1. NEW TECHNIQUES IN BREAST RADIOTHERAPY HELLENIC SCHOOL OF MASTOLOGY: 17-18 SEPTEMBER2010, ATHENS XENOPHON VAKALIS RADIATION ONCOLOGIST MEDICAL CENTER OF ATHENS & 401 MILITARY HOSPITAL OF ATHENS

2. Historical Perspective Interstitial Radium Brachytherapy for Breast Cancer, 1917 Radiotherapy for Breast Cancer, London Hospital, c. 1917

3. Prospective Randomized Trials of Lumpectomy +/- Radiotherapy

5. 60 Gy to the lumpectomy cavity + margin

6. 1.8 – 2 Gy fraction given 5 days/ week

10. Image-based Conformal Radiation Therapy: 60 Gy 62 Gy 50 Gy 20 Gy 45 Gy axial sagittal Left Breast

12. Accelerated Whole Breast Irradiation:Reducing the burden of care Canadian Phase III Randomized Trial: 42.5 Gy – 16 fractions – 22 days vs. 50 Gy – 25 fractions – 35 days 1,234 patients - T1 – T2, N 0 (80% T1)- ER positive - 71% - Median F/U: 69 months

13. Randomized Boost Trials

15. Accelerated Whole Breast Irradiation:A Phase II clinical trial of a 4 week course of RT for breast cancer using hypo fractionated IMRT with a concomitant boost. 4 week course – 20 treatments 45 Gy whole breast dose 56 Gy boost dose Results: 16 patients treated Acute toxicity: Grade I 57%, Grade II 43%

17. Regional Nodal RTAwaiting results of two large trials (France and EORTC)

18. Regional Nodal RT in BCS Ongoing Trials

19. Axillary Treatment with CS

23. Full SCLV Field

24. IM Nodal Radiation Technique

25. IM Nodal Radiation Technique

28. Cured from Breast Cancer Died of Cardiac Toxicity Adapted from Larry Marks, Duke

29. Overall survival: radical mastectomy + / - RT First 10 years Next 25 years Cuzick et al: Recent Results Cancer Research 111:108-129, 1988

30. XRT worse XRT better XRT better XRT worse XRT better XRT worse Overall Survival Cardiac Mortality Breast Ca Mortality Cuzick JCO 12:452, 1994

33. The shape of the breast and the position of the heart in relation to the chest wall can vary enormously

34. Decrease cardiac Exposure to RT Partial Breast Irradiation Decubitus or Prone positions Breath Hold Technique Respiratory gating technique Proton therapy

35. Patient’s Position Prone and IMRT Lateral Decubitus Campana et al 2005 DeWyngaert et al 2007

36. Radiation techniques Active Breathing Control + IMRT Breath hold in deep inspiration Remouchamps et al 2003 Lu et al et al 2000

37. Cardiac Sparing V5 Volume receiving 5% of the dose

38. Heart Block Examples Midline Heart Block Recent Patient Marks IJROBP 1994. Marks et al

39. Late cardiac morbidity(EBCTCG,Lancet 2000;355:1757-1770) field Breast cancer mortality reduced by 13% Increase in annual mortality rate from other causes by 21% Increase primarily due to excess deaths from cardiovascular causes Cardiac effects may not emerge until 15 yrs after treatment Breast contour Heart contour Maximum Heart Distance (MHD)

41. Prone Breast RT

43. Prone Breast RT

44. Goodman Figure 1a. Customized prone breast board with adjustable aperture and wedge for contralateral breast.Figure 1b. Ipsilateral breast and anterior chest wall hang in a dependent fashion away from the thorax while the ipsilateral arm is placed above the head

45. Goodman Figure 6. Left breast irradiation using prone breast IMRT technique can spare left ventricle and coronary arteries.

46. 3-DCRT for left prone breast radiation: Improved targeting and avoidance of lung Sagittal 45 Gy 60 Gy Lumpectomy 50 Gy PTV Transaxial

47. Pattern of In-Breast Cancer Recurrences Following Breast Conserving Therapy The majority of cancer recurrences in the treated breast occur at the lumpectomy site

48. Potential Benefits of Partial Breast Irradiation Reduce time and inconvenience of BCT Improve documented underutilization of breast conserving therapy (BCT)? Potentially reduce acute and chronic toxicity Reduce burden of care for patients Eliminate scheduling problems with systemic chemotherapy

49. Rationale for Partial Breast Irradiation (PBI) 10%-40% of those who are candidates for breast conservation therapy actually do not receive it. Why? Patient’s choice Complex and prolonged treatment course can be inconvenient for those with poor access to a radiation facility, the elderly and working women Physician bias

50. Techniques for PBI Interstitial brachytherapy with HDR or LDR Intracavitarybrachytherapy with Mammosite Intraoperative electron beam therapy 3D conformal radiation therapy Proton beam

51. Partial breast irradiation techniques

52. Three Established Methods For PBI Mammosite® Multi Catheter 3-D Conformal

53. Accelerated Partial Breast Irradiation Treatments delivered twice daily (with treatments separated by six hours) for 10 treatments delivered in 5 treatment days. Delivery of radiation limited to lumpectomy site with a margin of normal tissue. Each treatment takes approximately 10 minutes to deliver.

54. Target definition

55. Accelerated Partial Breast Irradiation Benefits: Limited radiation exposure to normal tissue Treatments completed in one week instead of six weeks

56. Accelerated Partial Breast Irradiation Limitations: May require additional surgical procedure Requires twice daily treatment Newer modality with far fewer patients treated and much shorter follow-up As of now, no direct comparison with standard radiation

58. Who is eligible for PBI? (Off study) Tumors < 3 cm Negative margins (> 2mm) Node negative Invasive ductal carcinoma or DCIS Older women (>45 yrs) Revised Consensus Statement for Accelerated Partial Breast Irradiation, 12/8/05

59. Interstitial brachytherapy Catheters are placed intraoperatively or later; usually 2 planes Typical doses with HDR = 30-36 Gy and LDR = 45-60 Gy Treatment delivered over one week.

60. Breast Brachytherapy

61. Multi-Catheter Brachytherapy

62. Dose Distribution of MultiCatheter PBI PTV 100% isodose

63. Breast Appearance Following Multi-catheter Brachytherapy 5 years post treatment

64. Patient Selection for Breast Brachytherapy Patients older than 45 Tumors less than 2 cm. in size >2mm. Margins Preferably Infiltrating Ductal or loclized low grade DCIS. No Lobular CA There must be at least 7mm. of tissue between the catheter surface and the skin of the breast.

65. Advantages of Breast Brachytherapy vs. External Beam RT 6 weeks (30 fractions) Homogeneous dose Logistical problem for patients Difficult for frail, elderly, or chronically ill patients Interferes with schedule of working women Some BCT candidates will opt for mastectomy 5 days (10 fractions) Dose is higher to tissue at greatest risk for sub-clinical malignant cells Reduction in skin, cardiac and lung dose Ideal for patients who live far from RT Center Convenient May increase number of women treated with BCT

66. Disadvantages of Breast Brachytherapy vs. External Beam RT Noninvasive Can cover nodal regions Treats multi-centric carcinoma Low complication rate Linear accelerators widely available Most radiation oncologists experienced Invasive Not useful for treatment of nodal basins May miss tumor foci in other quadrants Low, but definite risk of infection and/or fat necrosis Requires special skills for performing; in placing catheters and dosimetry

67. MultiCatheter PBI:HDR/ LDR 61 mo. 5% 89% 61 y 1.4 cm 17.5% Average:

68. Breast Brachytherapy There has got to be a better way than all of those needles. Mammosite device from Proxima Therapeutics may be the answer. FDA approved the device in May 2002

70. Dual lumen single catheter with expandable balloon at end

71. Balloon expands to fill the lumpectomy cavity

72. Radiation dose prescribed to 1 cm beyond balloon surface

73. Uses 192Ir (HDR) as the source

75. 5th Int. Meeting ISIORT Madrid, June 2008 GTV PTV Skin Volume Definition PTV: GTV + 1.5 – 2.0 (clinical margin) + 0.5 (setup margin) excluding skin and chest wall Skin: 5 mm depth below skin surface

76. Difficulties with Mammosite Balloon must conform to cavity shape without air gaps. Device explanted in ~ 10-15% of pts. Ideal is to have 7 mm b/w balloon and skin to decrease risk of erythema. Very dependent on surgical placement.

77. CT Planning for MammositeBrachytherapy Isodose Lines 50% 80% 100% 120% 140% 200% Mammosite® balloon

79. 10 fractions over 5 -7days3-Dimensional rendering of applicator surface and prescription dose cloud.

80. Day 2 on treatment

81. Day 2 on treatment

82. 2 weeks post treatment

83. 4 months after PBI

84. Breast Appearance after MammoSite® 3 years post treatment

85. MammoSite PBI Average: 4% 0% 83% 64 y 26 mo 1 cm

86. Toxicities of Mammosite Seroma formation: Risk is increased with open technique for placement. In Beaumont series, found 60% risk with open cavity vs. 30% in closed cavity; overall rate of 45%, with 10% symptomatic. Fat necrosis: Risk may be slightly lower than with HDR and no difference with placement technique.

87. Conclusion The MammoSite RTS is the most commonly used PBI technique MammoSite is minimally invasive, offers acceptable cosmetic results, and induces mild side effects The duration of treatment is only five days making it more convenient for patients The MammoSite RTS has criteria which prevent some patients from eligibility New devices such as SAVI, ClearPath, and Contura are overcoming those limitations

88. … and Mammosite begat …. Contura ClearPath™ SAVI 5th Int. Meeting ISIORT Madrid, June 2008

89. PBI: 3D-CRT Target definition

90. PBI: 3D-CRT Beam Arrangement 3.85 Gy BID x 10 fractions

91. PBI: 3D-CRT Isodose Distribution 3850 3752 3655 3557 3460 axial sagittal coronal

92. 3-DCRT PBI Summary: 273 63 21 0.9 < 1 0

93. Accelerated Partial Breast Irradiation:Summary Accelerated partial breast irradiation allows patients to complete a course of treatment in one week as opposed to the standard six weeks. Treatment limited to part of the breast may be associated with less morbidity of treatment and better cosmetic outcome. Hopefully, the randomized, prospective NSABP trial will answer the question of equivalence of partial and standard breast irradiation.

96. Secondary:Distant disease-free survival Overall survival QOL: Cosmesis, fatigue, symptoms, burden of care

98. Spherical applicators with diameters of 15-50 mm in steps of 5 mm

100. The pliable breast tissue is wrapped around the applicator. Subcutaneous stitches aid conformation, while ensuring that the skin is at least 1cm from the applicator surface.

103. Intraoperative Radiation Therapy (IORT) for PBI TARGIT trial is comparing whole breast irradiation to IORT delivering a single dose of 20 Gy. Primary accrual is in Europe. Using the Intrabeam Photon Radiosurgery System, 50 kV x-rays. Trial has enrolled 900 patients with target of 2200 patients.

104. Trials of partial breast RT

105. Intensity Modulated Radiation Therapy (IMRT) Dose distribution to breast with standard tangential fields Dose distribution to breast using IMRT

106. Intensity Modulated Radiation Therapy (IMRT)

107. IMRT for Early Breast

108. Intensity Modulated Radiation Therapy (IMRT) Phase III Randomized Study of Intensity Modulated Radiation Therapy Versus Standard Wedging Technique for Adjuvant Breast Radiotherapy J. Pignol, et. al. Toronto, ON and Victoria, BC Presented ASTRO 2006, Plenary Session

109. Tangential Fields vs IMRT 358 patients randomized to standard breast irradiation or IMRT Dose of up to 50 Gy+ 16 Gy boost Endpoints of acute skin reaction and incidence of moist desquamation

110. Tangential Fields vs IMRT 311 Patients included in analysis Decreased moist desquamation with IMRT- 31% vs 48% (p=0.0019) Decreased moist desquamation in inframammary fold with IMRT- 26% vs 43% (p=0.0012) IMRT lowers the dose of radiation to the lung and to the heart (in patients with left sided breast cancers).

111. Moist Desquamation

112. Intensity Modulated Radiation Therapy (IMRT)- Summary We would not expect to see any differences in terms of recurrence or survival with IMRT We would hope to see improvement in side effect profile It may take years or decades to document a benefit in terms of cardiac toxicity

113. Goodman Figure 4a. Transverse Dose Distributions IMRT Conventional Isodose in % 113 108 100 90 50 102 10

114. DVH – Coronary artery region

115. Other Clinical Scenarios Inoperable presentations Bulky, non-resectable recurrent cancer IMRT plans have sometimes looked significantly better than 3D conformal, on a CASE BY CASE basis

116. 5th Int. Meeting ISIORT Madrid, June 2008 Proton/Photon Comparison Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Figure 1: Two-field proton PBI plan in axial, coronal, and sagittal views Photon Photon Proton Proton Isodose lines — 103% — 100% — 75% — 50% — 25%

120. 5th Int. Meeting ISIORT Madrid, June 2008 Dose to Heart

121. 5th Int. Meeting ISIORT Madrid, June 2008 Dose to Lung

122. 5th Int. Meeting ISIORT Madrid, June 2008 Cost vs. Benefit: Protons vs. Photons Benefit: Volume of non-target breast tissue receiving 50% of the prescribed dose is reduced 40% to 45% Cost: WBI+B $10.6K 3D-CPBI proton $13.2K (+25%) 3D-CPBI-photon $5.3K (-50%) A. Taghian et. al. IJROBP. 65:1404-1410; 2006

123. ΕΥΧΑΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ