This document discusses therapeutic approaches to breast cancer treatment, focusing on radiotherapy techniques. It provides a historical overview of radiotherapy and highlights results from randomized trials demonstrating the benefits of radiotherapy after lumpectomy in reducing local recurrence rates and improving survival. Modern external beam radiotherapy techniques like 3D conformal radiation therapy and accelerated partial breast irradiation are described. Various techniques for partial breast irradiation including brachytherapy, MammoSite, and 3D-CRT are summarized along with their benefits, limitations, and results from studies. Ongoing trials evaluating partial breast irradiation are also mentioned.

1. Θεραπευτική αντιμετώπιση καρκίνου μαστού – Ακτινοθεραπεία Τεχνική & Πρόοδος ΕΛΛΗΝΙΚΗ ΣΧΟΛΗ ΜΑΣΤΟΛΟΓΙΑΣ: Β' ΚΥΚΛΟΣ ΣΠΟΥΔΩΝ - 4η ΣΕΙΡΑ ΑΘΗΜΑΤΩΝ, 16-17 ΣΕΠΤΕΜΒΡΙΟΥ 2011, ΑΙΓΛΗ ΖΑΠΠΕΙΟΥ ΒΑΚΑΛΗΣ ΞΕΝΟΦΩΝ ΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ ΟΓΚΟΛΟΓΟΣ ΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝ & 401 ΣΤΡΑΤΙΩΤΙΚΟ ΝΟΣ. ΑΘΗΝΩΝ

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

4. 42 000 women in 78 randomized trials Mastectomy node-pos ↓LR: 17% ↓DSM: 5.4% BCS node-neg BCS node-pos ↓LR: 16% ↓DSM: 5% ↓LR: 30% ↓DSM: 7% Lancet 2005; 366: 2087

5. Lancet 2005; 366: 2087

7. 60 Gy to the lumpectomy cavity + margin

8. 1.8 – 2 Gy fraction given 5 days/ week

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

13. Example of guidelines for PMRT RT is recommended to patients scoring ≥ 3 (Cambridge, UK)

15. 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

16. Randomized Boost Trials

18. 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%

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

23. Full SCLV Field

24. IM Nodal Radiation Technique

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

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

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

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

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

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

36. Prone Breast RT

37. 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

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

39. 3-DCRT for left prone breast radiation: Improved targeting and avoidance of lung Sagittal 45 Gy 60 Gy Lumpectomy 50 Gy PTV Transaxial

40. Intensity Modulated Radiotherapy (IMRT) … + Image Guidance (IGRT) Breast is a moving target !

41. Double Trouble ! Heart

42. Solution = Gated Radiotherapy Heart

43. Varian RPM respiratory management system

44. Deep Inspiration Breath-Hold (DIBH) Rosenzweig Int. J. Radiation Oncology Biol. Phys. 2000

45. Increase spatial separation between target and organs at risk

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

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. What about IMRT?

107. Μερική ακτινοβόληση μαστού

108. Ακτινοβόληση έσω μαστικών λεμφαδένων

109. Ταυτόχρονο boostΔεν πρέπει να περιμένουμε βελτίωση στον τοπικό έλεγχο, αφού είναι ήδη πολύ υψηλός.

111. 3D-CRT με σφηνοειδή φίλτρα vs. IMRT

112. 50 Gy/ 25 fr ± boost 8x2 Gy

113. Πρωτογενές καταληκτικό σημείο: Οξεία τοξικότητα δέρματος κατά τη διάρκεια της θεραπείας και 1-6 εβδομάδες μετάJCO 2008; 26: 2085

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

115. Intensity Modulated Radiation Therapy (IMRT)

116. DVH – Coronary artery region

117. 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

118. 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%

122. ΕΥΧΑΡΙΣΤΩ ΓΙΑ ΤΗΝ ΠΡΟΣΟΧΗ ΣΑΣ