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Postmastectomy Radiation Bruce G.Haffty, MD Professor and Chair Dept of RadiationOncology

Postmastectomy Radiation Bruce G.Haffty, MD Professor and Chair Dept of RadiationOncology UMDNJ-RWJMS Cancer Institute of New Jersey. POSTMASTECTOMY RT Objectives/Outline. Rationale and Supporting Evidence Indications and Controversies Role in Neo-adjuvant therapy

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Postmastectomy Radiation Bruce G.Haffty, MD Professor and Chair Dept of RadiationOncology

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  1. Postmastectomy Radiation Bruce G.Haffty, MDProfessor and Chair Dept of RadiationOncology UMDNJ-RWJMS Cancer Institute of New Jersey

  2. POSTMASTECTOMY RT Objectives/Outline • Rationale and Supporting Evidence • Indications and Controversies • Role in Neo-adjuvant therapy • Complications/Toxicities • Technical Considerations • Timing/Reconstruction

  3. CASE REPORT • 41 y/o s/p mastectomy and tram reconstruction for T1 (1.3 cm), N1 (2/26 + Nodes), ER/PR+, Her2 Neg, + Slight LVI • Treated AC+T Enrolled on RTOG randomized trial in 2001 to NO PMRT • Did well for 5+ years • Recurred in Internal Mammary and SC Regions

  4. Internal Mammary Recurrence

  5. Supraclavicular Recurrence

  6. Curing Breast Cancer • Series of additive incremental improvements • chemo vs. no • anthracycline vs. non-anthracycline • anthra + taxane vs. anthra alone • dose dense vs. none • herceptin

  7. Is Radiation Use Another Incremental Improvement ??

  8. YES Persistent Local-Regional Disease Is A Cause of Distant Metastases and Subsequent Death

  9. Postmastectomy RadiationOxford: Mastectomy +/- XRT Trials Local Recurrence Breast Ca Deaths LN - Disease • Local Recurrence • 2/3 reduction • Breast Ca Survival • none in LN- • 5% for LN+ 8% vs. 3% 28% vs. 31% LN + Disease 60%vs. 55% 29% vs. 8% • Lancet 366:2087, 2005

  10. EBCTCG-Meta-analysis(EBCTCG, Lancet 366:17,2005) • 42000 women in 78 Randomized Trials-RT vs No RT • Comparisons involving <10% difference in LR had little impact on mortality • Comparisons involving >10% difference in LR had substantial impact-5% absolute difference in mortality • Over 15 years-Avoidance of one breast cancer death for every 4 local relapse

  11. Whelan Meta-analysis JCO, 18:1220, 2000 Analyzed only trials that included syst rx 18 trials, 6300 pts, almost exclusively +LN Local-regional relapse Radiation reduced odds of LRR by 75%

  12. Whelan Meta-analysis JCO, 18:1220, 2000 Overall Survival Radiation reduced odds of death by 17%

  13. Modern Randomized TrialsMastectomy +/- XRT • Danish 82b NEJM 337:949, 1997 • 1708 premen: mast/CMF +/- XRT • Vancouver BCJNCI 97:116, 2005 • 318 premen, +LN: mast/CMF +/- XRT • Danish 82c Lancet 353:1641, 1999 • 1385 postmen: mast/tam +/- XRT

  14. Modern randomized trialsMAST +/-RT Danish 82b No XRTXRT (10-year) LRR 32% 9% p<0.0001 Survival 45% 54% p<0.0001 Vancouver BC (20-year) LRR 39% 13% p=0.0005 Survival 37% 47% p=0.03 Danish 82c (10-year) LRR 35% 8% p<0.0001 Survival 36% 45% p=0.03

  15. Fig 4. Kaplan-Meier estimates of all distant metastases (DM) either as first or subsequent failures among women treated with systemic treatment and randomly assigned to radiotherapy (RT) or no RT Nielsen, H. M. et al. J Clin Oncol; 24:2268-2275 2006

  16. Magnitude of Survival Benefit • Disease Free and/or Overall Survival benefit for patients with +LN Absolute Benefit • Chemotherapy 12% • Tamoxifen 11% • Herceptin 10% • Radiation 9%

  17. What Should Be Indications • According to randomized trials • all LN + disease • distribution of +LN in studies • 1-3 +LN: 62% (Danish), 58% (VBC) • >4 +LN: 38% (Danish), 35%(VBC)

  18. Criticisms • High local recurrence rates in these trials • Danish trials: inadequate axillary surgery • 15% 0-3 LN removed, 75% had under 9 • underestimates true number of +LN • unacceptably high axillary recurrence • Van BC trial • median # of LN removed – 11 • LRR risk for 1-3 +LN > than US series

  19. Who is at Risk? • ECOG (N = 2,016) LRRJCO 19:1539, 2001 • > 4 +LN 29% • 1 - 3 +LN 13% • MDACC (N = 1,031) JCO 18:2817, 2000 T3/4, or > 4 +LN 27% • T1/2, and 1 - 3 +LN12%

  20. Who is at Risk? • NSABP (N = 5,758) LRRJCO 22:4247, 2004 • > 4 +LN 14-25% • 1-3 +LN 6-11% • IBCSG (N = 5,352) JCO 21:1205, 2003 • T3/4, or > 4 +LN 25-35% • 1-3 +LNwith LVSI20-30% • 1-3 +LN w/o LVSI 14%

  21. Who is at Risk? Truong et al. Int J Rad Onc. 61:2005 • 821 women with T1/2, 1-3 positive nodes • Systemic Therapy-94%, FU-7 yrs • LRF >20% with any of these factors in Univariate (All 1-3+ Nodes) • Age <45 • ER Negative • >25% Nodal Ration, Also > 1 Node • Medial Location • T2 Disease • Multivariate analysis: Age <45, >25% nodal involvment, ER Negative and Medial Location were significant

  22. Co-Factors That Increase theLRR Risk for Patients with 1-3 +LN • 10-yr LRR > 15% (1-3 +LN)Reference • LVSI IBCSG • younger age NSABP/BC • ER Negative BC • tumors >4 cm MDACC • ECE over 2mm MDACC • 3 +LN NSABP • Nodal Ratio>20% (25%) MDACC/BC • Medial Location BC • close margins MDACC

  23. Even if patients with 1-3+LN have a low risk of LRR, does radiation still offer a benefit?

  24. T1 or T2, 1 to 3 nodes XRT No XRT 97% vs. 87% P<0.001 P<.003 Int J Rad Oncol Biol Phys, 57:336, 2003

  25. Updated Oxford Metaanalysis • Updated recently and reported at national meetings • Full manuscript under development, but probably won’t be published for at least a year or two • Demonstrates Survival benefit in 1-3 Positive Nodes • ?Survival benefit Still driven by British Columbia and Danish Trials?

  26. Mast+AC+RT vs. Mast+AC

  27. Mast+AC+RT vs. Mast+AC Isolated local recurrence by pathological nodal status

  28. Mast+AC+RT vs. Mast+AC Breast cancer mortality by pathological nodal status

  29. Mast+AC+RT vs. Mast+AC Any death by pathological nodal status

  30. Survival Benefits of Chemo in 1-3 +LN • OS Survival Benefits • CMF vs. none 15% • Anthra vs. CMF 4% • Taxane vs. none (approx 3%) • Increase Density (approx 3%) • Radiation Therapy (around 3-5%)

  31. Conclusion • Radiation Therapy • reduces LRR after mastectomy + sys rx • proportional reduction stays similar – 70% • improvements have overcome mortality risk • reduction in LRR improves OS • degree of OS benefit increases w/ • improvements in systemic treatment

  32. Response to controversy regarding post mastectomy RT for 1-3 positive nodes • Appropriately, a randomized clinical trial, multi-group, was mounted • Eligibility: Mastectomy, 1-3 positive nodes, chemo choice of oncologists • Modern chemotherapy, modern RT techniques, adequate surgery (>10 nodes removed) • Unfortunately, accrual was poor and trial has been closed leaving question unanswered

  33. Randomized Trials • SWOG/Intergroup • closed due to poor accrual • SUPREMO • MRC trial run out of Scottland • Stage II w/ 0-3 +LN: XRT vs. none

  34. ASCO Guidelines-PMRT(J Clin Oncol: 19:2001) • Patients with 4 or More +Nodes • PMRT is recommended • Level of evidence II: Grade B • Patients with T1-T2/1-3 +Nodes • There is insufficient evidence to make recommendations for patients with T1/T2 tumors and 1-3 Positive Nodes • ? Will this change with new meta-analysis?

  35. Post-Mastectomy RTIndicated in T3N0 disease? • Subset represents very small component of breasts cancers (<5%) • Traditionally treated and included in some of the PMRT randomized trials • Due to small numbers data is limited, but recent evidence suggests not all T3N0 benefit from PMRT

  36. PMRT-T3N0 Taghian et al. JCO, 24: 2006 • >8000 patients from NSABP data bases of which 313 had T3N0 disease • Local-regional Failure <10% in these trials • Conclude PMRT not always indicated in this setting

  37. PMRT-T3N0 Floyd et al. Int J Rad Onc. 66:2006 • 70 T3N0 from Harvard, Yale, MD Anderson • LRF rate < 10% • LVI significantly increased failure rate • Conclude T3N0 with LVI: PMRT may be indicated

  38. PMRT-T3N0 Helinto et al. Radiother Oncology. 52: 1999 • 3 of 5 Patients Not Treated (60%) sustained a local-regional relapse compared to: • 3 of 33 Treated (9%) sustained a local relapse, P <.003 • Treated cohort: better distant disease free and overall survival

  39. T3N0 PMRT ?Suggested Approach • Similar to T1-2, with 1-3 + Nodes • Treat for: • Larger T3N0 • Any LVI in Primary Tumor • Medial Location • Younger Age • Close/Involved Margin • ER Negative

  40. Post-mastectomy radiation • Ongoing Canadian and European trials may provide data in the future regarding the benefit of regional irradiation in patients with 1-3 nodes • Currently, given the modest but significant benefit, discussion of the risks/benefits in patients with 1-3 nodes positive is prudent

  41. Potential application of molecular/genetic markers-PMRT • Research area ripe for further investigation • Identification of factors which put patients with 1-3 nodes, or even patients with node negative disease at high risk for local-regional relapse who may or may not benefit from RT • Molecular Markers • ER, PR, COX-2, Her2/neu,P53 • Genetic Profiling of tumors

  42. Molecular Predictors-PMRTP53 Status • Zellars R et al. JCO, 18:1906, 2000. • 1271 Patients treated with mastectomy –No RT • P53 by IHC -significant factor for local-regional relapse • 9.1% P53 negative vs 16.5% P53 +

  43. Molecular Predictors-ER Status Cheng JC et al. J Formos Med.99:2000 Truong et al. Int J Rad Onc:61:2005 Cheng:83 patients with 1-3 positive nodes, Mastectomy No RT • 3 Year local relapse rates • 31% ER negative vs 11% ER Positive Truong: 821 Patients from BVC, 1-3 positive nodes, Mastectomy No RT • ER Negative LRR-19% in univariate • Multivariate analysis ER Negative predicted for Higher LRR (RR=2.02)

  44. Fig 2. Unsupervised two-dimensional cluster analysis of 258 genes in 62 patients revealed two distinct groups of tumors; their locoregional recurrence rates were 41.4% (12 of 29) compared with 18.2% (six of 33) Cheng, S. H. et al. J Clin Oncol; 24:4594-4602 2006

  45. Genetic Profiling-PMRT Cheng SH et al. JCO 24:4594, 2006 • Genomic profiling/258 and 34 gene profile • 94 patients post-mastectomy (No RT) • 67 without LRR • 27 with LRR • Predictive index <0.8 or > 0.8 • Local-regional control • 91% vs 40%

  46. Genomic Predictors of LRR Cheng SH et al. JCO 24:4594, 2006

  47. Fig 3. Kaplan-Meier survival estimates for locoregional control in validation data set by (A) 258-gene and (B) 34-gene prediction tree models Cheng, S. H. et al. J Clin Oncol; 24:4594-4602 2006

  48. Fig 4. Ten-year Kaplan-Meier estimates of the proportions of locoregional recurrence (LRR) according to recurrence score (RS), initial locoregional treatment, and age in the 895 tamoxifen-treated patients in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14/B-20 trials Mamounas, E. P. et al. J Clin Oncol; 28:1677-1683 2010

  49. Postmastectomy Radiation After Neoadjuvant Chemotherapy

  50. Neoadjuvant Chemotherapy • History • once reserved for inoperable disease • excellent response rates • now increasingly more common • its increased useraises new questions

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