Indications for Post- Mastectomy Radiotherapy and Considerations in Treatment Planning Lori J. Pierce M.D., FASTRO Professor of Radiation Oncology University of Michigan Comprehensive Cancer Center
Post-Mastectomy Radiotherapy Effect of RT after mastectomy and ALND on 10-year risk of locoregional and overall recurrence and 20-year risk of BC mortality in No disease EBCTCG, Lancet 2014
Post-Mastectomy Radiotherapy PMRT and High-Risk Operable Breast Cancer Treated with CMF or Tamoxifen: DBCG 82b and 82c Kaplan-Meier estimates of overall survival among women with high risk disease (all N+ and HR N-) treated with CMF + RT (82b) and Tam+ RT (82c) Overgaard et al, NEJM 1997 Overgaard et al, Lancet 1999
Post-Mastectomy Radiotherapy PMRT in High-Risk Breast Cancer Following CMF: 20-Year Results of British Columbia Trial Chemo-alone Chemo + RT arm therapy arm Survival, # events/ Survival, # events/ Outcome % # pts. % # pts. RR P All 318 patients Survival free of isolated 74 27/154 90 12/164 0.36.002 locoregional disease Systemic breast cancer- 31 104/154 48 84/164 0.66.004 free survival Breast cancer-specific 38 95/154 53 75/164 0.67.008 survival Overall survival 37 101/154 47 89/164 0.73.03 Ragaz et al, JNCI 2005
Post-Mastectomy Radiotherapy Effect of RT after mastectomy and axillary dissection (Mast+AD) on 10-year risks of locoregional and overall recurrence and on 20-year risk of breast cancer mortality in 3131 women with pathologically node-positive (pn+) disease EBCTCG, Lancet 2014
Radiotherapy reduces the risk of loco-regional recurrence as first recurrence by two-thirds
For BCT: In the hypothetical absence of any other causes of death, 1 breast cancer death would be avoided for every 4 local recurrences avoided. For PMRT in N+ disease: One breast cancer death would be avoided in 20 years after RT for every 1.5 recurrences avoided 10 years after RT.
Post-Mastectomy Radiotherapy Effect of radiotherapy (RT) after mastectomy and axillary dissection (Mast+AD) on 10-year risks of locoregional and overall recurrence and on 20-year risk of breast cancer mortality in 1314 women with one to three pathologically positive nodes (pn1-3) and in 1772 women with four or more pathologically positive nodes (pn4+) EBCTCG, Lancet 2014
Post-Mastectomy Radiotherapy Effect of radiotherapy (RT) after mastectomy and axillary dissection (Mast+AD) on 10-year risks of locoregional and overall recurrence on 20-year risk of breast cancer mortality in 1133 women with one to three pathologically nodes (pn1-3) in trials in which systemic therapy was given to both randomized groups. EBCTCG, Lancet 2014
MD Anderson 1-3 Positive Nodes Following Mastectomy and Systemic Treatment Era # pts LRR without RT* LRR with RT* Early (1978-97) 505 9.5% 3.4% p=.028 Later 522 2.8% 4.2% (2000-07) p=.48 *at 5 years McBride et al, IJROBP 2014
Post-Mastectomy Radiotherapy: Indications for Treatment The Danish Breast Cancer Cooperative Group Paraffin blocks from 1,000 patients with 8 or more nodes removed randomized on DBCG 82B and 82C stained for ER, PR HER-2 Median F/U 17 years for 1,000 patients Established three prognostic subgroups Kyndi et al, Radio Oncol 2009
Post-Mastectomy Radiotherapy: Indications for Treatment High local recurrence is not associated with large survival reduction after PMRT 3 prognostic groups established: Good: four out of five favorable criteria (< 3 positive nodes, tumor size < 2 cm, grade 1; ER + or PR+, HER2 neg) Poor: at least two out of three unfavorable criteria (>3 positive nodes, tumor size > 5 cm, grade 3) Intermediate: other than good or poor Kyndi et al, Radio Oncol 2009
5-year local recurrence probability and 15-year breast cancer mortality within the good, the intermediate and the poor prognostic subgroups in high-risk breast cancer patients randomly assigned to receive or not receive PMRT Kyndi et al, Radio Oncol 2009
Post-Mastectomy Radiotherapy SUPREMO TRIAL (Selective Use of Postoperative Radiotherapy after MastectOmy) under auspices of Scottish Cancer Trials Breast Group Phase III trial of PMRT in intermediate risk breast cancer pt 1 N 1 or pt 2 N 0-1 negative mastectomy margins 1-3 positive nodes or N 0 with grade 3 histology or ALI
Rec+/HER- Rec+/HER+ Rec-/HER- Rec-/HER+ Kaplan-Meier probability plots of overall survival and locoregional recurrence probabilities in high-risk breast cancer patients as a function of randomization to postmastectomy radiotherapy. Kyndi et al, JCO 2008
21 Gene Recurrence Score and Locoregional Recurrence Percentage of patients with locoregional recurrence at 10 years according to various subgroups in the B-14/B-20 trials (node neg, ER+, Tam, chemo) Mamounas et al, JCO 2010
Recurrence Score and Locoregional Recurrence Ten-year Kaplan-Meier estimates of the proportions of locoregional recurrence according to recurrence score, initial locoregional treatment, and age in the B-14/B-20 trials. Mamounas et al, JCO 2010
Recurrence Score and Locoregional Recurrence Multivariate Cox Regression Analysis of Predictors of Locoregional Recurrence in the Cohort of 895 Tamoxifen-Treated Patients from NSABP Trials B-14 and B-20 Hazard Wald Variable Ratio 95% CI Test P Age (> 50 v < 50) 0.40 0.25 to 0.65.0002 Mastectomy v L + XRT 0.62 0.39 to 0.99.047 Clinical tumor size (> 2 v < 2 cm) 0.98 0.61 to 1.59.933 Tumor grade (moderate v well) 1.10 0.54 to 1.92.113 Tumor grade (poor v well) 1.76 0.89 to 3.48 Recurrence score 2.16 1.26 to 3.68.005 Hypothesis-generating; needs validation Mamounas et al, JCO 2010
Post-Mastectomy Radiotherapy PMRT NIH Consensus Conference Consensus Statements (ASTRO, ACR, ASCO) For which patients should PMRT be recommended? 4 positive axillary nodes T 4 lesions tumor invading skin, musculature positive margins Controversial with T3; high risk node negative disease; and 1-3 positive nodes. These patients should be seen in consult by a Radiation Oncologist. XYZ03 19
Are the risk factors for LRR after neo-adjuvant chemotherapy the same as after adjuvant chemotherapy?
Post-Mastectomy Radiotherapy Patterns of LRF in Patients Receiving Neoadjuvant Chemotherapy Combined Analysis of B-18 & B-27 Analysis of 2 prospective trials to assess rates of LRF after BCT and mastectomy No regional RT in BCT patients; no PMRT Path CR = no invasive disease in breast + negative axillary nodes Median F/U 12.1 yrs. Mamounas et al, JCO 2012
Radiation Questions after Preoperative Systemic Therapy CONSORT diagram for NSABP B-18 & B27 trials Mamounas et al, JCO 2012
Radiation Questions after Preoperative Systemic Therapy NSABP B-18 & B27 Predictors of LRR after NAC: Combined Analysis BCT: RT to breast only; no regional RT No PMRT allowed per NSABP policy Mamounas et al, JCO 2012
10-Year Cum. Incidence of LRR According to Treatment Arm 14.3 12.2 P=0.08 8.5 9.5 P=0.02 P=0.05 Mamounas et al, JCO 2012
Radiation Questions after Preoperative Systemic Therapy LRR at 10 yrs with BCT in (A) age > 50 yrs (B) age < 50 yrs LRR at 10 yrs with mastectomy on (A) < 5 cm (B) > 5cm Mamounas et al, JCO 2012
Observations from NSABP trials: BCT Increased rates of LRR with residual disease in the breast and/or lymph nodes Increased rates of LRR in younger women Mastectomy Increased rates of LRR with residual disease in the breast and/or lymph nodes Increased rates of LRR for cancers > 5 cm Low rates of LRR with path CR in breast and nodes
Breast Cancer Symposium Abstract 61: Loco-regional Recurrence (LRR) After Neoadjuvant Chemotherapy (NAC): Pooled-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) Eleftherios P. Mamounas, Patricia Cortazar, Lijun Zhang, Gunter Von Minckwitz, Keyur Mehta, David A. Cameron, Herve R. Bonnefoi, Luca Gianni, Pinuccia Valagussa, Norman Wolmark, Sibylle Loibl, Jan Bogaerts, Sandra M. Swain, Rajeshwari Sridhara, Joseph P. Costantino, Stewart J. Anderson, Priya Rastogi, Charles E. Geyer Jr., Holger Eidtmann, Bernd Gerber and Michael Untch National Surgical Adjuvant Breast and Bowel Project and the UF Health Cancer Center - Orlando Health, Orlando, FL; U.S. Food and Drug Administration, Silver Spring, MD; German Breast Group/University Frankfurt, Neu-Isenburg, Germany; German Breast Group, Neu-Isenburg, Germany; University of Edinburgh, Edinburgh, United Kingdom; Institut Bergonie Cancer Center, Bordeaux, France; San Raffaele Scientific Institute, Milan, Italy; Fondazione Michelangelo, Milan, Italy; National Surgical Adjuvant Breast and Bowel Project; The Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA; German Breast Group/Sana Klinikum Offenbach, Neu-Isenburg, Germany; European Organisation for Research and Treatment of Cancer, Brussels, Belgium; MedStar Washington Hospital Center, Washington, DC; Biostatistical Center, National Surgical Adjuvant Breast and Bowel Project and Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA; University of Pittsburgh Medical Center, Pittsburgh, PA; Massey Cancer Center, Virginia Commonwealth University School of Medicine & NRG Oncology, Richmond, VA; University Kiel, Kiel, Germany; University Rostock, Rostock, Germany; Helios Klinikum Berlin-Buch, Berlin, Germany
5-Year Cumulative Incidence of LRR (%) 5-Year Cumulative Incidence of LRR(%) 5-Year Cumulative Incidence of LRR(%) 5-Year Cumulative Incidence of LRR: By Breast pcr and Path Nodal Status 25 20 15 25 20 Mastectomy 25 20 15 25 20 Lumpectomy 10 15 (n=1188) 10 15 5 0 10 5 0 (n=300) 3.3 3.3 (n=553) 8.2 13.1 13.1 5 10 0 5 0 (n=887) 7.2 (n=1274) 5.9 (n=1050) 10.3 ypt0/is ypn0 ypt1-3 ypn0 yptany ypn+ ypt0/is ypn0 ypt1-3 ypn0 yptany ypn+ ypt0/is ypn0 ypt1-3 ypn0 yptany ypn+ ypt0/is ypn0 ypt1-3 ypn0 yptany ypn+ Mamounas et al, BCS 2014
5-Year Cumulative Incidence of LRR (%) 5-Year Cumulative Incidence of LRR(%) 5-Year Cumulative Incidence of LRR According to Tumor Subtypes 25 25 20 15 20 10 15 5 10 0 (n=596) 9.2 (n=709) 14.8 (n=965) 9.7 (n=1088) 12.2 5 (n=1894) 4.2 0 HR+/HER2- GR 1,2 HR+/HER2-, Grade 1/2 HR+/HER2- GR 3 HR+/HER2-, Grade 3 HR-/HER2+ HR+/HER2+ HR-/HER2- HR-/HER2+ HR+/HER2+ HR-/HER2- Mamounas et al, BCS 2014
Data in all pn+ mastectomy patients suggest rates of LRF which justify strong consideration of PMRT particularly if cn+ and also pn+ RT not randomized so uncertain what impact RT would have had on survival RT not randomized so uncertain whether a patient with positive node negative nodes would have the same survival +/- RT
Use of neo-adjuvant therapy requires a multi-disciplinary team.
Radiation Treatment Planning for Breast Cancer: Indications and Treatment Planning Techniques
Patterns of Failure Help define regions to be treated Depending upon situation, target regions can include: Breast (especially lumpectomy cavity) Chest wall (especially mastectomy scar) Axillary lymph nodes Supraclavicular lymph nodes Internal mammary lymph nodes XYZ03 34
RT Treatment Planning BCS vs. BCS + RT in Early Stage Breast Cancer No. of % Local Recurrence F/U Trial Patients No RT RT (yr) NSABP B-06 1262 39 14 20 Milan III 579 24 6 10 Ont 837 35 11 8 Swedish 381 24 9 10 British 418 35 13 6 Scottish 589 25 6 5 XYZ03 35
RT Treatment Planning Loco-Regional Recurrence Patterns after Mastectomy and Doxorubicin-Based Chemotherapy Sites of LRR Site of LRR Isolated LRR (%) Total LRR (%) Chest Wall 98 68 Supraclavicular 33 40 Axilla 17 14 Infraclavicular 8 7 Internal mammary --- 8 Katz et al, J Clin Oncol XYZ03 2000 36
LRR first Ax sampling +/- RT ALND +/- RT Ax sampling +/- RT Breast cancer mortality ALND +/- RT EBCTCG, Lancet 2014
Patterns of Failure in Danish Trials 82b and 82c Frequency and Localization of Locoregional Recurrence (first site of failure) as a Function of Radiation Therapy Localization of Recurrence No Local Chest Sup./Inf. All Treatment Recurrence Wall Axilla Clavicular Recurrences Radiotherapy 92% 5% (2%) 2% (1%) 2% (1%) 8% (3%) No radiotherapy 67% 16% (3%) 13% (2%) 5% (2%) 33% (6%) Data from 3,083 patients included in DBCG 82 b & c trials Numbers in parentheses indicate patients with concomitant distant metastasis Overgaard et al, Sem Rad Onc 1999
RT Treatment Planning Risk of Histologic Internal Mammary Chain Involvement According to Histologic Axillary Node Status and Tumor Site No. of IMC Axillary Status Tumor site Patients Involvement (%) N ( ) External 332 8 Internal or central 299 11 N (+) External 464 22 Internal or central 331 37 Data on 1,426 patients included in an IMC dissection trial: Adapted from Lacour et al. XYZ03 39
RT Treatment Planning Results of Randomized Trials Comparing IMN Prophylaxis to Observation Disease-free Survival Overall Survival F/U Author No. patients Rx Obs Rx Obs Yrs. Hennequin 1,334 NS NS 62 59 10 Morimoto 192 83 87 92 93 5 Meier 123 --- --- 74 60 10 central/medial tumors 86 60 (.03) --- Fisher (B04) 717 57 55 59 54 10 Host, 186 57 43 (.04) 58 53 (.15) 10 (Oslo II, Stage II) Lacour, 1,453 56 51 56 53 10 Inst. Gustave Roussy N+ central/medial tumors 53 28 (.05) 15
RT Treatment Planning National Cancer Institute of Canada MA.20 Phase III Trial Regional Radiation Therapy in Early Stage Breast Cancer BCT T1-T3 N(+) -or- N(-) with primary tumor 5 cm -orprimary tumor 2 cm and <10 axillary nodes removed and ER-, SBR grade 3, -or- lymphovascular invasion Standard Breast RT RT to Breast + IMN + SCV Axilla XYZ03 41
Clinical Implications of the MA 20 Trial MA 20 5-Year Results WBI WBI + RNI p Isolated LR DFS* 94.5% 96.8%.02 Distant DFS 87.0% 92.4%.002 DFS 84.0% 89.7%.003 OS 90.7% 92.3%.07 *identical no. IBTR s in each group Whelan et al, ASCO 2011 XYZ03 42
Clinical Implications of the MA 20 Trial MA20 Adverse Events WBI WBI + RNI p Pneumonitis 0.2% 1.3%.01 > grade 2 Lymphedema 4.1% 7.3%.004 F/P cosmesis 29% 36%.047 Whelan et al, ASCO 2011 XYZ03 43
RT Treatment Planning EORTC Phase III Trial 22922/10925 Internal Mammary and Medial Supraclavicular Irradiation in Stages I-III Breast Cancer N ( ) -or- N (-) with medial/ central lesions No RT to IM-MS nodes RT to IM-MS nodes to 50 Gy Inclusion criteria: Tx, T 0 -T 3, N 0 -N 2 Mastectomy or BCT XYZ03 44
EORTC 22922/10925 Accrual 7/96 1/04 4004 patients randomized 10.9 years median F/U ~75% BCT No IMN-MS IM-MS Endpoint (n=2002) (n=2002) Local recurrence 5.3% 5.6% Regional recurrence 4.2% 2.7% Distant recurrence 19.6% 15.9% DFS 69.1% 72.1% p=0.44 Deaths from B.C. 310 259 Metastases-free survival 75.0% 78.0% p=.02 Overall survival 80.7% 82.3% p=.056 European Cancer Congress 2013
These results should be considered when discussing the relative merits of PMRT in patients with 1-3 positive nodes.
Radiation Therapy Uses high energy ionizing x-ray beams (MV) Photons interact with electrons resulting in direct and indirect effects Ultimately leads to reproductive cell death or apoptosis XYZ03 47
Direct and Indirect Action OH H 2 0 NEGATIVE ION e p photon INDIRECT ACTION e p photon DIRECT ACTION 20Å XYZ03 48
Therapeutic Ratio Tumor and normal tissues sustain damage after each radiation treatment Normal tissues better able to repair damage up to a point Ideally want sufficient dose to eradicate residual disease with acceptable normal tissue toxicity XYZ03 49
Adjacent Normal Tissues & Associated Complications Involved breast (poor cosmetic outcome) Uninvolved breast (contralateral breast cancer) Chest wall (rib fracture, sarcoma) Lungs (pneumonitis, lung cancer) Lymphatics (lymphedema) Brachial plexus (transient weakness) Heart (primarily CAD) XYZ03 50
Magnitude of Cardiac Risk with RT No threshold Dose effect on the heart Darby et al, NEJM 2013
Magnitude of Cardiac Risk with RT 10 Gy 3 Gy Cumulative risks for 50-year old after breast cancer diagnosis Darby et al, NEJM 2013
Avoidance of Cardiac Toxicity Risk of Cardiac Death after Adjuvant Radiotherapy for Breast Cancer M.D. Anderson (SEER data) Kaplan-Meier survival curves by breast cancer laterality and year of diagnosis. blue lines = 1973-1979 cohort solid lines = left red lines = 1980-1984 cohort dotted lines = right green lines = 1985-1989 cohort Giordano et al, JNCI 2005
RT Treatment Planning XYZ03 54
3-D Conformal Treatment Planning CT based Explicit definition of target and normal tissue structures Optimization of radiation dose distribution Homogenous dose to target while minimizing the dose to surrounding normal structures XYZ03 55
RT Treatment Planning CT-Based Treatment Planning Superior Tangents Inferior Tangents with Block XYZ03 56
Cardiac Effects of Modern Radiotherapy Individualizing Treatment Planning Techniques Box plots of CW and heart V30 and NTCP by technique Pierce et al, IJROBP 2002
RT Treatment Planning Definition of Supraclavicular and Infraclavicular Nodes Transverse CT sections of SCV and IFV fossae Madu, Pierce, Radiology 2001 XYZ03 58
Supraclavicular and infraclavicular nodes Potential benefits: 1) Decreased shoulder stiffness and pain 2) Decreased arm lymphedema Madu, Pierce, Radiology 2001, edited XYZ03 59
RT Treatment Planning 95% IDL XYZ03 60
RT Treatment Planning IMRT = Intensity Modulated Radiation Therapy 3D conformal therapy which allows the photon fluence/intensity pattern to vary across a field. Instead of one uniform intensity across a field, the intensity can vary to achieve a more conformal plan XYZ03 61
2 D Tangents 60-69 55-59 53-54 48-52 45-47 40-44 30-39 20-29 10-19 5-9 1-4
IMRT Tangents 60-69 55-59 53-54 48-52 45-47 40-44 30-39 20-29 10-19 5-9 1-4 med lat
Randomized Studies of Outcomes Using 2-D vs. IMRT Planning in Early Stage Breast Cancer Institute # patients Results Sunnybrook, 331 Significant reduction in moist desquamation; Vancouver Island, BC IMRT use did not correlate with pain and QOL Pignol et al, JCO 2008 Royal Marsden, UK 306 Significant reduction in skin induration at pectoral and inframammary folds, boost site at 2 and 5 years; No difference in pain or QOL Donovan et al, Radio & Onc 2007 Cambridge, UK 667 Significant reduction in telangiectasia and signif improvement in cosmesis with IMRT Patient-reported outcomes at 5 yrs not sign diff Mukesh et al. JCO 2013 Mukesh et al. Radioth Oncol 2014
RT Treatment Planning Treatment planning techniques have resulted in decreased rates of cardiac mortality over the years. Standard 2D techniques used to treat the intact breast only result in excellent rates of tumor control. CT-based planning may reduce the exposure of the heart to radiotherapy for leftsided breast cancers and can reduce the volume of lung treated in some cases. IMRT techniques improve dose homogeneity and have been shown to reduce skin toxicity and improved cosmesis in some women compared to 2D techniques. No one planning technique is uniquely superior for all cases. Individualized treatment planning is critical to minimize radiation-associated long-term toxicities. XYZ03 66