Indications for Post- Mastectomy Radiotherapy and Considerations in Treatment Planning

Transcription

1 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

2 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

3 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

4 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/ / locoregional disease Systemic breast cancer / / free survival Breast cancer-specific 38 95/ / survival Overall survival / / Ragaz et al, JNCI 2005

5 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

6 Radiotherapy reduces the risk of loco-regional recurrence as first recurrence by two-thirds

7 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.

8 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

9 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

10 MD Anderson 1-3 Positive Nodes Following Mastectomy and Systemic Treatment Era # pts LRR without RT* LRR with RT* Early ( ) % 3.4% p=.028 Later % 4.2% ( ) p=.48 *at 5 years McBride et al, IJROBP 2014

11 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

12 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

13 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

14 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

15 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

16 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

17 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

18 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) to Mastectomy v L + XRT to Clinical tumor size (> 2 v < 2 cm) to Tumor grade (moderate v well) to Tumor grade (poor v well) to 3.48 Recurrence score to Hypothesis-generating; needs validation Mamounas et al, JCO 2010

19 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

20 Are the risk factors for LRR after neo-adjuvant chemotherapy the same as after adjuvant chemotherapy?

21 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

22 Radiation Questions after Preoperative Systemic Therapy CONSORT diagram for NSABP B-18 & B27 trials Mamounas et al, JCO 2012

23 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

24 10-Year Cum. Incidence of LRR According to Treatment Arm P= P=0.02 P=0.05 Mamounas et al, JCO 2012

25 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

26 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

27 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

28 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 Mastectomy Lumpectomy (n=1188) (n=300) (n=553) (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

29 5-Year Cumulative Incidence of LRR (%) 5-Year Cumulative Incidence of LRR(%) 5-Year Cumulative Incidence of LRR According to Tumor Subtypes (n=596) 9.2 (n=709) 14.8 (n=965) 9.7 (n=1088) (n=1894) 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

30 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

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32 Use of neo-adjuvant therapy requires a multi-disciplinary team.

33 Radiation Treatment Planning for Breast Cancer: Indications and Treatment Planning Techniques

34 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

35 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 Milan III Ont Swedish British Scottish XYZ03 35

36 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 Supraclavicular Axilla Infraclavicular 8 7 Internal mammary Katz et al, J Clin Oncol XYZ

37 LRR first Ax sampling +/- RT ALND +/- RT Ax sampling +/- RT Breast cancer mortality ALND +/- RT EBCTCG, Lancet 2014

38 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

39 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 Internal or central N (+) External Internal or central Data on 1,426 patients included in an IMC dissection trial: Adapted from Lacour et al. XYZ03 39

40 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 Morimoto Meier central/medial tumors (.03) --- Fisher (B04) Host, (.04) (.15) 10 (Oslo II, Stage II) Lacour, 1, Inst. Gustave Roussy N+ central/medial tumors (.05) 15

41 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

42 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

43 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

44 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

45 EORTC 22922/10925 Accrual 7/96 1/ 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 Metastases-free survival 75.0% 78.0% p=.02 Overall survival 80.7% 82.3% p=.056 European Cancer Congress 2013

46 These results should be considered when discussing the relative merits of PMRT in patients with 1-3 positive nodes.

47 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

48 Direct and Indirect Action OH H 2 0 NEGATIVE ION e p photon INDIRECT ACTION e p photon DIRECT ACTION 20Å XYZ03 48

49 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

50 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

51 Magnitude of Cardiac Risk with RT No threshold Dose effect on the heart Darby et al, NEJM 2013

52 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

53 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 = cohort solid lines = left red lines = cohort dotted lines = right green lines = cohort Giordano et al, JNCI 2005

54 RT Treatment Planning XYZ03 54

55 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

56 RT Treatment Planning CT-Based Treatment Planning Superior Tangents Inferior Tangents with Block XYZ03 56

57 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

58 RT Treatment Planning Definition of Supraclavicular and Infraclavicular Nodes Transverse CT sections of SCV and IFV fossae Madu, Pierce, Radiology 2001 XYZ03 58

59 Supraclavicular and infraclavicular nodes Potential benefits: 1) Decreased shoulder stiffness and pain 2) Decreased arm lymphedema Madu, Pierce, Radiology 2001, edited XYZ03 59

60 RT Treatment Planning 95% IDL XYZ03 60

61 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

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63 2 D Tangents

64 IMRT Tangents med lat

65 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

66 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