Partial Breast Irradiation for Breast Conserving Therapy

To Radiate or Not? Is APBI the Right Compromise Solution? Partial Breast Irradiation for Breast Conserving Therapy Julia White MD Professor, Radiation Oncology

Agenda Role of radiotherapy in breast conservation what are the goals of treatment? Accelerated partial breast irradiation ( APBI) rationale, outcome and indications Comparison of APBI to Omission of radiotherapy post lumpectomy Intraoperative Partial Breast Irradiation ( IPBI).

Breast Conservation with Lumpectomy and Radiotherapy (RT) Equivalent long term survival is evident from breast conservation compared to mastectomy from numerous Phase III randomized trials from the U.S. and Europe - now with > 20 years of follow-up. Equivalent local regional cancer recurrence now reported from breast conservation compared to mastectomy from analyses that reflect modern treatment era; e.g. complete excision, systemic therapy, etc. Breast conservation affords many benefits including faster recovery, lower health costs, intact sensation, among others. Increasingly, modern registry and cost analysis support the benefit of breast conservation for early stage invasive breast cancer

Agarwal, JAMA surg 2014 Improved Disease Specific Survival with Breast Conservation Therapy vs Mastectomy SEER 1998-2008: 132,149 patients, BCT 92,671 (70.1%), Mastectomy alone 34,999 (26.5%), and mastectomy with RT 4479 (3.4%).

Whole Breast Irradiation post-lumpectomy WBI method used in: Randomized control trials demonstrating equivalency of BCT to MRM Early Breast Cancer Trialists Collaborative Group s meta-analysis Registry Analyses 10-16 Gy 5-8 Fractions 50 Gy/25 Fractions 42.56 Gy/ 16 Fractions Total: 60-66 Gy 30-33 Fractions

Alternatives to WBI Post-Lumpectomy: Subject of Clinical Investigation for Decades! Randomized Trials Accrued Prior to 1990

Goals of Post-lumpectomy Radiotherapy Invasive breast cancer: Maximize local control Equivalence to mastectomy Prevent Distant Metastases Optimize breast cancer/ overall survival Maintain sensate and acceptable cosmetic breast appearance

ACCELERATED PARTIAL BREAST IRRADIATION (APBI)

Scientific Rationale for Radiation Targeted to the Tumor Bed Only Recurrences (LR) Away From Tumor Bed ( Elsewhere Failures-New Primary cancers): Much lower frequency after lumpectomy alone or followed by whole breast RT - LR Roughly 2-3% w/o RT and < 1% with RT * Major Effect Of Post-Lumpectomy RT: Reduce risk of recurrence in tumor bed region LR Roughly 10-25% w/o RT and 3-4% with RT * Potential Benefits: Less toxicity Reduced burden of care Better utilization of BCT * Milan 3, OCOG UOBCG

Accelerated Partial Breast Irradiation Definition: Delivery of hypo fractionated ( i.e.larger doses/fraction) radiation to the high risk breast only (lumpectomy cavity plus 1-2 cm margin) AFTER Lumpectomy using brachytherapy or external beam irradiation techniques Goals: to achieve local control post-lumpectomy that is equivalent to WBI Accelerated PBI 30-38 Gy/ 6-10 treatments 5-8 days

20 Years of Clinical Trials in APBI: Where Do We Stand? 1997-2000 RTOG 9517 Multi catheter APBI Phase II/ feasibility 2000-2001 MammoSite APBI Phase II/ feasibility 2002 MammoSite FDA Approval 2002-2004 ASBS Registry MammoSite APBI 2003-2004 RTOG 0319 3DCRT APBI Phase II/ feasibility 2004 NASBP B39/ RTOG 0413 Phase III opens 2006 OCOG 3DCRT RAPID Phase III opens 2009 ASTRO Consensus Guidelines 2011 OCOG 3DCRT RAPID Phase III closes 2013 NSABP B39/ RTOG 0413 Phase III closes 2013 OCOG RAPID Reports Cosmetic Interim Analysis 2015 Phase III University of Florence Trial reports Cancer Outcomes 2016 Phase III ESTRO Clinical Trial reports Cancer Outcomes

APBI Success Supported by Important Trends in Breast Cancer Clinical Investigation 1. Technology development Single Entry Devices for Brachytherapy Integration of advanced technology for external beam RT (3DCRT, IMRT, etc) 2. Re- evaluation of Breast Cancer Radiobiology Safety of larger dose/ treatment (fraction) for Breast RT Linear Quadratic Equation allows calculation of different schemes to deliver biologically effective dose 3. Breast Cancer Heterogeneity better understood Intrinsic Subtypes have different local regional recurrence after BCT

Multicatheter (MCT) APBI Single Entry Device (SED) APBI Brachytherapy 50% 80% 100% 120% 140% 200% Advantages Irregularly shaped cavities Skin and chestwall sparing Durable results demonstrated Disadvantages Invasive Procedure Technically complicated Restricted access Advantages Simplified approach Improved technology access Surgeon acceptance Disadvantages Invasive Procedure Potential Cavity Misfit Availability Limited

APBI Single Entry Brachytherapy: Next Generation are Multi-Channel Advantages: dosimetric coverage sparing of skin and chestwall SAVI Ciana medical Contura SenoRx

External Beam APBI 3DCRT IMRT Advantages Non Invasive Linear Accelerators Ubiquitous Disadvantages Variable Target Definition Inter- and Intrafraction error Linear accelerator delivery

APBI Success Supported by Important Trends in Breast Cancer Clinical Investigation 1. Technology development Single Entry Devices for Brachytherapy Integration of advanced technology for external beam RT (3DCRT, IMRT, etc) 2. Re- evaluation of Breast Cancer Radiobiology Safety of larger dose/ treatment (fraction) for Breast RT Linear Quadratic Equation allows calculation of different schemes to deliver biologically effective dose 3. Breast Cancer Heterogeneity better understood Intrinsic Subtypes have different local regional recurrence after BCT

Reduced Local Recurrence after Lumpectomy and WBI in Luminal Subtype by IHC 1434 BCT patients with 7 year median F/U Local Recurrence: Lum A 0.8% Lum B 2.3% Lum HER 7.4% HER 2 10.8% TNBC 6.7% Arvold, et al JCO 2011

Phase II Multi-institution Trials That Established APBI Efficacy Post-lumpectomy for BCT Clinical Trial n APBI Type Dose Target Definition Population (%) T1 N0 ER+ Median F/u % IBR RTOG 9517 99 MCT Brachy 34 Gy, 10F, BID C/PTV: 2cm radial 1cm Ant/post 88 81 74 12.2 yrs 6.2 MammoSite Industry 43 SED Brachy 34 Gy, 10F, BID C/PTV: 1 cm expansion 100 100-5.5 yrs 0 RTOG 0319 52 3DCRT Austrian 274 MCT Brachy 38.5 Gy, 10 F, BID 32Gy 8 F CTV: 1.5 cm PTV: 1.0 cm 94 92 83 8 yrs 7.7 C/PTV: Variable 92 100 100 5.3 yrs 2.9

Three Randomized Trials Comparing APBI to WBI Post Lumpectomy Have Reported Outcomes Trial Years APBI method Dose Eligibility T U. Florence 1 Age > 40 yrs 2005-2013 IMRT 30 Gy/ 5 F/ QOD Tsz < 2.5 cm NIO Budapst 2 1998-2004 GEC-ESTRO 3 2004-2009 MCT Brachy HDR MCT Brachy HDR 36.4 Gy/ 5.2 Gy x 7 high-dose-rate (HDR) 32 Gy/ 4 Gy x 8/ BID 30 Gy/ 4.3 Gy x 7/ BID pn0, G1-2 Tsize < 2.0 cm Age > 40 Tsz < 3 cm pn0, pn1mi 1 Livi et al. Eur J Ca 2015 2 Polgar et al. Rad & Onc, 2013 3 Strnad et al. Lancet Oncol 2016

No Difference in Local Recurrence in 3 Phase III Clinical Trials Comparing APBI Vs. WBI Local Recurrence Regional Recurrence n Median Follow up APBI Method APBI WBI APBI WBI U. Florence 1 520 5 years IMRT 1.5% 1.4% 1.4% 1.9% NIO Budapest 2 287 10.2 years MCT 5.5% 4.6% 2.5% 1.7% GEC-ESTRO 3 1184 6.6 years MCT 1.4% (1.9%) * 0.92% (1.67%) * 0.49% 0.56% 1 Livi et al. Eur J Ca 2015 2 Polgar et al. Rad & Onc, 2013 3 Strnad et al. Lancet Oncol 2016 *Local + 2 nd Primary

Three APBI Phase III Trials: Similar Low Risk Hormone Sensitive Breast Cancer Populations Age > 50 yr/ post Menop N0 Median T size Grade 1-2 %ER/PR + U. Florence 1 83 % 86.2 % - # 88.9 % 95.4 % NIO Budapest 2 76 % 94 % 1.3 cm 100 % 88.4 % GEC-ESTRO 3 80 % 95 %* 1.2 cm 90 % 95 % 1 Livi et al. Eur J Ca 2015 2 Polgar et al. Rad & Onc, 2013 3 Strnad et al. Lancet Oncol 2016 *Axillary staging was not performed in DCIS cases 4.5% (53/1185) # Median not given. ~ 95% < 2 cm

APBI Caution: Adverse Biology n F/ up mo. Method APBI Factor Local Rec % University WI 1 322 60 MCT Histopath 12.7 MGH 2 98 71 3DCRT TNBC 33 GER-Aust 3 274 64 MCT ER+ but no endocrine therapy 12 1 Cannon et al., Ann Surg Oncol 2013 2 Pashtan et al, IJROBP 2012 3 Ott et al, IJROBP 2011

Adverse Cosmetic Results for 3DCRT APBI OCOG RAPID Early Reporting Adverse Cosmetic Outcome ( Fair Poor) Nurse Assessment at Baseline and 3 years Baseline n=1995 3 years n=850 WBI ABPI- 3DCRT Difference APBI-WBI (95% CI) p value 17% 19% 2% (2-5%) 0.35 19% 32% 13% (7-19%) < 0.0001 Olivotto et al, JCO 2013

Improved Cosmetic Results for IMRT APBI University of Florence Harvard Scale (Excellent, good, fair, poor) Physician Assessment Physician-rated Cosmesis WBI % APBI % Overall p value Excellent 89.6 95.1 Good 9.6 4.9 Fair 0.8 0 Poor 0 0 0.045 Livi et al, European J Cancer 2015

Numerous Additional Phase III Trials Will Build on the Current Findings Clinical Trial Status Accrual APBI Method NSABP B-39/ RTOG 0413 Closed 2013 4214 3-DCRT SED MCT RAPID OCOG Closed 2012 2135 3-DCRT IMPORT Low MRC Closed 2011 1935 IMRT/3D IRMA Open to accrual 3302 3DCRT SHARE Open to accrual 2796 3DCRT 14,382

2009 ASTRO Consensus Statement for Treatment with APBI Outside a Clinical Trial Suitable Cautionary Unsuitable Patient Factors Age > 60 years 50-59 < 50 BRCA 1-2 no no Yes Path Features T-size <2cm 2.1-3.0 cm > 3.0 cm T stage T-1 T-0 T-2 T 3- T4 Margins Negative ( 2 mm) Close (< 2 mm) Positive LVSI No Limited, focal Extensive ER Pos. Neg. - Multicentric Unicentric Unicentric Present Multifocal Clinically unifocal Clinically unifocal Clinically multifocal Histo IDC ILC - DCIS, EIC No, No Yes, Yes (< 3 cm) > 3 cm Nodes N stage pn0 (i +, -) - pn1, N2-3 Nodal Surgery yes yes no Smith, IJROBP,4:2009

Suitable Group Update 2016 ASTRO Consensus Statement for APBI Selected Factors Suitable Patient Factors: Age > 60 years > 50 years Path Features: T-size <2cm T stage T-1 Margins Negative ( 2 mm) ER Positive Nodes: N stage pn0 (i +, - ) * With Permission Update of the ASTRO APBI Consensus Statement

HOW IS APBI DOES A COMPROMISE APBI COMPARE TO IN OMISSION THE QUESITON OF POST OF LUMPECTOMY RADIOTHERAPY? RADIATE OR NOT?

Rationale for Omission of RT Early Breast Cancer Trialists meta-analysis in 2011 of 17 randomized trials of RT vs No RT post lumpectomy Post lumpectomy RT results in 15% reductions in any recurrence and 3% gains in survival in node negative patients However, low risk node negative with low absolute reduction in recurrence did not derive a survival benefit This means it s feasible to identify low risks patient that omission of RT will not threaten survival but will have higher local recurrence that may be acceptable EBCTCG Lancet 2011; 378: 1707 16

RCT in Hormone Responsive pn0 Breast Cancer Evaluating RT Benefit in Addition to Anti Endocrine Therapy Post-lumpectomy Age T sz < ER/PR In-breast F/U > 50 y 2 cm + Tam/AI Grade recurrence (%) Clinical Trial n yrs (%) (%) (%) (%) 1-2 (%) RT No RT PMH 769 5.6 100 83 80.5 100 68.3 0.6 7.7 ABCSG 8a 869 4.48 99 90 100 100 95 0.4 5.1 CALGB 9343 626 12.6 100 3 98 97 100-1.9 10 PRIME 2 1326 5 100 89 90 100 97 1.3 4.1 Low risk features: Older age, pn0, small size, ER/PR+, G1-2, anti endocrine therapy

Elderly Women with Hormone Sensitive Stage 1 Breast Cancer CALGB 9343 N= 626 > 70 yo (median 77 yrs) 12 year follow up PRIME2 N=1326 > 65 yo ( median 70 yrs) 5 year follow up RT No RT RT No RT Local regional recurrence 1.9% (6) 10% (32) 1.3%(5) 4.1% (26) Death From Breast Cancer 4.1% (13) 2.5% (8) 0.6% (4) 1% (8) Death from all causes 52% (166) 52% (168) 6% (40) 7.3% (49) Mastectomy free rate 98% (-) 96% (-) 99.7% (2) 98% (12) Hughes et al, JCO, 2013 Kunkler et al, Lancet Oncol, 2015 PRIME2: Increase LRR with Estrogen poor tumors w/o RT ~ 9%

Conclusions APBI 1. APBI post lumpectomy results in LRR equivalent to WBI in Stage 1 hormone sensitive, HER 2 negative breast cancer 2. Updated ASTRO consensus guidelines for APBI are recommended 3. APBI role remains questionable pending further RCT results in other breast cancer subtypes and in more advanced stages 4. In contrast to APBI, omission of RT post lumpectomy yields higher local regional recurrences that are unlikely to be associated with excess breast cancer mortality and may be clinically acceptable to patients trials are pending. 5. Women must be included on decision making for personalizing their breast conservation therapy.

INTRAOPERATIVE RADIOTHERAPY (IORT) FOR PBI

Definitions Partial Breast Intraoperative Radiotherapy (IORT): the delivery of a single high dose (~18-21 Gy) of irradiation directly to the post excision tumor bed during surgery prior to wound closure

Intraoperative PBI ADVANTAGES Very localized dose Direct visualization of area to treat Reduce patient burden of care Reduce travel for external beam WBI Spare second procedure for brachytherapy APBI DISADVANTAGES Too localized dose Final pathology unknown Patient may receive unnecessary treatment Additional O.R time

Electron IORT Breast Cancer Mobile linear accelerators in O.R. 6-8 MeV electrons ( 4-15 MeV) 5-8 cm diameter cones for treatment ~ 1 3 cm depth of breast tissue ELIOT Developed European Institute of Oncology, Milan, Italy Added lead shield under mobilized breast to protect chestwall

The TARGIT Technique Courtesy J.Vaydia 2010 ~ 5-7 Gy at depth of 10 mm INTRABEAM A miniature electron generator and accelerator A point source of 50 kv energy x-rays applicator 20 Gy at Surface

Radiotherapy Target Volumes Differ for TARGIT and ELIOT IORT Targit: 5 mm Eliot: 20 mm

PBI with Intraoperative Electrons (IOERT): Representative Studies Montpellier (Lemanski) Verona (Maluta) # ELIOT (Leonardi) n F/up Mo. s Age Median yrs ER + % N-1 % Margins + % Local Rec (%) 42 72 72 100 - - 9.2 # 226 46 63 91 22.1 7 0.4 1822 60 58 89 27 2.9 4.1 # Retrospective analysis # median time to failure 62.4 months

ELIOT PBI: by ASTRO Consensus Guidelines for APBI 5 year rates Suitable Cautionary Unsuitable p n 294 698 812 Ipsilateral in-breast recurrence 1.5 % 4.4 % 8.8 % 0.003 Regional nodal failure 1.5 % 1.9 % 1.1 % 0.55 Distant metastases 1.5 % 1.7 % 3.9 % 0.047 Cause specific survival 99.1 % 98.7 % 96.5 % 0.025 Leonardi, IJROBP, 2011

ELIOT Phase III Randomized Trial Median follow-up 5.8 years 2000-2007: randomized 1305 women > 48 years T size < T1 85%, ER + 90%, N-1 21% ~5.5% N-2 receive XRT to breast and nodes 5-year event rates WBI 50 Gy/25 + boost ELLIOT 21 Gy/1 Ipsilateral in- breast recurrence 0.7 % 5.3 % <0.0001 In Quadrant 0.7 % 3.2 % < 0.002 Outside quadrant 0 2.1 % < 0.001 Regional nodal 0.4 % 1.1 < 0.02 p Veronesi et al, Lancet Oncol 14: 2013

TARGIT-A Phase III Randomized Trial Median follow up: 29 months 2000-2012: randomized 3451 women > 45 years T size < T1 81.4%, ER + 90%, N-1 17% ~15% randomized to TARGIT received WBI XRT to breast and nodes Vaiyda, Lancet 383, 2014 5-year event rates WBI TARGIT p In- breast recurrence: ALL 1.3 % 3.3 % <0.042 Immed. IORT ( n=2298) 1.1% 2.1% 0.31 Delayed IORT (n=1153) 1.7% 5.4% 0.069 Breast Cancer Mortality 1.9% 2.6% 0.51 All Cause Mortality 5.5% 3.9% 0.099

Summary IORT PBI Expanding evidence regarding IORT PBI Will benefit from additional follow up and analysis to find a population of breast cancer patients best suited for this approach Recommend if used to focus on ASTRO suitable group: > 50, ER +, Node Negative, < 2 cm tumors. Likely will benefit patients most who have some local control risk but whose risk for distant metastases is inherently low and the intent is its use will maximize breast conservation success.

Comparison of Alternatives to WBI for Hormone Sensitive Stage I Breast Cancer Equivalent local control to WBI in Phase III RCT APBI IORT PBI Observation yes no no Indication ASTRO Suitable *ASTRO Suitable Method - Brachytherapy, - External bean ( 3DCRT, IMRT) - Electrons - TARGIT (limited F/U) - Elderly - ER rich --

QUESTIONS?