Local Breast Irradiation Controversies Following Neoadjuvant Chemotherapy: Can Radiotherapy Be Downstaged As Well?

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1 Local Breast Irradiation Controversies Following Neoadjuvant Chemotherapy: Can Radiotherapy Be Downstaged As Well? Nancy Wiggers, MD Northside Radiation Oncology Consultants Atlanta, Georgia

2 Approximately 25 years ago, Gilbert Fletcher and Eleanor Montague, two leading experts in breast cancer radiation treatments, wrote, there is, perhaps, no more controversial subject in the management of cancer than the use of postoperative irradiation in conjunction with mastectomy

3 Advantages of Performing Surgery First Reduces the interval between diagnosis and effective treatment for patients with disease that is resistant to chemotherapy Provides clear information concerning the original extent of disease Provides clear prognostic information concerning the risk of recurrence after mastectomy and therefore the indications for using postmastectomy radiation Advantages of Neoadjuvant Chemotherapy May allow breast conservation after effecting a disease response Allows an in vivo assessment of sensitivity to a chemotherapy regimen Allows chemotherapy to be changed if the disease proves resistant Permits an assessment of pathologic disease response, which allows for the further stratification of an individual patient s prognosis Allows direct comparison of different treatment regimens in clinical trials with a short-term study endpoint (pathologic complete response) Allows serial biopsies and images of tumor to be obtained during treatment to gain insight into the molecular mechanisms of tumor sensitivity and resistance

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5 Tools Clinical exam Mammogram US MRI Biopsy PET

6 Clinical Exam In a breast cancer patient with a clinically + axilla, there is a 25% chance that the axilla is negative In a patient with a T1 - T2 breast cancer and a clinically negative axilla, there is a 30% chance of pathologic axillary involvement

7 SLN Biopsy The practice of performing an SLN biopsy prior to neoadjuvant chemotherapy is a focus of debate Presence of axillary disease markedly affects prognosis, recommendations for postmastectomy radiation therapy, and breast reconstruction Assessment of the axilla prior to initiating systemic therapy is preferred, and preoperative axillary staging with ultrasonography and fine-needle aspiration (FNA) or core needle biopsy is being used

8 MRI MRI tumor size correlates with pathology size; however, a significant overestimation exists, particularly for tumors >2.0 cm.

9 PET Pre-chemotherapy 18F-FDG PET/CT upstages nodal stage in stage II-III breast cancer patients treated with neoadjuvant chemotherapy. In a study by Koolen, they found 23% of patients treated with NAC were upstaged to the high-risk group based on PET/CT information, potentially benefiting from regional radiotherapy. Koolen BB, et al. Breast Cancer Res Treat. 2013;141(2):

10 Risk of Local Recurrence Low risk - LRF rate 10% Intermediate risk - LRF rate 11%-19% High risk 20%

11 PMRT (Before There Was Neoadjuvant Chemotherapy) Consensus 4 axillary LN + margins T4 disease Strong Consideration Triple negative >5-cm tumor 1-3 LN Close margin

12 Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy PURPOSE: To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy. Retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospective trials with neoadjuvant chemotherapy, mastectomy, and radiation. These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation. Huang EH, et al. J Clin Oncol. 2004;22(23):

13 Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy Patients with stage II or IV disease who achieved a pcr had LRR benefit from RT- (33% vs 3% at 10-year rates) RT reduced LRR for patients with clinical T3 or T4, stage IIB disease, path tumor size >2 cm, or 4 or more positive nodes Huang EH, et al. J Clin Oncol. 2004;22(23):

14 Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy Huang EH, et al. J Clin Oncol. 2004;22(23):

15 Postmastectomy Radiation Improves Local-Regional Control and Survival for Selected Patients With Locally Advanced Breast Cancer Treated With Neoadjuvant Chemotherapy and Mastectomy Comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV (ipsilateral supraclavicular nodal) disease and for patients with four or more positive nodes. Radiation should be considered for these patients regardless of their response to initial chemotherapy. Huang EH, et al. J Clin Oncol. 2004;22(23):

16 LRR For Patients With Stage II Breast Cancer and One to Three Positive Lymph Nodes Extracapsular extension greater than 2 mm Tumor size over 4 cm Positive or close (2 mm) surgical margins Resection of less than 10 lymph nodes (19%), Lymphovascular space invasion (15%), or invasion of the skin, nipple, or pectoralis muscle (19%) Most important predictor of LRR was a 20% or greater lymph node involvement 10-year LRR 0-1 factors 4%, 2 factors 8%, 3+ factors 28%

17 According to the American Society of Clinical Oncology (ASCO) guidelines on post-mastectomy radiotherapy (PMRT), there is insufficient evidence to make recommendations or suggestions on whether all patients initially treated with preoperative systemic therapy should be given PMRT after surgery. However, ASCO recommended that, in general, patients who require mastectomy after systemic therapy receive PMRT. The rationale for this is based on the inability to accurately know initial pathologic stage, including tumor size and axillary lymph node status. March 2013

18 NSABP B-18 and B-27 Largest prospectively collected cohort of patients with operable breast cancer treated with neoadjuvant chemotherapy Regional radiation was not permitted 335 LRR events after 10 yrs f/u. In mastectomy pts (treated w/o RT), 10-yr cumulative LRR 12.3%. In lumpectomy pts (+RT), LRR 10.3%. Mamounas EP, et al. J Clin Oncol. 2012;30(32):

19 CONSORT Diagram for National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 Trials (T1-3, N0-1, M0) (T1-3, N0-1, M0) 3088 patients Mamounas EP, et al. J Clin Oncol. 2012;30(32):

20 Nomogram to Predict 10-Year Risk of Locoregional Recurrence (LRR) in Patients Treated With Mastectomy After Neoadjuvant Chemotherapy Mamounas EP, et al. J Clin Oncol. 2012;30(32):

21 Nomogram to Predict 10-Year Risk of Locoregional Recurrence (LRR) in Patients Treated With Lumpectomy Plus Breast External Radiotherapy (XRT) After Neoadjuvant Chemotherapy Mamounas EP, et al. J Clin Oncol. 2012;30(32):

22 Recurrence After Neoadjuvant Chemotherapy Without PMRT NSABP Conclusion: "In patients treated with NC, age, clinical tumor characteristics before NC, and pathologic nodal status/breast tumor response after NC can be used to predict risk for LRR and to optimize the use of adjuvant radiotherapy." Mamounas EP, et al. J Clin Oncol. 2012;30(32):

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24 Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, Formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. CONCLUSIONS: In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting.. Fowble BL, et al. Int J Radiat Oncol Biol Phys. 2012;83(2):

25 Nonrandomized Data for Overall Survival A statistically significant survival benefit with PMRT was reported in clinical stage III disease, those with 4 positive nodes or LVI, and in women aged <35 years. Small numbers of patients constituted many of the subgroups. Fowble BL, et al. Int J Radiat Oncol Biol Phys. 2012;83(2):

26 Summary of Risk Categories Suggest that clinical stage II (T1N0-1, T2N0) patients aged >40 years, with ER-positive disease who have a pcr or 0-3 positive axillary nodes without LVI or ECE, have little or no benefit from PMRT. Young patient age, advanced clinical or pathologic stage and triple-negative receptor status, and presence of LVI and/or ECE emerged as high-risk features that should warrant consideration of PMRT after NAC.

27 How Important Is pcr? Postmastectomy radiation therapy provides a significant clinical benefit for breast cancer patients who present with clinical stage III disease and achieve a pcr after neoadjuvant chemotherapy. Residual disease after NAC seems to have a greater implication for outcome for those in whom systemic therapy would have been expected to produce a more favorable response (ie, ER-negative, triple-negative, or HER2-positive disease treated with trastuzumab.) In series from MDACC, clinical stage II TN who had a pcr or neg axillary nodes had a 0%-1% 5-year risk of LRF after mast without RT, whereas those with 1-3 LN had a 37% risk LRF.

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29 Indications for RT - NCCN

30 NCIC CTG MA.20 Whelan TJ, et al. J Clin Oncol. 2011;29(Suppl): Abstract LBA1003.

33 Role Of Regional Lymph Node Irradiation In Patients With Negative Pathologic Node Status After Neoadjuvant Chemotherapy Chest wall and comprehensive nodal radiation were routinely used in the series from MDACC MA.20 suggests improved outcome with comprehensive regional nodal radiation NSABP B-18 and B-27 trials suggest that neoadjuvant chemotherapy leads to complete eradication of disease within lymph nodes in 20% 40% of patients. The rate of regional node failures in these trials for patients undergoing mastectomy without radiation was <5%. Buchholz and colleagues 1 also showed that omission of regional node irradiation in patients who were clinically and pathologically node negative did not result in an increased risk of regional failure or a decreased DFS or OS Buchholz TA, et al. J Clin Oncol. 2002;20(1):17-23.

34 Summary All locally advanced patients will benefit from RT even if pcr Radiation should be recommended on the basis of the initial extent of disease Data suggest that clinical stage II (T1N0-1, T2N0) patients aged >40 years, with ER-positive disease who have a pcr or 0-3 positive axillary nodes without LVI or ECE receive little or no benefit from PMRT.