03/14/2019. Postmastectomy radiotherapy; the meta-analyses, and the paradigm change to altered fractionation Mark Trombetta M.D.

Transcription

1 radiotherapy; the meta-analyses, and the paradigm change to altered fractionation Mark Trombetta M.D. Division of Radiation Oncology Allegheny Health Network Cancer Institute Professor of Radiation Oncology Drexel University College of Medicine 1 Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update JCO Abram Recht, Elizabeth A. Comen, Richard E. Fine, Gini F. Fleming, Patricia H. Hardenbergh, Alice Y. Ho, Clifford A. Hudis, E. Shelley Hwang, Jeffrey J. Kirshner, Monica Morrow, Kilian E. Salerno, George W. Sledge Jr, Lawrence J. Solin, Patricia A. Spears, Timothy J. Whelan, Mark R. Somerfield, and Stephen B. Edge Recommendations: Summary of Findings The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancers with one to three positive axillary nodes. 3 1

2 Recommendations: Summary of Findings However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. 4 Recommendations: Summary of Findings The panel agreed that clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer specific mortality, and/or increase risk of complications resulting from PMRT. 5 Recommendations: Summary of Findings Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes**** and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast. 6 2

3 History of ASCO recommendations - EBCTCG 2014 meta-analysis 22 trials 8135 women 3786 had Ax diss Lv I and II; 10 + nodes 7 History of ASCO recommendations - EBCTCG 2014 meta-analysis 1133 pts CTX 1-3 pos nodes 10yr isolated LRR: 21% vs 4.3% (XRT) 8 History of ASCO recommendations - EBCTCG 2014 meta-analysis 20 yr breast ca mort 50% vs 41.5% RR= node + benefits = multiple node benefits median F/U= 9.4 yrs (most not evaluable at 20) 9 3

4 History of ASCO recommendations - EBCTCG 2014 meta-analysis Trials were from 70 s and 80 s LRR rates much higher than later series (now most are 10% are lower) 10 History of ASCO recommendations - EBCTCG 2014 meta-analysis More current studies show decreasing tumor size; a smaller number of positive nodes; Larger number of resected nodes (10) (more complete dissections); better CTX (Adriamycin; Taxanes; Traz); less TMX; growth factors; AI s; 11 ASCO PANEL To provide recommendations for the use of PMRT in patients with T1 and T2 tumors (<5 cm) and 1-3 involved nodes. 12 4

5 ASCO PANEL FOUR QUESTIONS 13 ASCO PANEL Question 1: Is PMRT indicated in patients with T1-2 tumors with one to three positive axillary lymph nodes who undergo ALND? 14 Question 1: Recommendation 1a. The panel unanimously agreed that the available evidence shows that PMRT reduces the risks of LRF, any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. (type: evidence based; evidence quality: high; strength of recommendation: strong). 15 5

6 Question 1: Recommendation 1a. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. (type: evidence based; evidence quality: intermediate) 16 Question 1: Recommendation 1a. 1. Age > 40 Mitigating characteristics 2. Limited life expectancy because of older age or comorbidities 3. Pathologic findings associated with lower tumor burden (eg, T1 tumor size, absence of lymphovascular invasion, presence of only a single positive node and/or small size of nodal metastases: Substantial response to NAST) 4. Biologic characteristics of the cancer associated with better outcomes and survival and/or greater effectiveness of systemic therapy (eg, low tumor grade or strong hormonal sensitivity; (Type: informal consensus; evidence quality intermediate; strength of recommendation: moderate). 17 Question 1: Recommendation 1b. The decision to use PMRT should be made in a multidisciplinary fashion through discussion among providers from all treating disciplines early in a patient s treatment Course (type: informal consensus; evidence quality: insufficient; strength of recommendation: strong). 18 6

7 Question 1: Recommendation 1c. Decision making must fully involve the patient, whose values as to what constitutes sufficient benefit and how to weigh the risk of complications (type: informal consensus; evidence quality: insufficient; strength of recommendation: strong) 19 ASCO PANEL Question 2: Is PMRT indicated in patients with T1-2 tumors and a positive SNB who do not undergo completion ALND? 20 Question 2: In such cases where clinicians and patients elect to omit axillary dissection, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know that additional axillary nodes are involved (type: informal consensus; evidence quality: weak; strength of recommendation: moderate) 21 7

8 Question 2: It is not clear whether the clinical implications of positive nodes found on SNB are the same as those for patients undergoing ALND, because the extent of surgery is smaller, and there is a substantial chance of additional positive nonsentinel nodes remaining in the patient treated with SNB alone 22 Question 2: ACOSOG Z pts SNB + (1-2 nodes pos; micro or macro) ALND versus Not BCT with XRT 6.3 y mean No diff LRR or OS Did not reach SS Some protocol violations occurred 23 Question 2: IBCSG pts SNB + (1-2 nodes pos; micro only) ALND versus Not BCT with XRT but 84 had mastectomy 5 y mean No diff LRR or OS * 42 pts had no XRT post mastectomy or ALND 24 8

9 Question 2: IBCSG INTERPRETATION: Question 2: IBCSG Axillary dissection could be avoided in patients with early breast cancer and limited sentinelnode involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. 26 Question 2: EORTC (AMAROS) 1525 pts SNB + (1-2 nodes pos; micro or macro) ALND versus Not BCT with XRT but 18% had mastectomy 1/3 chest wall XRT 6.1 y mean No diff LRR or OS 27 9

10 Question 2: The panel agreed that it is inappropriate to subject patients to the potential acute and long-term toxicities of PMRT (including rare but potentially fatal second cancers and cardiac events) without careful consideration of whether these are justified compared with the potential toxicities of ALND. 28 ASCO PANEL Question 3: Is PMRT indicated in patients presenting with clinical stage I or II cancers who have received NAST? 29 Question 3: Patients with axillary nodal involvement that persists after NAST (eg, less than a complete pathologic response) should receive PMRT

11 Question 3: Observational data suggest a low risk of locoregional recurrence for patients who have clinically negative nodes and receive NAST or who have a complete pathologic response in the lymph nodes with NAST 31 Question 3: However, there is currently insufficient evidence to recommend whether PMRT should be administered or can be routinely omitted in these groups. The panel recommends entering eligible patients in clinical trials that examine this question (ie; B- 51) (type: informal consensus; evidence quality: low; strength of recommendation: weak) 32 Question 3: NRG 9353 trial (NSABP B-51) Schema 1. Biopsy + axillary nodes which convert to path neg 2. Mastectomy or breast-conserving surgery to either no irradiation or PMRT including the chest wall or reconstructed breast and RNI (if they undergo mastectomy) 3. Breast irradiation or breast plus RNI (if they undergo breast-conserving surgery) 33 11

12 Question 3: Alliance for Clinical Trials in Oncology A Sister Trial Patients with a positive SNB after chemotherapy ALND or axillary radiation therapy without additional surgery 34 ASCO PANEL Question 4: Should RNI include the internal mammary (IM) and/or supraclavicular-axillary apical nodes when PMRT is used in patients with T1-2 tumors with one to three positive axillary nodes? 35 Question 4: The panel recommends treatment generally be administered to both the IMNs and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast when PMRT is used for patients with positive axillary lymph nodes Them (type: informal consensus; evidence quality: intermediate; strength of recommendation: moderate) 36 12

13 Question 4: The minimum mandatory target volumes for PMRT that were agreed upon by the panel are the chest wall and supraclavicular/axillary apical nodes 37 Question 4: The panel also deemed it necessary to discuss the issue of RNI in patients with one to three positive nodes in view of the recent publications 1. French 2. Canadian 3. European 4. Danish (retrospective) 38 Question 4: All found 1%to 5%reductions in rates of relapse and breast cancer specific and overall mortalities in patients receiving more extensive irradiation. Only two were statistically significant (OS) EORTC and Danish(retro) 39 13

14 Question 4: French study was the only study developed to address the question of IM nodes (not statistically significant) Multiple NSABP and other studies IM failure rate alone <1% 40 Question 4: The consensus of the panel, on the basis of the EBCTCG meta-analysis and the Canadian and EORTC RNI trials, is that: Both the IMN and supraclavicular-axillary apical areas should generally be treated when PMRT is used (type: informal consensus; evidence quality: intermediate; strength of recommendation: moderate) 41 Question 4: However, certain subgroups may experience limited benefit from such treatment Pulmonary and cardiac morbidities being particular concerns even with improved radiotherapy techniques

15 1. What are the potential radiation related chest wall complications with shortened course radiotherapy (especially reconstructed)? 2. Is hypofractionation safe when treating regional nodal volumes (brachial plexus)? 43 Historic twin trials Three arms: Start A 50 Gy in 25 fx (2.0 Gy/fx) 39 Gy in 13 fx (3.0 Gy/fx) 41.6 Gy in 13 fx (3.2 Gy/fx) 44 Historic twin trials Two arms: Start B 50 Gy in 25 fx (2.0 Gy/fx) Gy in 15 fx (2.67 Gy/fx) 45 15

16 Historic twin trials Almost 5000 women Start A and B Approximately 25% of participants had regional nodal irradiation including the axilla At 10 yrs, only one pt developed plexopathy (Start A) No significant difference in cosmesis, LE, or fibrosis, except in the high dose arm of the Start A Trial 46 RT CHARM: PHASE III RANDOMIZED TRIAL OF HYPOFRACTIONATED POST MASTECTOMY RADIATION WITH BREAST RECONSTRUCTION 47 Pathologic stage T0 T1 N1-2a, T3 N0-2a All M0 status

17 Mastectomy with nodal evaluation/dissection +/- adjuvant chemotherapy *planned breast reconstruction 49 ARM1: Conventional PMRT 50Gy/2Gy Chest wall and/or reconstructed breast with 50Gy/2Gy to regional nodes* over 5-6 weeks. 50 ARM1: Hypofractionated PMRT 42.56Gy/2.66Gy to Chest wall and/or reconstructed breast with 42.56Gy/2.66Gy to regional nodes* over 3-4 weeks

18 Regional Nodes will include: Axilla (Levels I, II, III), supraclavicular fossa and IM nodes. If an axillary dissection has been performed, RT will only be directed to the un-dissected axilla. 52 Patients will be stratified before randomization for immediate versus delayed and autologous versus implant only reconstruction. All reconstruction must be completed before radiation to be classified as immediate and autologous reconstruction is autologous tissue +/- implant. 53 All patients will undergo reconstruction of the breast; either before or after radiation, but it must be completed within 18 months after finishing radiation

19 Primary Objective: To evaluate whether the reconstruction complication rate at 24 months post radiation is non-inferior with hypofractionation. 55 Secondary Objectives 1. To evaluate the incidence of acute and late radiation complications based on CTCAE 4.0 toxicity. 2. To evaluate the local and local regional recurrence rate. 3. To compare reconstruction complication rates based on reconstruction method (autologous +/- implant vs implant only) and timing of reconstruction received (immediate vs. intent for delayed). 56 Questions? 57 19