San Antonio Breast Cancer Symposium 2009: Highlights in Radiation Oncology Catherine Park, M.D. UCSF Radiation Oncology Outline IMRT Trial: Abstract#: 71 APBI for DCIS and IBC Background: ECOG 5194 Abstracts #: 951, 952 Background: ASTRO Consensus Statement Abstract #: 955 BRCA-1/BRCA-2: Abstract #: 959 Molecular phenotype and response to Neoadjuvant: Abstracts #: 957 Intraoperative Radiotherapy for BOOST treatment: Abstract #: 4104 1
Abs #71: A Randomised Controlled Trial of Forward- Planned Intensity Modulated Radiotherapy (IMRT) for Early Breast Cancer: Interim Results at 2 Years Follow- Up. Coles CE, Barne- GC, Wilkinson JS, Moody AM, Wilson CB, Twyman N, Hoole AF, Burnet NG, Wishart GS Cambridge Breast IMRT Trial : Methods Purpose: Single centre trial to investigate whether correction of dose inhomogeneities using IMRT reduces late toxicity and improves quality of life in pts with early breast cancer Methods: 1145 pts assessed for dose inhomogeneity in standard tangential plans as defined by the ICRU recommendations Pts with inhomogenous dose plans were randomized to either IMRT vs. Standard radiotherpay Pts with acceptable homogenous plans were treated with standard radiotherapy and followed 2
Cambridge Breast IMRT Trial : Methods Primary endpoint: photographic assessment of breast shrinkage Secondary endpoint: Photographic assessment of final cosmesis Clinical assessment of toxicity Patient-reported symptoms and quality of life Cambridge Breast IMRT Trial SCHEMA <2cm 3 of breast >107% N=330 Treated per standard T1-3, N0-1, M0; or Tis N=1145 3D imaging Dosimetry with standard tangen@al plans >2cm 3 of breast >107% N=813 RANDOMIZED STANDARD: CT- planned STANDARD: CT- planned Forward IMRT UK= 40Gy/15 FX 3
Cambridge Breast IMRT Trial: Interim Analysis Accrual: 6/03-6/07, completed 0.8% LR, 7 CBC, 16 DM, 12 deaths 3 of breast cancer Data from 632 randomized pts with 2 yr F/U No difference in Standard vs. IMRT for primary endpoint (shrinkage) Non- randomized had smaller breasts (p<0.0005) Improvement in telangiectasias in control vs. IMRT HR 1.63 (1.10-2.43) In randomized pts with good surgical cosmesis, there was a significant improvement in final cosmesis with IMRT (p<0.038) No differences in Boost, Tam, Chemotherapy Outline IMRT Trial: Abstract#: 71 APBI for DCIS and IBC Background: ECOG 5194 Abstracts #: 951, 952 Background: ASTRO Consensus Statement Abstract #: 955 BRCA-1/BRCA-2: Abstract #: 959 Molecular phenotype and response to Neoadjuvant: Abstracts #: 957 Intraoperative Radiotherapy for BOOST treatment: Abstract #: 4104 4
ECOG 5194: Local Excision Alone Without Irradia@on for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Coopera@ve Oncology Group Lorie L. Hughes, Molin Wang, David L. Page, Robert Gray, Lawrence J. Solin, Nancy E. Davidson, Mary Ann Lowen, James N. Ingle, Abram Recht, and William C. Wood ECOG 5194: Eligibility 5
ECOG 5194: Eligibility -Non-palpable disease -3 mm or larger -Suitable for lumpectomy, s/p excision with margin width >3mm Low or intermediate histologic grade: nuclear grade 1 or 2, limited or no foci of necrosis <2.5 cm High histologic grade: nuclear grade 3 atypia and comedo-type necrosis that was zonal (contiguous ductal spaces) <1.0 cm -Post-op MG required for any calcs; if + residual calcs disqualified -Receptor status not routinely determined -Central pathology in 97% of cases ECOG 5194: Results 6
ECOG 5194: Results Abs #951: Low Risk Ductal Carcinoma in situ (DCIS) Treated with Breast Conserving Surgery & Accelerated Partial Breast Irradation (APBI): Comparison of the Mammosite Registry Trial with Intergroup Study E5194 Sharad Goyal1, Frank Vicini2, Peter D. Beitsch3, Martin Keisch4, Jacqueline S. Jeruss5, Maureen Lyden6, Bruce G. Haffty1 7
Abs #901: METHODS A total of 194 patients with DCIS were treated between 2002 and 2004 on the Mammosite registry trial; of these, 70 patients met the enrollment criteria for E5194: 1. LIG: low to intermediate grade with a pathological size > 0.3cm but < 2.5cm and margins >3mm (n=40) or 2. HG: high grade, pathological size <1cm and margins >3mm (n=30). Abs #901: METHODS All patients were treated with lumpectomy followed by adjuvant APBI (34 Gy in 3.4 Gy fractions). Median follow-up for surviving patients was 51.5 months (range, 0-81.0). Hormonal therapy was given to 51% of these patients (compared to 30% of patients on E5194). Statistical analysis used SAS (v 8.2). 8
Abs #951: RESULTS All cases LIG Cohort HG Cohort Number of Breasts (All breasts) N=70 N(%) 5- yr Actuarial Rate N=41 N(%) 5- yr Actuarial Rate N=29 5- yr Actuarial Rate Breast Only Failures (IBTR) 1 (1.4) 1.98% 0 (0.0) 0% 1 (3.4) 5.16% TR/MM Failures 1 (1.4) 1.98% 0 (0.0) 0% 1 (3.4) 5.16% E Failures 0 (0.0) 0% 0 (0.0) 0% 0 (0.0) 0% Contralateral Failure 1 (1.4) 2.04% 0 (0.0) 0% 1 (3.4) 5.56% Distant Failure 0 (0.0) 0% 0 (0.0) 0% 0 (0.0) 0% Disease- Free Survival - - - 92.60% - - - 94.60% - - - 88.50% Overall Survival - - - 96.60% - - - 94.60% - - - 100.00% Cause- specific Survival - - - 100.00% - - - 100.00% - - - 100.00% Followup Time (Mo) Median Range 51.5 0.0, 81.0 50.3 0.4,72.2 52.5 0.0,81.0 Abs #951: RESULTS E 5194 cases Current LIG HIG LIG HIG Median Tumor Size 0.8 cm 0.6 cm 5 year IBTR 6.1% 15.3% 0% 5.3% 5 year CBC rate 3.5% 4.2% 0% 5.6% 5 year DFS 92.4% 5 year OS 96.5% 9
Abs #951: AUTHOR s CONCLUSIONS Adjuvant accelerated partial breast irradiation using Mammosite is a relatively convenient form of radiotherapy which shortens treatment time to 1 week. This study found that patients who met the criteria of E5194 treated with APBI had extremely low rates of recurrence: 0% vs. 6.1% in the low to intermediate grade (LIG) cohort and 5.3%vs. 15.3%in the high grade (HG) cohort. We conclude that all patients with DCIS who were eligible for E5194 have appreciable benefit in reducing the rate of IBTR using APBI. Abs #952: 3-Year Follow-up of the Partial Breast Irradiation Trial for DCIS using the MammoSite Brachytherapy Balloon Catheter Oscar E Streeter, Jr, MD1, Pamela Benitez, MD2, Frank Vicini, MD2, Vivek Mehta, MD3, Coral Quiet, MD4, Robert Kuske, MD4, Mary Hayes, MD5, Douglas Arthur, MD6, Henry Kuerer, MD7, Eric Strom, MD7, Gary Freedman, MD8, Mar@n Keisch, MD9, Thomas DiPetrillo, M.D10, David Khan, M.D11, Richard Hudes, MD12, Susan Groshen, PhD13, and Melvin J. Silverstein, M.D14 10
Abs #952: METHODS 100 patients entered from May 2003 through January 2006 The Mammosite balloon catheter was placed either at the time of lumpectomy or after the lumpectomy procedure with source optimization to provide the best conformance to the lumpectomy cavity. The minimum distance from the balloon surface to the skin surface (skin bridge distance) was > 5 mm. 34 Gy was delivered in 10 fractions over 5 days, each fraction was separated by at least 6 hours, and was prescribed to 1 cm from the applicator surface using an Iridium-192 high-dose rate brachytherapy applicator wire. The figure below demonstrates how the Mammosite Radiation Treatment System (MRTS) was delivered: Abs #952: METHODS > 45 years of age unicentric pure DCIS clinically node negative mammographic lesion of 3 cm or less lumpectomy negative margin (defined as 1 mm or more) postoperative final gross pathologic size of the removed tumor measuring 5 cm or less in its greatest dimension, post excision mammogram showing the absence of any residual suspicious micro-calcifications. Each patient was given a USC/Van Nuys Prognostic Index (USC/VNPI) score=6. If any of the eligibility criteria were not met and the MRTS was placed at the time of lumpectomy, it was explanted and the reason for removal was documented. 11
Abs #952: METHODS 133 patients were enrolled. mean age was 60.8 years. mean tumor size was 10.6 mm; mean actual closest margin was 6.8mm (range=0.1-40mm). balloon was placed post lumpectomy in 72% with a mean skin bridge of 13 mm, 89% of which were 7mm. median follow-up is 3 years. Harvard cosmetic results have been rated as excellent or good in 94% and fair in 6% with a follow-up time of at least 3 months in all of the patients treated. 84%were postmenopausal, 11% premenopausal, and 5% perimenopausal. ER+ 69% positive, 17% ER- and unknown in 14%. Fifty-two of the 100 women received endocrine therapy Abs #952: RESULTS There have only been four ipsilateral recurrences, all non-invasive; one was an ipsilateral recurrence outside the region of the original tumor cavity; There were no serious adverse events with an infection rate of only 9%-- 7 patients had breast infections, and 2 had cellulitis. 12
Abs #952: DISCUSSION This is the only prospective trial using the MammoSite or any other partial breast irradiation therapy technique for DCIS. It is well tolerated with an excellent to good cosmetic rate in 94% of the patients and fair in 6% of the patients with a 9% infection rate (7 breast infections; 2 cellulitis). There have been four recurrences, all noninvasive at this point. Each recurrence had at least one or more risk factors of a high USC/VNPI score, high nuclear grade, or comedo necrosis. There have not been any recurrences in nuclear grade 1 or nuclear grade 2 patients without comedo necrosis.. Accelerated Partial Breast Irradiation Consensus Statement from the American Society for Radiation Oncology (ASTRO) Benjamin D Smith, MD, DouglasW Arthur, MD, Thomas A Buchholz, MD, Bruce G Haffty, MD, Carol A Hahn, MD, Patricia H Hardenbergh, MD, Thomas B Julian, MD, Lawrence B Marks, MD, Dorin A Todor, PhD, Frank A Vicini, MD, Timothy J Whelan, MD, Julia White, MD, Jennifer YWo, MD, Jay R Harris, MD 13
APBI Patient Selection Criteria APBI Patient Selection Criteria 14
Abs #955: Outcomes following Accelerated Partial Breast Irradiation in ASTRO Consensus Statement Unsuitable Patients D.R. McHaffie, R.R. Patel, R.K. Das, H.M. Geye, G.M. Cannon at the University of Wisconsin. Abs #955: METHODS Between 2/2001 and 6/2006, a total of 322 consecutive patients were treated with HDR brachytherapy-based APBI All patients received 32 34 Gy in 8 10 bid fractions using multicatheter (93.5%) or Mammosite balloon (6.5%) HDR brachytherapy. A total of 107 unsuitable patients were identified: 80 pts (74.7%) age < 50, 19 pts (17.8%) node positive, 20 pts (18.7%) with LVSI, 3 pts (2.8%) with tumors > 3 cm, and 2 pts (1.9%) with multifocal disease (Table 2). 17 pts (15.9%) had multiple unsuitable features and 53 pts (49.5%) possessed additional cautionary features. Estimates of IBTR, LRR, DFS, CSS, and OS were made using the Kaplan-Meier method. The log-rank test was used to assess differences between patient groups. 15
Abs #955: METHODS Abs #955: RESULTS The median follow-up is 60 months (range 1.1-97.8 months). There were 6 in-breast tumor recurrences (IBTR), three of which had concurrent distant relapse. The 5 year actuarial rate of IBTR is 6.6% (95% CI: 1.7 11.5%). We observed 2 isolated axillary nodal failures. The 5 yr actuarial locoregional control rate is 91.3% (95% CI: 85.6 97%). The latency to LRR was 10 41 months. Four of 5 patients without distant disease at the time of locoregional recurrence (LRR) were successfully salvaged and had no evidence of disease at last follow-up. 16
Abs #955: RESULTS 5 yr disease free survival for the entire cohort is 89%, with a cause-specific survival and overall survival of 92.5% and 89%, respectively. There were no loco-regional recurrences observed among those with age < 50 without other unsuitable (LVSI, node +, > 3 cm, multifocality) or cautionary (ER -, EIC, tumor 2 3 cm, lobular histology, DCIS, < 2 mm margins) features (n = 31). Abs #955: RESULTS In comparison, the loco-regional recurrence rate is 12.3% for those deemed unsuitable by virtue of surgical and pathologic factors or age <50 with tumor-related cautionary features (n = 76). No individual unsuitable feature was prognostic on unvariate analysis. Loco-regional recurrences were observed in 2/19 node positive pts, 3/20 pts with LVSI, 1/2 pts with multifocal disease, 2/34 with age < 50 alone and cautionary features, and 0/3 pts with tumors > 3 cm. 17
Abs #955: RESULTS # at risk 107 96 90 81 63 50 33 15 1 Figure 1. Kaplan-Meier analysis of in-breast tumor recurrence (IBTR) probability. IBTR was defined as recurrence in the skin or parenchyma of the treated breast with or without concurrent regional or distant failure. No assessment of marginal miss versus elsewhere breast recurrences was made. Abs #955: RESULTS # at risk 107 96 89 79 62 50 33 15 1 Figure 2. Kaplan-Meier analysis of loco-regional control probability. Eight loco-regional recurrences were observed, including 2 isolated nodal failures. 18
Abs #955: RESULTS ------ 31 28 27 25 20 15 8 5 0 ------ 66 59 54 47 37 31 22 9 1 Figure 3. Kaplan-Meier analysis of loco-regional control probability in women < 50 years who otherwise meet suitable criteria 0% (RED) versus women with adverse tumor-related features 12.3% (BLUE), p = 0.064. Abs #955: AUTHOR s CONCLUSIONS The observed 5 yr loco-regional control rate of 91.3% +/- 5.7% is slightly lower than anticipated from historical breast conservation series, but confidence intervals are relatively large. Based upon the well-established benefits of whole breast radiotherapy, we continue to encourage clinical trial participation among this cohort of patients, specifically RTOG 0413 / NSABP B-39. Mature, phase III data are needed to guide patient selection. 19
Abs #955: AUTHOR s CONCLUSIONS Age < 50 years has consistently been shown to confer a higher risk of local recurrence following traditional breast conserving therapy. Although limited by patient numbers (n=31) and lack of statistical significance, the absence of local failures among women < 50 yrs without adverse histopathologic features (otherwise suitable) suggests they may be appropriate candidates for APBI. Outline IMRT Trial: Abstract#: 71 APBI for DCIS and IBC Background: ECOG 5194 Abstracts #: 951, 952 Background: ASTRO Consensus Statement Abstract #: 955 BRCA-1/BRCA-2: Abstract #: 959 Molecular phenotype and response to Neoadjuvant: Abstracts #: 957 Intraoperative Radiotherapy for BOOST treatment: Abstract #: 4104 20
Abs #959: Local Therapy in BRCA1/2 Carriers with Operable Breast Cancer: Comparison of Breast Conservation and Mastectomy Pierce LJ, Phillips KA, Griffith KA, Buys S, Gaffney DK, Moran MS, Haffty BG, Ben-David M, Kaufman B, Garber JE, Merajver SD, Balmaña J, Meirovitz A, Domchek SM Abs #959: METHODS Retrospective analysis of women prospectively followed with BRCA1/2 associated breast cancer Investigators from 10 institutions in the US, Spain, Israel and Australia identified women with invasive non-metastatic breast cancer and deleterious BRCA1/2 mutations treated with either BCT or Mx with or without PMRT. Statistical comparisons were made using the chi-square test for categorical characteristics and Student s t-test for continuous characteristics. 21
Abs #959: METHODS Rates of first failure and breast cancer-specific survival were estimated using the cumulative incidence method to account for competing events Cox regression models were constructed for local and distant failure, BCS OS and OS and CBC analyses Abs #959: RESULTS 655 patients with BRCA1/2 mutation and breast cancer were identified 302 were treated with BCT; 353 with Mx (241 without PMRT, 103 with PMRT and 9 RT unknown Median F/U: 8.2 years fo BCT and 8.9 years for Mx pts 22
Abs #959: RESULTS Abs #959: RESULTS 23
Abs #959: RESULTS Abs #959: AUTHOR s CONCLUSIONS We observed significantly greater local failures/new cancers following BCT vs. M in this cohort of BRCA1/2 carriers with early stage disease Use of chemotherapy significantly reduced the risk of local failures/new cancers following BCT Similar rates of distant failure, breast cancer-specific and overall survivals were observed between surgical cohorts. Comparable rates of systemic failure despite higher rates of IBTR suggest the development of new cancers in the treated intact breast rather than true IBTR s 24
Abs #959: AUTHOR s CONCLUSIONS Similar rates of CBC were observed independent of the use of RT suggesting no detectable increase in CBC attributable to scatter RT at 15 years These data may be helpful in discussions with patients with BRCA1/2 mutations and early stage cancer as they consider local treatment options. Outline IMRT Trial: Abstract#: 71 APBI for DCIS and IBC Background: ECOG 5194 Abstracts #: 951, 952 Background: ASTRO Consensus Statement Abstract #: 955 BRCA-1/BRCA-2: Abstract #: 959 Molecular phenotype and response to Neoadjuvant: Abstracts #: 957 Intraoperative Radiotherapy for BOOST treatment: Abstract #: 4104 25
Abs #957: Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy TK Yu MD PhD, W Tereffe MD, I Bedrosian MD, S Eksambi, EA Strom MD, J Litton MD, AM Gonzalez-Angulo MD, TA Buchholz MD, KK Hunt MD, and EA Mittendorf MD Abs #957: METHODS Clinicopathologic data from 593 breast cancer patients who received NCT and BCT from 1997 to 2005 were reviewed. Gene profile subtypes by surrogate marker: Lum A (52%) = ER+ or PR+ and Her2- Lum B (9%)=ER+ or PR+ and Her2+ Her2+ (7%)= ER- and PR- and Her2+ Basal (32%) = ER- and PR- and Her2- All patients received NCT and adjuvant radiation (RT) 98% received Anthracycline-based chemotherapy 84% received Taxane None received Trastuzumab Actuarial rates were calculated using the Kaplan-Meier method and compared using long-rank test. Cox proportional hazards models were used for multivariate analysis 26
Abs #957: METHODS Abs #957: RESULTS The median follow-up time was 65 months The 5 year LRC and overall survival rates for all patients were 94.2% and 87.9%, respectively The 5-year LRC rate was significantly better in patients with carcinoma of Luminal A and B than Her-2 or basal phenotypes A significantly higher proportion of patients with Her-2 and basal subtypes had pathologic complete response, smaller pathologic tumor size, less than 4 LN with disease, and higher nuclear grade. 27
Abs #957: RESULTS In addition, on univariate analysis, CSIII, >4 LN +, LVI+ and high nuclear grade significantly stratified patients with lower 5 year LRC. Among pts with no pcr or > 4LN after NCT, those with Her2+ and basal subtypes had poor 5 yr LRC while those with LumA and B subtypes still had good LRC Abs #957: RESULTS 28
Abs #957: RESULTS Abs #957: RESULTS 29
Abs #957: RESULTS Abs #957: AUTHOR s CONCLUSIONS 30
ER+ PR+ Her2- ER- PR- Her2+ 31
Abs #4104: Targeted Intraoperative Radiotherapy (Targit) Boost after Breast Conserving Surgery Results in a Remarkably Low Recurrence Rate in a Standard Risk Population: 5 Year Results Jayant S Vaidya1, Michael Baum1, Jeffrey S Tobias1, Frederick Wenz2, Samuele Massarut3, Mohammed Keshtgar1, Basil Hilaris4, Christobel Saunders5, Norman R Williams1, Chris Brew-Graves1, Tammy Corica5,Mario Roncadin3, Uta Kraus- Tiefenbacher2, Max Bulsara5, David Joseph5 Abs #4104: METHODS Patients: Suitable for breast conserving surgery from UK, USA, Australia, Germany and Italy. All patients had breast conserving surgery + Targit boost + EBRT Treatment: Wide local excision + axillary surgery TARGeted Intraoperative radiotherapy (TARGIT) was delivered to the tumour bed immediately after surgical excision during the same anaesthesia as previously described. In some patients especially in the Australian cohort, due to logistic reasons, this procedure was performed as a second operation within a few weeks. All patients received external beam radiotherapy to the whole breast as per local protocol, delivering 50Gy in 25 fractions over 5 weeks. 32
Abs #4104: METHODS Targeted Intraoperative radiotherapy was delivered using the Intrabeam device. The size of the tumour bed determined the size of the applicator (2.5 cm to 5cm diameter) The radiation dose received by the tumour bed was between 18 to 20 Gy. The dose at 1cm was 5Gy, over 20-35 minutes. The additional theatre time required for intraoperative radiotherapy was between 30 and 50 minutes, depending on the size of the applicator. Abs #4104: METHODS After completion of radiotherapy, the wound was closed and patients discharged home as usual. Patients were followed up as per local protocols, which all included at least a 6-12 monthly clinical examination and an annual mammogram. Statistical analysis for local recurrence was performed using SPSS software and compared with contemporary literature8,9. Cosmetic outcome was measured using standard techniques. 33
Abs #4104: METHODS Abs #4104: RESULTS 34
Abs #4104: RESULTS Abs #4104: RESULTS 35
Abs #4104: RESULTS Updates by the EBCTCG: Sarah Darby BCS +/- RT trials 11,000 women in 17 trials Median F/U 10 years Lumpectomy and L I- II ALND RT to conserved breast Boost in some Chemotherapy: few CMF/ no adriamycin Tamoxifen: most 36
Updates by the EBCTCG: Sarah Darby 15 year outcomes: Local Recurrence 5 YR 10 YR 15 YR NO RT 19.6% 26.2% 27.8% RT 5.3% 8.3% 9.9% Mortality 5 YR 10 YR 15 YR NO RT 7.8% 17.2% 25.3% RT 6.9% 14.6% 21.7% Pathologic Staging now 80% complete 15 year outcomes among NODE +, 1111 women: Local Recurrence 5 YR 10 YR 15 YR NO RT 40.5% 46.4% NA RT 11.2% 13.8% NA Mortality 5 YR 10 YR 15 YR NO RT 22.3% 41.9% 50.6% RT 20.4% 35.7% 44.0% 37
Pathologic Staging now 80% complete 15 year outcomes among NODE - : Local Recurrence 5 YR 10 YR 15 YR NO RT 17.5% 23.5% 24.9% RT 5.0% 7.6% 9.4% Mortality 5 YR 10 YR 15 YR NO RT 5.5% 12.8% 20.6% RT 4.6% 11.1% 17.4% 38