Current Status of Accelerated Partial Breast Irradiation Julia White MD Professor, Radiation Oncology
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Agenda ABPI Timeline APBI by Method Clinical Trials Consensus Guideline Summary
Accelerated Partial Breast Irradiation (APBI): Definition Delivery of larger doses/fraction of radiation therapy (RT) to the lumpectomy cavity (plus 1-2 cm margin) after breast conserving surgery using brachytherapy or external beam irradiation techniques Complete RT in < 5-8 days after lumpectomy instead of 6-7 weeks
17 years of APBI: What have we learned? 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
RTOG 95-17 phase I/II Multi-catheter APBI - 100 patients accrued between 1997-2000 10 institutions: HDR 66, LDR 33 34 Gy in 10 fractions, BID 5-8 days Breast Median Tsz. 1.3 cm, N-1 19%, ER/PR+ 77% Overall satisfaction with treatment at 5 yrs: 75% 94.6% would choose multicatheter APBI again Target volume: 1.5 cm breast tissue around the cavity Lumpectomy Advantages: Irregularly shaped cavities, skin and chestwall sparing
RTOG 95-17: A phase I/II trial to evaluate multi-catheter interstitial PBI Median follow-up: 12.1 yrs 5 year 10 year # at # at Event # (%) risk (%) risk ISOLATED in-breast recurrence 4 3.1 84 4.2 68 In field 3 2.1 85 3.1 69 Out of field 1 1.0 85 1.0 69 In-breast & Regional recurrence 2 1.0 84 2.1 68 ALL In-breast recurrences 6 4.1 86 6.2 69 ISOLATED Regional recurrence 3 3.1 84 3.1 68 ALL Regional recurrences 5 4.1 87 5.2 71 Contralateral Breast Cancer 5 3.1 88 4.2 70
MultiCatheter PBI (HDR/ LDR): Summary Institution Pt. No. Median age F/U mo. T size (cm) median N+ % ER + % Tam % LR % Exc/ good Cosmesis Oschner 163 63 65-15 65-3 - Median age Beaumont 199 65 65 1.1 12-57 1.2 99 Tufts-NEMC 32 63 84 1.3 9 79 61 9 93 *VCU 44 62 42 1.2 18-66 0 80 60.7 T size (cm) median 1.35 N+ 13% ER + 84% Nat. In. Onc. Budapest 45 56 81 1.2 2 82 16 6.7 97 Guys Cs 137 49 58 75 2.5 46 - - 18 81 * U. WI -low -high 183 90 63 47 48 49 1.1 1.4 0 18 100 83 57 50 2.2 4.4 95 *MCW 74 68 40 1.2 1.5 88 76 1.3 82 Ger-Austrian Multicenter 274 60.5 63 1.2 0 100 91.2 2.9 90 RTOG-9517 99 62 144 1.3 19 75-4 - LR 4.8% Exc/ good % Cosmesis 89%
APBI: Single Entry Brachytherapy Devices 1 st Generation: Mammosite balloon Target volume: 1 cm breast tissue around the balloon Dose : 34 Gy, 10 fractions 3.4 Gy BID, over 5-8 days Minimal balloon surface-skin distance - ideally 7 mm, - if 5-7 mm then confirm skin dose <145% DOSE 50% 80% 100% 120% 140% 200% Advantages: Simplified approach, improved technology access
Initial MammoSite Multi-institutional Phase II Study-Manufacturer Overview: 43 patients enrolled 5/2000-10/2001 34 Gy, 10 fractions BID @ 1 cm, 5-8 days Results: Median follow-up 65.2 months (n=36) - Median Age 69 years - All T1 N0, 79% > 10 mm in size Grade 1-2: 77%, G3 14% - No local recurrences - Telangiectasias 39.5%, Retraction 20.9% - 80% good/ excellent cosmesis - Cosmesis worse- skin spacing < 7 mm Keisch et al, IJROBP 2: 2003, Benitez, et al. Amer. J. Surg, 2007
ASBS APBI Registry 2002 2004: 1440 patients, 97 facilities 95% 34Gy/10 fractions BID, 89% > 7mm skin spacing > 20 Publications Median F/U: 58 months Invasive: (n=1249) median age: 66 median T-size: 10 mm 97% N-0 ER/PR: 87% In-breast failure: 3.9% DCIS: (n=194) median age: 62.1 median TIS size: 8 mm In-breast failure: 3.4% Vicini, IJROBP 79: 2011, Shah, IJROBP 2012
APBI Single Entry Brachytherapy: Next Generation Advantages: dosimetric coverage sparing of skin and chestwall SAVI Ciana medical Contura SenoRx
Trends in the use of implantable APBI in the U.S. FDA approval of MammoSite 0.4% in 2000 versus 6.8% in 2007 p < 0.001 SEER Database Abbott, et al, Cancer 2011
Select Single Entry Brachy APBI: Summary Institution Initial Manufacturer Median Multi- Institution age Pt. No. Median age (yr) F/U mo. T size (cm) median N+ % ER + % Local relapse % Exc/ good Cosmesis 43 69 65 1.0 0-0 81 *Rush Univ. 112 64-88% Tis/T1 7-0 80 *Tufts/ VCU 28 62 19 1.1 0 100 0 86 64 St. Vincent Hospital *Kaiser- Permanente T size (cm) median 1.1 N+ 5% ER + 88% LR 1% Exc/ good Cosmesis 87% 32 62 11 97% T-1 9 94-86 51 64 16 1.2 16 86 0 95 *MUSC 111 61 46-8 - 5 - % *Pooled multiinstitution 483-24 - - - 1.2 91 *ASBS Registry 1440 65.9 54 1.0 3 51 3.8 93
RTOG 0319 Phase I/II 3DCRT APBI 58 patients accrued 2003-2004 Feasibility of external beam method for APBI 38 Gy in 10 Fraction, BID 5-8 days Overall satisfaction at 3 years 86% 100% would choose 3DCRT APBI again sagittal Advantage: Linear accelerator delivery coronal
RTOG 0319 Results at 8 year median follow-up n 5-year estimate 7-year estimate Ipsilateral Breast Failure* 4 5.8% 7.7% Contralateral Breast Failure Ipsilateral Nodal Failure** 0 0% 0% 3 5.8% 5.8% Distant Failure 4 7.7% 7.7% * All IBFs were in T1N0, postmenopausal patients **All INFs were in T1N0, ER+, postmenopausal patients Rabinovitch, ASTRO 2013
3-DCRT APBI: Summary Institution Pt. No. Median age F/U mo. T size (cm) median N+ % ER + % Local relapse % % Exc./ Good Cosmesis Beaumont 96 62 36-1 - 1 90 Median age NYU 100 67.5 60 0.9 0 100 1 94 MGH 98 60 71 0.9 0 89 5 97 British Columbia 64 T size (cm) median 1.0 N+ 1.8% ER + 90% 127 62.6 37-0 82 1 82 Esperanza 105 67 60 1.4 0 96 0 100 LR 2.2% Exc/ good Cosmesis 90% RTOG 0319 58 61 40 1.0 8-6 -
NSABP B-39/RTOG 0413 Trial Phase III Stage 0, I-II breast cancer treated by lumpectomy Randomization WBI 50-50.4 Gy (1.8-2.0 Gy) Fractions to the whole breast followed by boost to 60-66.6 Gy APBI 34 Gy in 3.4 Gy fxs bid Mammosite, Contura, SAVI or Multicatheter brachytherapy OR 38.5 Gy in 3.85 Gy fxs bid 3D-CRT Targeted accrual = 4300
NSABP B39 / RTOG 0413 March 21, 2005 Opened for accrual - 3000 targeted accrual January 1, 2007 Accrual closed to low-risk population and targeted accrual increased April 11, 2013 Closed for accrual 4,216 accrued (Among patients with follow-up, mean follow-up time is 60.5 months.) APBI - # of patients randomized: 2107 Methods: 70.5 % (n=1474) 3-DCRT, 24.3% (n=512) MammoSite/other 5.2 % (n=109) MultiCatheter
NSABP B39 / RTOG 0413: Population Variable: % Age < 50 y 50-69 > 70 Race/ Ethnicity White Black Hispanic Disease Stage DCIS Invasive N-0 Invasive N-1 Hormonal Status ER or PR + ER and Pr- 38.4 47.7 13.9 89.8 7.1 4.1 24.3 65.4 10.1 81.3 18.7
Phase III Trials Comparing APBI to WBI Closed! Accrual PBI Method Eligibility NSABP B-39/ RTOG 0413 2013 4214 3-DCRT MST MCT > 18 yo, Stage 0-II, < 3cm, N-0 N-1 (< 3 LN+) GEC-ESTRO 2009 1300 MCT > 40 yo, Stage 0-II, < 3 cm, N-0 N mi, Negative margins (2 mm) RAPID OCOG 2012 2135 3-DCRT > 40 yo, Stage 0-II, < 3 cm, N-0, excludes inf. lobular (7649)
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 < 2 cm 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
5 year Mastectomy Rate Brachytherapy APBI versus WBI SEER-Medicare 92,735 cases Age > 67 2003-2008 3.95% 2.19% Smith, et al. JAMA, 307:2012
5 year Mastectomy Rate by ASTRO Consensus Guideline SEER-Medicare n Lump APBI EBRT p ALL 35,9457 4.2 3.0 1.4 < 0.001/0.001 Suitable 9,966 3.7 1.6 0.8 < 0.001/0.002 Cautionary 5,509 6.7 5.4 2.2 < 0.001/0.006 Unsuitable 10,119 5.0 3.6 1.6 < 0.001/0.02 Smith G, et al., IJROBP, 2:2014
No Difference in Mastectomy Rate in Older Suitable SEER-Medicare Age > 70 n = 7,450
Distribution by ASTRO Consensus Statement Grouping SEER: 4,172 Breast Cancer Cases treated with Brachytherapy Husain, Brachytherapy, 2011
Outcomes after APBI Cautionary University of Wisconsin 2001-2006 Median f/u: 60 mo.s 322 MCT APBI 79 Suitable 136 Cautionary 107 Unsuitable Reason Cautionary 63% age 50-59 23.5% DCIS 12.5 % EIC 9.6% 2 cm- 3cm T-size 8.1% ER neg. 7.4% ILC 7.4 % < 2 mm margin 27.9% multiple factors McHaffie, et al, IJROBP 2011
Stage I-II: IBTR by Cautionary Determinant Age: 0% Histopath: 12.7% p=0.018 McHaffie, et al, IJROBP 2011
MGH: 3DCRT APBI Using 32 Gy/ 8 BID 5-Year Results of a Prospective Study 2000-2005 N= 98 Stage I Er/Pr +: 89% Median F/U: 71 mo. Pashtan, IJROBP, 2012
ASBS MammoSite Registry 1225 invasive breast cancer Median f/u: 60 mo. 5 yr LR: 3.6% Beitsch, Ann Surg Onc 2012
Breast Cancer Mortality - Absolute reduction (%) in 15-year risk (95% CI) Relationship of Breast Cancer Recurrence and Mortality by absolute reduction in 10 -year risk of Any 1 st Recurrence < 10% absolute reduction in any recurrence risk by 10 years Lancet 378: 1707-16, 2011 Any First Recurrence Absolute reduction (%) in 10-year risk
RCT in Hormone Responsive pn0 Breast Cancer Evaluating RT Benefit in Addition to Anti Endocrine Therapy Post-lumpectomy Clinical Trial F/U yrs Age > 50 y (%) T sz < 2 cm (%) ER/PR+ (%) Tam/AI (%) Grade 1-2 (%) In-breast recurrence (%) n 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 98 97 100-2 8 Low risk features: Older age, pn0, small size, ER/PR+, G1-2, anti endocrine therapy Recurrence rate indicates UNLIKELY survival benefit from breast radiotherapy
OCOG RAPID Early Reporting of Cosmetic Results 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% 135 (7-19%) < 0.0001 Olivotto et al, JCO 2013
Summary: APBI APBI so far has demonstrated acceptable local control in mostly low risk cases: Stage 1, ER+, > 60 yo breast cancer patients Need to complete randomized trials to define broader applicability and durability of outcome in comparison to standard WBI Rigorous attention to technical delivery and Q/A is crucial
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