The Management of Breast Cancer 2015 ASTRO Spring Refresher

Transcription

1 The Management of Breast Cancer 2015 ASTRO Spring Refresher Gary M. Freedman, M.D. Associate Professor

2 Disclosure I have no conflicts of interest to disclose. 2

3 Learning Objectives Apply knowledge of randomized prospective trials to guide the selection process for radiation in early stage breast cancer. Be able to predict based upon current studies whether a patient is low, intermediate or high risk for local or regional recurrence without radiation. Determine through enhanced knowledge of the evidence based indications optimal patient selection for radiation treatment to regional lymphatics, hypofractionation or accelerated partial breast irradiation approaches. 3

4 Introduction Local Therapy and Survival in Breast Cancer

5 Models of Breast Cancer Halstedian s A local-regional disease Justification for more radical surgery / radiation Fisher s A systemic disease Justification for less radical surgery / radiation but more systemic therapy 5

6 NSABP B-04 3 Levels of Axillary Treatment (including regional node RT) No differences in survival Fisher et al NEJM 347: ;

7 NSABP B-06 3 Levels of Breast Treatment RT recommended for breast conservation not survival Fisher et al N Engl J Med 2002; 347:

8 CS + RT: Equal Survival as Mastectomy NCI Consensus Conference June 1990 Breast conservation treatment is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival rates equivalent to those of total mastectomy and axillary dissection while preserving the breast. Final nail in the Halstedian coffin There was an unstated assumption that mastectomy local control is probably better. JAMA 265: 391-5;

9 In the year 1990 If local control does not affect survival Does the patient selection for breast conservation, or the quality of the surgery or radiation matter? WHY GIVE PMRT? JUST LOCAL CONTROL FOR LOCALLY ADVANCED OR INFLAMMATORY CASES? WHY CARE ABOUT LUMPECTOMY MARGINS? 9

10 Spectrum Model 1990 s - Present Local-regional treatment will have an impact on survival in some patients Justification for careful patient selection and techniques for both breast conservation and postmastectomy radiation. 10

11 The Spectrum Model T I M E Not every local recurrence prevented improves survival but some do. Primary Treatment No Failure RT Local Failure Prevent This! Local and Distant Failure RT Distant Failure Alive Distant Failure Dead (Early) Dead (Late) 11

12 PMRT 1 st failures are not the whole story MRM ± radiation Node positive patients after 15 years No chemotherapy/endocrine therapy No XRT XRT Difference First Failure Local Failure 37% 10% - 27% Distant Metastases 34% 43% + 9% Total Failure Local Failure 56% 19% Distant Metastases 72% 54% - 18% Death 70% 61% - 9% Arriagada et al. JCO 13:

13 Early Breast Cancer Trialists Collaborative Group Message: Survival benefit is a result of the local-regional control benefit. 1 / 4 Ratio: One death from breast cancer avoided for every four LR recurrences avoided. Lancet 2005; 366:

14 Local Control Benefit Predicts the Late Survival Benefit No LC No Surv Big LC Big Surv EBCTCG Lancet 383: ;

15 T1-T2 Invasive Breast Cancer

16 BCT absolute contraindications Multicentric disease (tumors in more than one quadrant) Multifocal permitted if resected by single incision Diffuse or suspicious microcalcifications Persistently positive margins despite multiple re-excisions Unless an anatomic boundary Previous breast or chest RT Pregnancy Collagen vascular disease Scleroderma Active lupus? Not RA 16

17 BCT relative contraindications Ratio of tumor size to breast unacceptable for good cosmetic outcome T3 Neoadjuvant chemo may be attempted to convert the patient to a candidate for BCT Neoadjuvant chemo may be attempted to convert the patient to a candidate for BCT Subareolar location Patients may choose to sacrifice nipple BRCA 1/2 Survival outcomes with mastectomy equal Patients may accept high rate of new primaries 17

18 MRI: A Coin Flip? Affect of MRI on clinical management 22% affected management Examples - MRI-prompted mastectomy or additional biopsy Almost equal chance of help or harm Can you prove favorable effects were all really improving outcome? How do you know an add l focus would be source of LR? Tillman et al J Clin Oncol 20: ;

19 Meta-Analysis of MRI 9 studies 3,112 patients Increase in mastectomy No reduction in positive margins, re-excisions Houssami et al Ann Surg 2013;257:

20 Meta-Analysis of MRI 4 studies 3,169 patients 8-yr LR-free survival 97% vs. 95% HR MRI vs. No MRI 0.88 ( ) p=0.65 Houssami et al J Clin Oncol 2014;32:

21 BCS + RT Invasive Breast Cancer Factors associated with local recurrence Higher Positive margin Young age Subtype Lower Boost Systemic Therapy 21

22 Margins Meta-Analysis and Consensus Tumor on ink = positive margin Overall median rate of IBTR 5.3%. Makes non-significant differences in 1, 2 and 5 mm not clinically significant either. Moran et al Int J Radiat Oncol Biol Phys 88: ;

23 Re-excision of Margins American College of Radiology Invasive Breast Cancer A re-excision should be performed for an involved margin. Wider margins may be more important in select patients (young, estrogen receptor negative, or extensive intraductal component). American Society of Breast Surgeons Margin 1 mm usually adequate Consider re-excision for focally positive or < 1mm margins on a case-by-case basis. Re-excision usually needed for a positive margin. American Society of Clinical Oncology Endorses adoption of the SSO/ASTRO Guideline but flexibility in the application of the guideline is needed in some areas. Heightened emphasis needed on the importance of postlumpectomy mammography for cases involving microcalcifications. National Comprehensive Cancer Network A positive margin should generally undergo further surgery. Exceptions may be made for selected cases of focally positive margin and absence of extensive intraductal component. Society of Surgical Oncology / American Society for Radiation Oncology A positive margin should be defined as no tumor on ink. Negative margins are optimal for local control in most situations. Wider margins than no tumor on ink are not routine indications for further surgery. 23

24 Local Recurrence By Age - Then Bartelink et al J Clin Oncol 25: ;

25 Young Age Now Today the age effect is much diminished Selection Factors: BRCA, Imaging Treatment Factos: Margins, Systemic Therapy, Boost Arvold et al J Clin Oncol 29: ;

26 BCS + RT by Subtype Hattangadi-Gluth et al Int J Radiat Oncol Biol Phys 82: ;

27 Young Age Biology Adjusting for biology now the age effect is much diminished Margins not significant? Predictor AHR 95% CI P Age, years to BC subtype Luminal A 1 (reference) Luminal B to Luminal HER to HER to Triple negative to No. of positive nodes to Tumor size, cm to WB dose, Gy to Arvold et al J Clin Oncol 29: ;

28 Young Age Biology Adjusting for biology now the age effect is much diminished Demerci et al Int J Radiat Oncol Biol Phys 83: ;

29 Survival is equal But is it still the case that local control is better with Mastectomy versus BCS + RT? LOCAL CONTROL TODAY 29

30 BCS + RT: Node Positive NSABP BCS + Whole Breast Radiation. No Boost. Wapnir et al J Clin Oncol 2006; 24:

31 BCS + Hypofractionated Radiation UK START B Haviland et al Lancet Oncol 2014; 14:

32 BCS + RT: Margins Meta-Analysis Overall median rate of IBTR 5.3%. Includes positive close margins, low systemic therapy utilization in older studies. Houssami et al Ann Surg Oncol 21: ;

33 BCS + RT vs. Mastectomy T1-2 N0 triple negative Abdulkarim et al J Clin Oncol 29: ;

34 BCS + RT vs. Mastectomy T1-2 N0 triple negative Zumsteg et al Ann Surg Oncol 20: ;

35 Are there any subgroups of patients with T1 for whom we can safely omit adjuvant radiation?

36 Local Control Benefit Predicts the Late Survival Benefit EBCTCG Lancet 378:771-84;

37 EBCTCG BCS +/- RT No subgroup without a benefit from RT 37

38 CALGB 10 years local recurrence 10% vs. 2% 21 of 334 deaths from breast cancer (6%). Cause-specific survival 98-99%. Hughes et al J Clin Oncol 31:2382-7;

39 PRIME II Age 65 or older Hormone-positive Low-grade Node negative 5-year IBTR 4.1% vs. 1.3% San Antonio

40 Are there any subgroups of patients with T1 for whom we can safely omit adjuvant radiation? Older (>70) or reduced life expectancy T1 N0 (doesn t have to be pn0 always) ER or PR + Margin Willing / able to take 5 years endocrine therapy Willing to accept modest higher local recurrence

41 Shortening Postlumpectomy Radiation

42 Modern Trials Pre 2002! WHOLE BREAST HYPOFRACTIONATION RESULTS 42

43 Phase III Trials of Whole Breast Hypofractionation Years Fractionation Boost Local Time Trial Conducted # Gy/# of fractions (%) Recurrence (%) Point RMH/GOC / years / / START A / Years / / START B / Years / OCOG / Years / RMH/GOC: Royal Marsden Hospital, Sutton and Gloucestershire Oncology Centre START: Standardization of Breast Radiotherapy OCOG: Ontario Clinical Oncology Group 43

44 OCOG Randomized Trial 42.5 Gy 50 Gy Cosmesis gd/exc 70% 71% Whelan et al N Engl J Med Whelan et al 362:513-20; N Engl J Med 362:513-20;

45 UK START A/B Cosmetic Outcomes Haviland et al Lancet Oncol 2014; 14:

46 ASTRO Consensus Conference Hypofractionated WBI was suitable outside of a clinical trial in the following patients: pt1-2 tumor size node negative age greater than 50 years old patients who do not receive chemotherapy. My Guidelines DCIS or invasive Node positive or node negative Any age Any chemo Sequential boost allowed 42.5 in 16 fractions recommended for WBI Avoid hypofractionation for Large dose inhomogeneity Regional node irradiation The task force did not reach consensus on hypofractionated WBI when a tumor bed boost was thought to be indicated. Smith et al Int J Radiat Oncol Biol Phys

47 2D Planning s Wedged Tangent Central axis contour. Goal of 10% or lower dose inhomogeneity. Off-axis inhomogeneity even higher. Chest Wall/Lung Prescription Point 47

48 2000 s - Simple Forward Planning Basic segments over hot spots in beams eye views CTV/PTV not needed Vicini et al Int J Radiat Oncol Biol Phys 2002; 54:

49 Modern Volume-Based 3D Planning PTV and PTVeval Structures 49

50 Volume Based Forward Planning 3D Conformal Field in Field Forward Planning 50

51 Volume Based Inverse Planning IMRT Inverse Planning Sliding Window 51

52 Isodose Distribution Same DVH Goals for 3D or IMRT: PTVeval 95% > 95% V105 < 10% V110 = 0% 52

53 RTOG 1005 A PHASE III TRIAL OF ACCELERATED WHOLE BREAST IRRADIATION WITH HYPOFRACTIONATION PLUS CONCURRENT BOOST VERSUS STANDARD WHOLE BREAST IRRADIATION PLUS SEQUENTIAL BOOST FOR EARLY-STAGE BREAST CANCER Stratify Age < 50 vs. 50 Chemotherapy Yes/No ER positive/negative Histologic Grade 1, 2 vs. 3 5/24/2011 6/20/2014 Targeted Accrual 2312 R A N D O M I Z E ARM 1: Standard fractionation Whole Breast 50 Gy / 25 fractions / 2.0 Gy daily Optional fractionation of 42.7 Gy in 16 fractions permissible Sequential Boost 12 Gy /6 fractions /2.0 Gy daily or 14.0 Gy /7 fractions /2 Gy daily ARM 2: Hypofractionation (15 fractions total) Whole Breast 40 Gy/15 fractions/2.67 Gy daily Concurrent boost 48.0 Gy/3.2 Gy daily 53

54 Accelerated Partial Breast Irradiation APBI 54

55 Intracavitary Balloon Catheter Radiation Simplest dosimetry. Treats 1-2 cm around lumpectomy cavity. Less operator skill dependent. Watch for tissue conformance skin distance Arthur and Vicini J Clin Oncol 23: ; RTOG / NSABP B-39 55

56 MammoSite Registry 1,449 cases Local recurrence Shah et al Ann Surg Oncol 20: ;

57 Complications in Catheter APBI Device removal Catheter leak Catheter rupture Infection Seroma Skin toxicity Fat Necrosis Fibrosis Telangiectasia 57

58 3D Conformal External Beam 38.5 Gy in 10 fractions BID for 5 days. Noninvasive. Better dose homogeneity than brachytherapy. Needs greater margin for set-up and motion. Vicini et al Int J Radiat Oncol Biol Phys 63: ;

59 Results of 3D Conformal APBI Vera et al Practical Rad Onc 4:147-52;

60 RAPID: Randomized Trial of Accelerated Partial Breast Irradiation Age 40 or older DCIS, T1 or T2 < 3 cm Negative Margin Non-lobular Whole Breast: 42.5 Gy / 16 fx 50 Gy / 25 fx Boost allowed Versus APBI: 38.5 Gy / 10 fx BID 3D CRT only Olivotto et al J Clin Oncol 31: ;

61 Multicatheter Interstitial Brachytherapy Importance of Technique Operator Dependent Volume as low as possible Minimize hot spots Dose uniformity must be high Watch skin and chest wall dose DHI = Dose Homogeneity Index Wazer et al Int J Radiat Oncol Biol Phys 64: ;

62 National Institute of Oncology Budapest, Hungary Randomized Trial Arm I: External Beam Whole Breast RT 2 Gy x 25 fractions Arm II: APBI Interstitial 5.2 Gy x 7 fx Electrons 2 Gy x 25 fx Selection Criteria T1 N0 N1mic Grade 1-2 Nonlobular No extensive in-situ Polgár Int J Radiat Oncol Biol Phys 69: ;

63 ASTRO Consensus Statement APBI Smith et al J Am Coll Surg 209: ;

64 Results of 3D Conformal APBI Caution needed in patient selection Pashtan et al Int J Radiat Oncol Biol Phys 84:e271-7;

65 NSABP B-39 / RTOG

66 APBI Nonrandomized Results SEER subsequent mastectomy risk Local control close enough for most patients? Smith G et al. Int J Radiat Oncol Biol Phys 88:274-84;

67 DCIS

68 Breast-Conserving Surgery How do you assess the completeness of an excision? Margins Specimen radiograph Post-excision pre-irradiation mammogram (PPM) 68

69 DCIS: Breast-Conserving Surgery + RT Factors associated with local recurrence Higher Younger age Mode of detection Positive margin Large size / volume excised Diffuse calcifications Lower Radiation Tamoxifen Boost 69

70 DCIS: Consistent Benefit to BCT + RT EBCTCG Local recurrence reduced regardless of: Age at diagnosis Extent of surgery Use of tamoxifen Method of detection Margin status Grade Comedonecrosis Architecture Tumor size J Natl Cancer Inst Monogr 2010;2010:

71 DCIS: Young Age - CS + XRT Solin Int J Radiat Oncol Biol Phys 50: 991;

72 DCIS: Margins - CS + XRT Solin Int J Radiat Oncol Biol Phys 50: 991;

73 DCIS: Margin Meta-analysis 4,660 patients treated with BCT+RT. Negative margins superior to positive margins (OR=0.36; 95% CI, ) Negative margins superior to close margins (OR=0.59; 95% CI, ) > 2 mm margins superior to <2 mm (OR 0.53, 95% CI ) No difference in > 2 mm compared to > 5mm Dunn et al J Clin Oncol

74 DCIS: Radiation +/-Tamoxifen A. Invasive Ipsilateral Recurrence B. DCIS Ipsilateral Recurrence Wapnir et al. J Natl Cancer Inst

75 DCIS: Boost vs. No Boost vs. No XRT Omlin et al Lancet Oncology 1-5;

76 Are there any subgroups of patients with DCIS for whom we can safely omit adjuvant radiation?

77 Breast-Conserving Surgery No RT Factors associated with local recurrence Higher Younger age Grade Necrosis Mode of detection Positive margin Diffuse calcifications Lower Tamoxifen 77

78 Van Nuys Index Silverstein and Lagios. J Natl Cancer Inst Monogr 2010; 41:

79 Harvard Study Prospective single arm study from May 1995 July 2002 Eligibility: DCIS of nuclear grade 1 or 2, necrosis noted but not excluded Mammogram or clinical exam with lesion 2.5cm Wide excision with final margins 1cm OR negative re-excision Radiologic confirmation that all calcifications were removed Exclusion criteria No Tamoxifen Wong et al, JCO 2006 (24: ). 79

80 ECOG E5194 Low/Int Grade (n=565) High Grade (n=105) 18% 10.5% DCIS nuclear grade 1 or 2, with lesion 2.5 cm -OR- DCIS nuclear grade 3, with lesion 1 cm Wide excision with final margins 3 mm OR negative re-excision Radiologic confirmation that all calcifications were removed Hughes et al, JCO 2009 (27: ). 80

81 RTOG Good Risk DCIS Prospective randomized trial Eligibility Mammographically detected disease Low or intermediate nuclear grade <2.5 cm size Margins 3 mm. 62% had Tam - no impact on LR Median follow-up (F/U) time was 6.46 years. 7 years Local recurrence 1% RT vs. 6% No RT (p=0.0023, HR [95%CI] = 0.14 [0.03, 0.61]). McCormick et al J Clin Oncol 30,

82 Are there any subgroups of patients with DCIS for whom we can safely omit adjuvant radiation? Older (>60) or reduced life expectancy Low-Int grade no or mimimal necrosis ER or PR + Margin (at least 3 mm 1 cm + optimal) +/- endocrine therapy Willing to accept modest higher local recurrence

83 Risk factors for local-regional recurrence after mastectomy Indications for Postmastectomy Radiation

84 Case 1 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N2 3 cm invasive ductal carcinoma 5 of 15 positive lymph nodes No lymphovascular invasion Margins negative High Risk Features For Local-Regional Recurrence 4 positive axillary nodes 84

85 National Comprehensive Cancer Center 85

86 ACR Appropriateness Criteria High Risk for Local-Regional Recurrence 86

87 Early Breast Cancer Trialists Collaborative Group High Risk for LRR 4 positive nodes EBCTCG Lancet 383: ;

88 Case 2 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N0 3 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins negative Low Risk Features For Local-Regional Recurrence T1-2 Tumor Size 0 positive axillary nodes 6 nodes dissected Margins negative 88

89 National Comprehensive Cancer Center 89

90 ACR Appropriateness Criteria Low Risk for Local-Regional Recurrence 90

91 Early Breast Cancer Trialists Collaborative Group Low Risk for LRR 0 positive nodes EBCTCG Lancet 383: ;

92 Case 3 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N1 3 cm invasive ductal carcinoma 2 of 15 positive lymph nodes No lymphovascular invasion Margins negative Intermediate Risk Features For Local-Regional Recurrence T1-2 Tumor Size 1-3 positive axillary nodes 6 nodes dissected 92

93 National Comprehensive Cancer Center 93

94 ACR Appropriateness Criteria Intermediate Risk for Local-Regional Recurrence 94

95 Early Breast Cancer Trialists Collaborative Group Intermediate Risk for LRR EBCTCG Lancet 383: ;

96 Mastectomy N 1-3+ Breast Cancer ECOG 10-year Isolated 1-3 Nodes (# pts) 4-7 Nodes (# pts) 8 + Nodes (# pts) LRR (%) T1 9 (407) 11 (180) 20 (110) T2 7 (576) 17 (349) 20 (297) T3 23 (35) 29 (33) 7 (29) Recht et al J Clin Oncol 1999;17:

97 Mastectomy N 1-3+ Breast Cancer NSABP # Isol LRR LRR+/-DF ,045 6% 11% ,489 10% 15% > % 11% % 20% % 24% > % 31% % 26% % 33% > % 34% Taghian et al J Clin Oncol 2004;22:

98 Mastectomy N 1-3+ Breast Cancer MDACC T1 T2 T Katz et al J Clin Oncol 18: ;

99 Mastectomy N+ Breast Cancer MDACC Importance of 20% positive nodes Katz et al Int J Radiat Oncol Biol Phys 2001; 50:

100 Mastectomy N 1-3+ Breast Cancer low risk? Cleveland Clinic 1-3 positive nodes Tendulkar et al Int J Radiat Oncol Biol Phys 2012; 83:e

101 Microscopic Extranodal Extension International Breast Cancer Study Group ECE not significant for local-regional recurrence when number of positive of nodes included in analysis Gruber et al J Clin Oncol 2005; 23:

102 Mastectomy N 1-3+ Breast Cancer low risk? MD Anderson T1-2, 1-3 positive nodes Early era ( ) vs. later era ( ) Early era 5-year 9.5% without PMRT and 3.4% with PMRT Late era 5-year 2.8% without PMRT and 4.2% with PMRT McBride et al Int J Radiat Oncol Biol Phys 89:392-8;

103 Young Age NSABP Node Positive Breast Cancer Age # Isol LRR LRR+/-DF % 26% % 21% % 17% % 14% p=0.13 p< Significant on Multivariate Analysis Taghian et al J Clin Oncol 2004;22:

104 Lymphovascular Invasion& Positive Nodes Matsunuma et al Int J Radiat Oncol Biol Phys 2012;83:

105 Case 4 45 year old woman Clinical T3N0 Left Breast 6 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T3N0 6 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins negative Risk of Local-Regional Recurrence Various Data T3 Tumor Size 0 positive axillary nodes 6 nodes dissected No Lymphovascular Invasion Negative Margin No Very Young Age 105

106 National Comprehensive Cancer Center 106

107 Mastectomy for T3N0 Breast Cancer NSABP Isolated LRF 7% Taghian J Clin Oncol 2006;24:

108 Mastectomy for T3N0 Breast Cancer MGH, Harvard, MD Anderson, Yale Importance of LVI 21% 7.6% Floyd et al Int J Radiat Oncol Biol Phys 2006;66:

109 ACR Appropriateness Criteria Risk for Local-Regional Recurrence? 109

110 Case 5 45 year old woman Clinical T2N0 Left Breast 3 cm tumor size Clinically node negative Core biopsy positive invasive ductal carcinoma ER/PR positive, Her-2 negative Modified radical mastectomy Pathologic T2N0 3 cm invasive ductal carcinoma 0 of 15 positive lymph nodes No lymphovascular invasion Margins positive Intermediate Risk Features For Local-Regional Recurrence T1-2 Tumor Size 0 positive axillary nodes 6 nodes dissected Positive Margins 110

111 National Comprehensive Cancer Center 111

112 Close/Positive Margins MGH, Harvard Node negative women Jagsi et al Int J Radiat Oncol Biol Phys 2005; 62:

113 Close/Positive Margins Brigham & Women s Hospital and Dana-Farber Positive margin + LVI = 27% + grade 3 = 13% + triple - = 33% Childs et al Int J Radiat Oncol Biol Phys 84:1133-8;

114 ACR Appropriateness Criteria Intermediate Risk for Local-Regional Recurrence 114

115 Indications for PMRT 4 positive axillary lymph nodes T3 node positive tumors T4 1-3 positive axillary nodes T3 node negative tumors Limited / no axillary dissection Close / positive margins Lymphovascular invasion High grade Young Age Gross ECE Triple Negative? Multicentric disease? T1-2 Node Negative Margin Negative High Risk Definitely RT Often RT but not always Intermediate Risk Sometimes RT for 2-3 factors but not always Low Risk No RT 115

116 Molecular subtype A Reason for PMRT? T1-2 N0 Truong et al Int J Radiat Oncol Biol Phys 88: 57-64;

117 Regional nodal radiation therapy

118 S Clav and Axilla LEVEL I/II DISSECTION 118

119 Supraclav and Axilla RT 1980 to 2000 Level I-II Dissection (6+ nodes) N- Breast Only Chest Wall Only (T3, Margin + cases) N+ 1-3 Breast Only (except >20-40%+? S clav) CW + S clav 4+ Breast/CW + S clav No Low Axilla Consider for gross ECE or >40-50% node ratio + 119

120 Classic Supraclavicular Field Meant to cover undissected Level III (infraclav) and S clav Madu et al Radiology 221:333-9;

121 Mastectomy: Axillary Treatment NSABP B04 Axillary RT not needed if 6+ nodes removed Fisher et al Surg Gyn Obstet 1981;152:

122 Mastectomy: S clav and Axillary Treatment Strom et al Int J Radiat Oncol Biol Phys 63: ;

123 BCS + RT: Node Positive NSABP BCS + Whole Breast RT. 2/ nodes, 1/3 4 or more + nodes. No Regional RT. Wapnir et al J Clin Oncol 2006; 24:

124 BCS + RT: Node Positive Regional node recurrence rare for N0-3 with breast RT alone. Vicini et al Int J Radiat Oncol Biol Phys 1997; 39:

125 BCS + RT: Node Positive BCS + Whole Breast Radiation. No Regional Radiation. Isolated regional node recurrences at 8 years: S clav 1.3%, axilla 1.2%, infraclav 0.4% and IMN 0.3% Galper et al Int J Radiat Oncol Biol Phys 1999; 45:

126 BCS + RT: Node Positive Consider axillary RT for >40-50% node ratio? Consider s clav RT for and >40% node ratio? Fortin et al Int J Radiat Oncol Biol Phys 2006; 65:

127 S Clav and Axilla NO DISSECTION 127

128 Supraclav and Axilla RT 1980 to 2000 No Dissection or Incomplete Dissection ( 5) S clav and Full Axilla 128

129 Dissection or Radiation NSABP B clinically node negative patients RM TM+ XRT TM Node Positive 40%?? 1st Failure LR 10% 5% 15% Axillary 1% 3% 1% (18%) Distant 30% 31% 32% 129

130 Dissection or Radiation All lumpectomy + Breast Radiation Age < 70, 3 cm size or less, cn0 Level I/II axillary dissection N + received RT to s clav, IMN N received RT IMN if central / medial No Dissection RT included IMN and axilla Louis-Sylvestre et al J Clin Oncol 22: ;

131 Supraclav and Axilla RT 2000 to Present No Dissection Average patient should have had axillary assessment but didn t for some reason. S clav and Low Axilla Older, favorable patient High tangents Only 131

132 BCS + RT: Undissected Axilla Wong 2008 BCS + Whole Breast Radiation. No Axillary Surgery. No Regional Radiation. No Local-regional Recurrences. Wong et al Int J Radiat Oncol Biol Phys 2008; 72:

133 No Axillary Dissection Older Women IBCSG Women 60, cn0, ER + Surgery + Axillary clearance + Tam vs. Surgery + Tam J Clin Oncol 24: ;

134 BCS + RT: Undissected Axilla CALGB 70 T1 Axillary node dissection was allowed but not encouraged. 1/3 pn0, 2/3 cn0 RT to whole breast and level I/II nodes Hughes et al J Clin Oncol 31:2382-7;

135 BCS + RT: Incomplete Dissection Regional node recurrence rare for N0-3 with breast RT alone. Vicini et al Int J Radiat Oncol Biol Phys 1997; 39:

136 No or Incomplete Dissection PreSentinel Node Galper et al Int J Radiat Oncol Biol Phys 48:125-32;

137 Sentinel Node Biopsy Sentinel Node Biopsy pre-2000 N0 - Treat like a negative level I/II dissection N+ - Complete the dissection OR treat like an incomplete dissection (Treat the s clav and low axilla). 137

138 Sentinel Node Biopsy - Positive Sentinel Node Biopsy Resistance to completion dissection Era of the Nomogram If nomogram suggests low risk for additional + nodes then may omit s clav and axilla Number of + SN Size of + SN / micromet Number of SN LVI T size Histology Etc. Etc. 138

139 BCS + RT: Sentinel Node Positive ACSOG Z patients with positive SNB Clinical T1/T2, Clinical N0 H&E detected metastases in 1-2 nodes No ECE Breast tangents only Additional nodal metastases in 27% of patients having completion node dissection. 98% Systemic Therapy (58% chemo) Local-regional recurrence 3.3% without completion dissection 4.3% with completion dissection P=0.28 Giuliano et al JAMA 2011;305:

140 BCS + RT: Sentinel Node Positive ACSOG Z0011 Breast tangents only? 15% s clav RT 50% high tangents Additional nodal metastases in 27% of patients having completion node dissection. 98% Systemic Therapy (58% chemo) Local-regional recurrence 3.3% without completion dissection 4.3% with completion dissection P=0.28 Jagsi et al J Clin Oncol 32: ;

141 BCS + RT: Sentinel Node Positive IBCSG Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases 931 patients (10% mastectomy) Galimberti et al Lancet Oncol 2013; 14:

142 BCS + RT: Sentinel Node Positive EORTC AMAROS trial Radiotherapy or surgery of the axilla after a positive SN 12% mastectomy All three levels of the axilla together with the medial part of the supraclavicular fossa were considered clinical target volume. The prescribed dose to the axilla was 50 Gy in 25 fractions. Postoperative axillary irradiation in patients undergoing ALND was allowed in patients with four or more tumor-positive nodes (pn2 or pn3). 5-year axillary recurrence rate after a positive SNB was 0.54% (4/744) after ALND 1.03% (7/681) after ART Rutgers et al ASCO

143 Sentinel Node Biopsy Sentinel Node Biopsy post Z0011 N0 - Treat like a negative level I/II dissection N+ - Patient selection / judgment needed Option A: Complete the dissection will it affect systemic therapy? Option B: Treat like an incomplete dissection Treat the s clav and low axilla AMAROS Option C: Treat a high tangent or a normal tangent Z0011 / IBCSG 143

144 IMN 144

145 IMN Treatment Clinical IMN Recurrence is Exceedingly Low Incidence of IMN positivity is Low High in old series of advanced breast cancer Much lower in modern series Randomized Trials of IMN Treatment Negative or <1-2% survival benefit What is the added cost in toxicity of treatment? Cardiac effects 145

146 Clinical IMN Recurrence - Mastectomy Any IMN? Recht et al J Clin Oncol JCO 17: : ; ;

147 Clinical IMN Recurrence - Lumpectomy BCS + Whole Breast Radiation. No Regional Radiation Galper et al Int J Radiat Oncol Biol Phys 1999; 45:

148 Extended Radical Mastectomy Old Data IMN positive (%) Axilla Negative Axilla Positive Series # Inner Central Outer Total Inner Central Outer Total Cáceres Donegan Handley Lacour et al Livingston and Arlen Sugg Urban and Marjani Veronesi et al < 10% 30% 148

149 Sentinel Node Studies Review of 6 prospective studies of SNB and IMN Modern incidence of + IMN is likely <5% Hindie et al Int J Radiat Oncol Biol Phys 83: ;

150 IMN Irradiation Old Negative Studies Radical Mastectomy Radical Mastectomy Series # + IMN irradiation* # Alone Follow-up DM OS DM OS Fisher et al % 56% % 62% 5 years P=NS Høst et al. Stage I % % 15 years P=0.08 Stage II 95 34% 42% 91 50% 44% 15 years P=NS P= years Palmer & Ribeiro Node % % 30 years P=0.13 Node % % 30 years P=0.7 Arriagada 41 51% 59% 31 35% 74% 15 yr crude P=0.22 p=0.29 Veronesi % (DFS) % (DFS) 10 years P=NS * Includes supraclavicular +/- axillary irradiation Includes patients treated with lumpectomy and breast radiation 150

151 Randomized Trial IMN Radiation DBCG-IMN study 3,000 + Node positive Right breast IMN RT Left breast no IMN RT Median follow up of seven years. OS 78% versus 75% in favor of IMN radiotherapy. HR=0.86 (95% CI (0.75; 0.99), p=0.04. Thorsen et al, ESTRO Vienna

152 Randomized Trial IMN Radiation French Study Mastectomy and N + or central/medial tumors. All patients received postoperative irradiation of the chest wall and supraclavicular nodes. Randomly assigned to receive IMN irradiation or not. Hennequin et al Int J Radiat Oncol Biol Phys 86: 860-6;

153 Randomized Trial IMN / Sclav Irradiation NCIC CTG MA with median 62 months follow-up 1832 patients with high risk node negative (T3) or node positive breast cancer Nodes 85% OS 92.3% vs 90.7% (HR.76, p =.07) LR DFS 96.8% vs 94.5% (HR.59, p=.02) DFS 89.7% vs 84 % (HR.68, p =.003) Whelan et al ASCO

154 Randomized Trial IMN / Sclav Irradiation EORTC trial Axillary lymph node involvement and/or a centrally or medially located tumour. 4,004 patients (76% BCT) OS at 10 years was 82.3% with and 80.7% without radiation therapy to the internal mammary and medial supraclavicular lymph nodes (HR=0.87 (95%CI: 0.76, 1.00), Logrank p=0.056). Poortmans et al, ESTRO Vienna

155 IMN / Sclav Irradiation Could all benefit be from the s clav/axillary treatment? Budach et al Radiat Oncol 8: 267;

156 Early Breast Cancer Trialists Collaborative Group Is IMN RT benefit from underestimated incidence that never become apparent local recurrence? Or all from the S clav? IMN benefit in absence of local control doesn t fit the EBCTCG model! Lancet 2005; 366:

157 Radiation after neoadjuvant chemotherapy

158 Mechanism of Increased Breast-Conserving Surgery after Neoadjuvant Chemotherapy Decrease in clinical tumor size. More favorable ratio of tumor to breast size. Post-chemo Volume? Pre-chemo Volume 158

159 NSABP B-18 Breast Conservation Modest increase in breast conservation Modest increase in local recurrence in downstaged patients IBTR (%) as site of 1st treatment failure Postop Preop # Chemo # Chemo p=0.12 Downstaged Lump initially # to lump # proposed p=0.04 Wolmark et al J Natl Cancer Inst Monogr 2001;30:

160 Breast Conservation after Neoadjuvant Chemotherapy NSABP B-18 and B-27?Add a boost Breast-conserving surgery and whole breast radiation No regional nodal radiation Add Sclav RT for ypn+ Mamounas et al J Clin Oncol 2012;30:

161 Neoadjuvant Chemotherapy and Mastectomy MDACC Generally ct3 or pn+ indications for PMRT Buchholtz et al J Clin Oncol 2002;20:

162 Neoadjuvant Chemotherapy and Mastectomy NSABP B-18 and B-27 No postmastectomy radiation RT for pn+?cn+ and ypnneed more data Mamounas et al J Clin Oncol 2012;30:

163 NSABP B-51/RTOG 1304: pn1 to ypn0 163

164 Radiation therapy for inflammatory breast cancer

165 Inflammatory LABC Clinical findings: Rapid onset Edema, redness, skin changes Peau D orange > 1/3 of the breast. Clinical diagnosis of inflammatory BUT pathology is needed! Core biopsy of a node Skin punch biopsy Breast incisional biopsy Dermal lymphatic invasion is not required for diagnosis. Not the same as locally advanced neglected cancer. 165

166 Management of Inflammatory LABC Neoadjuvant Chemotherapy Second Line Chemotherapy if < ccr Preop Radiation if < ccr Modified radical mastectomy Endocrine Therapy (if ER/PR+) Postmastectomy radiation 166

167 Inflammatory LABC Breast Conservation 167

168 Inflammatory LABC PENN CW / Breast 50 Gy Bolus Supraclav in all Axilla in most IMN in few Harris et al Int J Radiat Oncol Biol Phys 2003;55:

169 Inflammatory LABC CW 50 Gy + 10 Gy Boost or 51 Gy BID + 15 Gy Boost MDACC Comprehensive nodal RT Dose escalation for < partial chemotherapy response, close/positive margins, and age < 45 years Bristol et al Int J Radiat Oncol Biol Phys 2008;72:

170 Inflammatory LABC MSKCC CW 5,040 Gy Bolus Daily Damast et al Int J Radiat Oncol Biol Phys 2010;77:

171 The End! Thank you Gary M. Freedman, M.D. Associate Professor