NEOADJUVANT CHEMOTHERAPY BREAST CANCER RADIATION ONCOLOGY ISSUES To Whom and How?

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1 NEOADJUVANT CHEMOTHERAPY BREAST CANCER RADIATION ONCOLOGY ISSUES To Whom and How? Bruce G. Haffty, MD Professor and Chair Department of Radiation Oncology Rutgers, The State University of New Jersey Cancer Institute of New Jersey, Robert Wood Johnson Medical School and New Jersey Medical School

2 Conflict of Interest Disclosure Bruce G Haffty I have no financial relationships with a commercial entity producing healthcare-related products and/or services.

3 For Discussion Who is a candidate for Neo-adjuvant chemotherapy? What are the indications for radiation following neo-adjuvant chemotherapy? BCS MASTECTOMY What fields should be treated following neoadjuvant chemotherapy? Based on response? Based on original presentation? BCS vs Mastectomy? Sentinel Node vs. Complete Axillary Dissection Can PMRT be eliminated in any subset of patients? What are the future directions and trials addressing radiation oncology specific issues?

4 Neo-adjuvant chemotherapy in breast cancer Who is a candidate? Inflammatory Breast Cancer-Definite Locally Advanced Unresectable-Definite Locally Advanced Resectable-Depending on goals, physician and patient preference Breast Conservation Desired, but would be suboptimal cosmetic result without down-staging prior to surgery Early Stage Invasive breast cancer-depending on physician and institutional preference even early stage patients who can be conservatively treated may consider neo-adjuvant chemotherapy prior to surgery

5 Neo-adjuvant Therapy in Operable Breast Cancer Multiple studies suggest that neo-adjuvant therapy (chemo or hormonal) results in high clinical response rates (>80%) and respectable complete pathologic response rates (>25%) Complete pathologic response correlates with better disease free and overall survival rates Neoadjuvant therapy will result in significant downstaging to allow increase utilization of breast conserving surgery in those patients desiring breast conservation Overall survival and disease free survival rates appear to be the same as patients treated with similar systemic therapy adjuvantly

6 Relevance of B18 and B32 to Radiation CRITICAL POINT-NO PMRT Allowed in trials For Residual Node Positive Disease after Neo-adjuvant Chemotherapy in these groups of patients with operable breast cancer the 8 year risk of local regional relapse was 15%, suggesting the need for PMRT in patients with residual node positive disease For those with residual node negative disease the risk of local-regional relapse was less then 10%, suggesting PMRT might be eliminated in those patients with a complete response

7 Ten-year cumulative incidence of locoregional recurrence (LRR) in patients with (A) 5-cm tumors treated with mastectomy and (B) > 5-cm tumors treated with mastectomy. pcr, pathologic complete response [after neoadjuvant chemotherapy]; ypn, pathologic noda... Mamounas E P et al. JCO 2012;30:

8 Indications for RT following neoadjuvant systemic therapy and BCS All patients receiving neoadjuvant therapy followed by BCS should receive post lumpectomy whole breast irradiation with or without regional nodal irradiation-as will be discussed later Available data suggests excellent local control rates in this setting Outside of a clinical trial, patients receiving neo-adjuvant therapy should not be considered for accelerated partial breast irradiation Use of Hypofractionated whole breast remains controversial due to lack of substantial data in this setting

9 BCS following Neo-adjuvant MDACC Experience Chen et al. JCO 22: , Cases treated with neoadjuvant followed by BCS Median followup of 5 years Local-Regional Relapse Free survival-91% at 5 years Advanced nodal involvement, residual tumor burden, lymphascular space invasion and multifocal residual disease were predictors of higher local-regional relapse rates Overall even for initial T3 or T4 disease, neo-adjuvant chemotherapy followed by BCS and RT resulted in acceptable outcomes

10 Local-regional recurrence (LRR) -free survival rates according to the absence or presence of lymphovascular space invasion (LVSI). Chen A M et al. JCO 2004;22:

11 Neoadjuvant Therapy and BCS All patients should receive WBRT Nodal irradiation as indicated and will be discussed High local control rates in most patients Some subsets of patients may have higher local relapse rates which could be the subject of future trials such as concurrent chemo-rt or dose escalation The role of hypofractionated whole breast following neo-adjuvant therapy remains controversial (These patients are eligible for our hypofractionated whole breast trial)

12 Indications for PMRT following Neo-adjuvant therapy and mastectomy The majority of patients receiving neoadjuvant therapy and mastectomy should receive PMRT Absolute indications include locally advanced (T3,T4, Clinical N+) and inflammatory disease Highly indicated based on studies to date include any patient with residual node positive disease Controversial and unanswered question in those patients with a complete pathologic CR or who convert from node positive to node negative following neoadjuvant therapy Probably not needed in patients with T1/T2 N0 who underwent neoadjuvant and mastectomy-though we rarely see these patients

13 Neoadjuvant Chemo and mastectomy with or without RT MDACC Experience B-18 and B-27 (A); 10-year locoregional recurrence for patients with clinical stage III disease and pathological complete response to chemotherapy (B); 5-year locoregional recurrence for patients younger than 35 years and with clinical stage II or III disease (C); and 5-year locoregionalrecurrence for patients with clinical T3N0 disease (D). Locoregional recurrence among patients in NSABP B- 18 and NSABP B-27 trials who received neoadjuvant chemotherapy, mastectomy, and no postmastectomy radiation therapy, stratified by pathological extent of breast and lymph-node disease at resectionpathological complete response (pcr) was defined as no invasive tumour in the breast

14 Fields following neo-adjuvant therapy Concepts Traditional design of radiation fields is based on results of surgery without neoadjuvant therapy Should field design be based on original presentation or final results of pathology? Field design is further complicated by the increasing use of sentinel node sampling post neoadjuvant therapy General principles: Treat areas at risk for subclinical microscopic disease For node positive patients treat the undissected regional nodes

15 Patients at high risk for LRR despite neoadjuvant therapy and mastectomy and PMRT Despite chemotherapy, mastectomy and PMRT some patients remain at high risk for local regional relapse and might benefit from more aggressive therapy, such as concurrent chemo-rt, BID or other dose escalation programs This is an area ripe for future investigations Identification of those patients at increased risk for local regional relapse remains an area of investigation Several recent papers have identified patients at risk

16 Inflammatory Breast Local Relapse in TN Li et al. Oncologist, 16:12, 2011

17 Prognostic factors on risk of LRR with neoadjuvant and PMRT Wright et al. Cancer, 2012

18 Predictors of LRR with Neoadjuvant and PMRT Wright et al. Cancer, 2012 Retrospective analysis of 464 patients who received neoadjuvant chemotherapy, mastectomy and PMRT Followup 50 Months: 5 Year Risk of LRR was 6% Predictors of Higher Rates of LRR included Presenting Stage Receptor Status (ER Negative and Triple Negative) Pathologic Response to Neoadjuvant Therapy Omission of Supraclavicular Field

19 Future Directions More aggressive therapy for those patients at higher risk for LRR despite neoadjuvant therapy Inflammatory Triple Negative High Residual Disease Burden Local-Regional Treatment options following Neoadjuvant Therapy Axillary Dissection vs. Axillary Radiation Omission of PMRT in complete responders Omission of SCV RT in selected patients post BCS or Post Mastectomy

20 A The role of axillary lymph node dissection in breast cancer patients (ct1-3 N1) who have positive sentinel lymph node disease after receiving neoadjuvant chemotherapy Judy C. Boughey MD, Buchholz MD, Bruce Haffty MD, MD, Vera Suman PhD Tom Kelly Hunt

21 Study Objectives Primary Objectives: To evaluate whether axillary radiation alone is not inferior to axillary radiation and axillary lymph node dissection (ALND) in terms of invasive breast cancer recurrence-free interval in women with a positive SLN after completion of neoadjuvant chemotherapy. Secondary Objectives: To evaluate the impact of axillary radiation alone relative to axillary radiation and axillary lymph node dissection (ALND) on the incidence of invasive loco-regional recurrences in patients with a positive SLN after completion of neoadjuvant chemotherapy. To compare the incidence of lymphedema and symptoms in both treatment arms

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23 SLN positive patients randomized to: Arm 1 or No further axillary surgery (no ALND) Radiation to the breast (if BCS) or chest wall (if mastectomy), and axillary radiation directed to level I, II and III lymph nodes and the supraclavicular fossa. Arm 2 Axillary lymph node dissection (ALND) level I and II Radiation to the breast (if BCS) or chest wall (if mastectomy), and axillary radiation directed to level III and the supraclavicular fossa.

24 Sample size Up to 1967 patients to be enrolled SLN positive (40%) patients per arm Assume 5 year RFI = 63% for ALND and nodal XRT patients (extrapolated from NSABP B-18 & B-27) Non-inferiority HR 0.8 or greater (DFI of 57/5% or less) 85% power to reject null hypothesis of inferiority of nodal RT to ALND + nodal RT in terms of recurrence-free interval A total of 1947 women would need to be pre-registered to obtain 1168 women with SLN positive disease after neoadjuvant chemotherapy. Plus 10% for patients going off study (due to SLN not identified etc), so target accrual 1967 patients.

25 NRG (NSABP/RTOG Group) Patients with same eligibility as Alliance Trial Those Converting to Node Negative Will be entered onto NRG study for randomization Mastectomy Patients Randomized to PMRT to chest wall and regional nodes vs No PMRT Lumpectomy Patients Randomized to Whole Breast RT vs Whole Breast and Regional Nodes

26 Nodal Treatment for Alliance and NRG Study Alliance ( Sentinel Node Positive after NAT) RT to Chest Wall(Mastectomy) or Breast (Lumpectomy) for all Randomized to Axillary Dissection RT to Supraclav (Undissected Axilla) and IM Randomized to Axillary Radiation RT to Supraclav, Axilla and IM NRG (Node Negative) Randomized to no nodal RT Lumpectomy-RT to breast Only Mastectomy-No PMRT Randomized to RT Lumpectomy RT to Breast SC and IM Mastectomy-RT to Chest Wall, SC and IM

27 CASE 1 BCS and full AXD after Neoadjuvant 45 Year Old, T3, N1 by FNA pre-chemo Undergoes chemo followed by BCS and Axillary Dissection with residual 5 mm tumor and 1 of 12 positive nodes Whole breast RT with boost Supraclavicular field to treat undissected nodes With or without internal mammary field-use partially wide tangent if possible to treat IM

28 Case 2-Similar but with + sentinel node 45 Year Old, T3, N1 by FNA pre-chemo Undergoes chemo followed by BCS and SNB with residual 5 mm tumor and 1 of 2 positive sentinel nodes Whole Breast RT RT to SC and Full Axilla With or without internal mammary

29 Case 3 BCS with negative sentinel node before neoadjuvant 45 year old with large T2 undergoes sentinel node prior to CTX and that was negative. Has neoadjuvant to downstage and successfully undergoes BCS with negative margins. No axillary dissection done Whole breast RT Given original sentinel node was negative no need to treat regional nodes as false negative rate for sentinel node prior to chemo is low.

30 Case 4 BCS with negative sentinel node after neoadjuvant 45 year old with large T2 with LVI clinically node negative by imaging and exam prior to CTX. Has neo-adjuvant to downstage and successfully undergoes BCS with negative margins. Sentinel nodes negative Whole breast RT with boost Controversial whether to treat or not treat nodes since we have no idea if nodes were positive or negative prior to neoadjuvant. Given LVI and young age I would probably consider treating SCV and Axilla, but no nodal tx is acceptable.

31 Case 5 BCS with positive sentinel node after Neoadjuvant 45 year old with large T2 with LVI clinically node negative by imaging and exam prior to CTX. Has neo-adjuvant to downstage and successfully undergoes BCS with negative margins. Sentinel node reveals 1 of 2 positive. No axillary dissection done Whole breast RT with boost RT to Supraclav and Full Axilla With or without internal mammary treatment

32 Case 6 Mastectomy for LAD with complete response 50 year old with locally advanced disease (T3 N2 clinically) undergoes neoadjuvant and mastectomy with complete pathologic response: no residual tumor in breast and 0 of 10 positive nodes Chest wall RT Supraclavicular RT to treat undissected axilla With or without internal mammary

33 Case 7 Mastectomy and Inflammatory 50 year old with inflammatory disease and positive nodes by PET in SC, AX and internal mammary undergoes neoadjuvant with complete clinical, PET, and pathologic response and 0 of 6 positive nodes at dissection Treat chest wall with bolus to tolerance and boost Could consider MD Anderson BID regimen Treat supraclav and full axilla in this case Treat internal mammary chain for sure

34 Case 8 Mastectomy for earlier stage with complete pathologic CR to Neoadjuvant Tx 56 year old considering BCS with large T2,N1(by FNA), undergoes neoadjuvant then decides on mastectomy. Has complete pathologic response with no residual in breast and 10 negative nodes Could consider PMRT to chest wall and SCV Could consider observation based on data from NSABP 18 and 27

35 Case 9 Mastectomy with good response: Issue of need for axillary dissection 50 year old with T3, N1 (by ultrasound guided FNA) has neoadjuvant with good response. At mastectomy has only residual DCIS with microscopic disease in 1 of 2 sentinel nodes. Asked at tumor board if surgeon should go back for full axillary dissection, since if nodes are clear patient won t need PMRT? Would argue that patient needs PMRT regardless based on initial T3 disease and original N1 disease. Would argue that additional surgical procedure is not necessary as RT can control axilla Would treat CW, SC+Axilla, with or with internal mammary

36 Conclusions Radiation after neoadjuvant therapy plays an important and critical role Neoadjuvant therapy results in high response rates and downstages a significant number of patients, increasing the possibility for BCS in a majority of patients Local Control following both BCS and mastectomy are excellent, but there remain some selected patients with higher relapse rates who may benefit from more aggressive therapy, which could form the basis of future investigations There remain unanswered questions regarding the appropriate use of RT and field arrangements, particularly in patients with complete pathologic responses Trials currently under development will hopefully help to answer some ot these issues

37 Thank you Bruce G. Haffty, MD