify patients at > risk of LR who would be more suitable for EBRT or IORT plus EBRT longer follow up needed as time to LR after XRT + adjuvant treatment can be delayed IORT part of discussion to decide on personalized treatment regimen clinical trials not ready for prime time! Shared Decision Making Thank you! Patient Preference Clinical Trial Data Treatment Decision Quality of Life Risk of Recurrence Local Resources Additional risk of LR? 22