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Radiation after Neoadjuvant Systemic Therapy: Are the Rules Different?

Radiation after Neoadjuvant Systemic Therapy: Are the Rules Different?. Julia S. Wong MD Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women' s Hospital. I have no conflicts of interest. Background.

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Radiation after Neoadjuvant Systemic Therapy: Are the Rules Different?

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  1. Radiation after Neoadjuvant Systemic Therapy: Are the Rules Different? Julia S. Wong MD Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women's Hospital

  2. I have no conflicts of interest

  3. Background • Rationale for neoadjuvant chemotherapy (NAC)/preoperative systemic therapy: • Prognostic information • Evaluate new drugs/protocol therapies • Convert mastectomy to breast-conserving therapy • Possibly decrease extent of axillary surgery

  4. Questions • How do we interpret post-chemotherapy pathology to make radiation therapy decisions? • Postmastectomy RT (PMRT): yes or no • Extent of nodal RT • In BCT setting: what is an acceptable margin

  5. Rules for RT Based on Pathology after Initial Surgery • Can we use the “old” rules (when surgery is first) or do we have enough data to change the rules? • Pathologic findings (downstaging) after NAC may not have the same significance as those found at initial surgery • Limited, retrospective data with NAC and RT

  6. Rules for RT after Initial Surgery • After mastectomy and chemotherapy, PMRT if >4 +LNs • Often considered in 1-3 +LNs • Infrequently recommended for node-negative • After breast-conserving surgery (BCS), RT generally recommended provided negative margins achieved • Nodal field used depending on extent of nodal involvement and extent of axillary surgery

  7. When to Consider Postmastectomy RT (PMRT) After Initial Surgery • After MRM and adjuvant chemotherapy, LRR is related to # of positive nodes • Data from ECOG and MDACC: # + nodesLRR (%) 0 3-5 1-3 10-13 >4 20-30 Recht A, JCO 1999; Katz A, JCO 2000

  8. 10-Year Risk of LRR After MRM and Adjuvant CT (ECOG) # + Nodes N LRR+/-D LRR 1-3 1018 13% 8% 4-7 62 29% 19% Recht A, JCO 1999

  9. LRR (NAC  Mastectomy) • N = 150; no inflammatory breast CA • Median FU 4.1 yrs • Preop doxorubicin or paclitaxel • No PMRT • Clinical stage at diagnosis: I 1% II 43% III 48% IV 7% Buchholz J Clin Oncol 2002

  10. LRR (NAC  Mastectomy) • 5 and 10 yr LRR: 27% • LRR associated with: • Increased T stage • Increased clinical stage • Size of residual tumor • # involved LNs • No tamoxifen • LRR for pCR (n=18): 19% • On logistic regression LRR associated with: CS IIIB (or higher), >4 +LNs, no tam Buchholz J Clin Oncol 2002

  11. NAC vs Adjuvant Chemo (Mastectomy) • Follow up study • Same N = 150 (NAC group); N = 1031 (adjuvant) • Clinical stage higher in NAC group • Path tumor size and #+LNs less in NAC group • 5 yr LRR 27% (NAC) vs 15% (adjuvant) • LRR higher in NAC for: • All tumor sizes • > 4 +LNs • T2 and 1-3 +LNs (32% vs 8%) Buchholz IJROBP 2002

  12. PMRT after NAC • N = 542 (compared with N = 134 without PMRT) • Median FU 69 months • Mainly Stage II/III (RT patients higher stage) • LRR at 10 yrs: PMRTNo PMRT Overall 11% 22% Stage III/IV + pCR 3% 33% • PMRT benefit on MVA for LRR and CSS Huang J Clin Oncol 2004

  13. PMRT after NAC with Pathologic Complete Response • N = 106 • Mainly Stage II/III • pCR after NAC • Med FU 62 months • LRR at 10 yrs: PMRT (n=72)No PMRT (n=34) Stage I/II 0% 0% Stage III 7% 33% (p=0.04) McGuire IJROBP 2007

  14. LRR after NAC in Stage II • N = 132 • Stage I (5%) or II (95%) • 1974 – 2001 • Mastectomy, no RT; doxorubicin-based chemo • Median FU 46 months • LRR at 5 and 10 yrs: 10% • LRR correlated with: clin T3N0, >4+LNs, age <40, no tamoxifen • LRR at 5 yrs for clin T1-2, 1-3+ LNs (n=42): 5% Garg IJROBP 2004

  15. Summary: Mastectomy after NAC • Retrospective data with imbalances; higher stage that adjuvant studies • LRR associated with higher stage, more residual disease, lack of pCR • Benefit to PMRT in Stage III, any T3, any > 4+LNs • PMRT benefit in limited nodal involvement and pCR in need of further study

  16. Breast-Conserving Therapy:LR after Initial Surgery • 1980s: LR approximately 10-15% (early-stage) • Recent series: about 2-8% • Better mammography, margins, systemic therapy

  17. Planning for BCT after NAC • Pre- and post-NAC imaging • Assess extent of calcifications if present • Clip placement at time of initial core bx • Axillary ultrasound and FNA if indicated (also for PMRT considerations)

  18. BCT after NAC • N = 340 • 1987 – 2000 • Stage I: 4%, II: 58%, III: 38% • Positive margins in 4% • Median follow up: 60 months (10-180) • IBTR-free: 94%; LRR-free: 91% • Predictive of IBTR and RNF: clin N2/3, path size >2cm, multifocal residual, LVI Chen J Clin Oncol 2004

  19. “Concentric” vs. “Splotchy” Response to CT

  20. BCT after NAC (Institut Curie) • N = 257 • 1985 – 1994 • Clinical T1-3 (84% T2) • Tumors had to be < 3 cm after NAC • Median FU: 93 months • Margins: Positive 11% < 2 mm 17% > 2 mm 67% Indeterminate 4% Rouzier J Clin Oncol 2001

  21. BCT After NAC: Results • LR at 10 yrs: 22% • Predictive for LR on MVA: • Age < 40 • Margin < 2 mm (32% vs 17%) • S-phase > 4% • Clinical tumor size > 2 cm at time of surgery • IBTR predicted for distant mets Rouzier J Clin Oncol 2001

  22. Effect of Subtype on LRR (BCT) • N = 751 • 2005 – 2012 • Median follow up: 4.6 yrs Swisher Ann Surg Oncol 2016

  23. Effect of Subtype on LRR (BCT) • NACBCT • N = 160, • Med FU 28 mos • 80% of HER2+ received trastuzumab • LRR 8% overall • On MVA, LRR higher in TNBC (p=0.04) Zhang SpringerPlus 2015

  24. Effect of Subtype on LRR (NAC + PMRT) • N = 233 • Stage II/III; med FU 62 mos • pCR in 14%; 5 yr LRR 8% overall • LRR 0% in pCR, 9% if no pCR (p=0.05) • TNBC and path LN+ associated with LRR • TNBC had higher LRR (20%) compared with HER2+ (6%) and HR+ (4%) Yang TJ Ann Surg Oncol 2015

  25. Predictors of LRR after NAC: NSABP Experience • B-18 and B-27 NAC trials (AC, docetaxel) • BCT or mastectomy (no PMRT) • pCR = no residual invasive tumor • 1988 – 1993 • N = 3088; 10 yr follow up • Clinical T1-3, N0-1 • LRR 12% (mastectomy), 10% (BCT) Mamounas J Clin Oncol 2012

  26. Predictors of LRR after NAC: Multivariate Analysis Mamounas J Clin Oncol 2012

  27. LRR after Neoadjuvant Chemotherapy Mamounas, J Clin Oncol 2012

  28. Figure 2 NSABP B‑51/RTOG 1304 (NRG 9353) trial schema King, T. A. & Morrow, M. (2015) Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.63

  29. Figure 1 Alliance for Clinical Trials in Oncology A11202 trial schema King, T. A. & Morrow, M. (2015) Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.63

  30. Summary • Neoadjuvant chemotherapy provides advantages to adjuvant chemotherapy in selected clinical settings • Local recurrence higher in earlier reports but now generally felt to be comparable to adjuvant setting • In BCT, insufficient data for what margin width is adequate; clearly negative margins seems prudent (different patterns of tumor regression)

  31. Summary • Retrospective series suggest that there may be subgroups that can safely avoid RT or have more limited RT, without compromising local regional control • The rules for when to use RT (or PMRT) are evolving; data from randomized trials critical

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