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 ΖΑΠΠΕΙΟΥΒΑΚΑΛΗΣ ΞΕΝΟΦΩΝΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ ΟΓΚΟΛΟΓΟΣΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝ&401 ΣΤΡΑΤΙΩΤΙΚΟ ΝΟΣ. ΑΘΗΝΩΝ

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

3. Prospective Randomized Trials of Lumpectomy +/- Radiotherapy

4. 42 000 womenin 78 randomized trialsMastectomy node-pos↓LR: 17%↓DSM: 5.4%BCS node-negBCS node-pos↓LR: 16%↓DSM: 5%↓LR: 30%↓DSM: 7%Lancet 2005; 366: 2087

5. Lancet 2005; 366: 2087

6. Radiation Therapy for Early Stage Breast Cancer Following LumpectomyWhole Breast IrradiationRationale: Addition of whole breast irradiation following lumpectomy yields local control rates comparable to mastectomyTreatment: Whole breast irradiation 45-50 Gy to the entire breast

7. 60 Gy to the lumpectomy cavity + margin

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

9. 5 – 7 week total treatment durationBreast Irradiation TechniqueExternal BeamTreats “whole breast”Large volume of incidental tissuesRequires protracted (6—7 week) delivery

12. Image-based Conformal Radiation Therapy: 60 Gy62 Gy50 Gy20 Gy45 GyaxialsagittalLeft Breast

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

15. Accelerated Whole Breast Irradiation:Reducing the burden of careCanadian Phase III Randomized Trial:42.5 Gy – 16 fractions – 22 days vs. 50 Gy – 25 fractions – 35 days1,234 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 doseResults: 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 fromBreast CancerDied of CardiacToxicity Adapted from Larry Marks, Duke

27. Overall survival: radical mastectomy + / - RTFirst 10 yearsNext 25 yearsCuzick et al: Recent Results Cancer Research 111:108-129, 1988

28. XRT worseXRT betterXRT betterXRT worseXRT betterXRT worseOverall SurvivalCardiac MortalityBreast Ca MortalityCuzick 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 RTPartial Breast IrradiationDecubitus or Prone positionsBreath Hold TechniqueRespiratory gating techniqueProton therapy

34. Patient’s PositionProne and IMRTLateral DecubitusCampana et al 2005DeWyngaert et al 2007

36. Prone Breast RT

37. GoodmanFigure 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. GoodmanFigure 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 lungSagittal45 Gy60 GyLumpectomy50 GyPTVTransaxial

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

41. Double Trouble !Heart

42. Solution = Gated RadiotherapyHeart

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 SparingV5 Volume receiving 5% of the dose

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

48. Potential Benefits of Partial Breast IrradiationReduce time and inconvenience of BCTImprove documented underutilization of breast conserving therapy (BCT)?Potentially reduce acute and chronic toxicityReduce burden of care for patientsEliminate 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 choiceComplex and prolonged treatment course can be inconvenient for those with poor access to a radiation facility, the elderly and working womenPhysician bias

50. Techniques for PBIInterstitial brachytherapy with HDR or LDRIntracavitarybrachytherapy with MammositeIntraoperative electron beam therapy3D conformal radiation therapyProton beam

51. Partial breast irradiation techniques

52. Three Established Methods For PBIMammosite®Multi Catheter3-D Conformal

53. Accelerated Partial Breast IrradiationTreatments 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 IrradiationBenefits:Limited radiation exposure to normal tissueTreatments completed in one week instead of six weeks

56. Accelerated Partial Breast IrradiationLimitations:May require additional surgical procedure Requires twice daily treatmentNewer modality with far fewer patients treated and much shorter follow-upAs of now, no direct comparison with standard radiation

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

59. Interstitial brachytherapyCatheters are placed intraoperatively or later; usually 2 planesTypical doses with HDR = 30-36 Gy and LDR = 45-60 GyTreatment delivered over one week.

60. Breast Brachytherapy

61. Multi-Catheter Brachytherapy

62. Dose Distribution of MultiCatheter PBIPTV100% isodose

63. Breast Appearance Following Multi-catheter Brachytherapy5 years post treatment

64. Patient Selection for Breast BrachytherapyPatients older than 45Tumors less than 2 cm. in size>2mm. MarginsPreferably Infiltrating Ductal or loclized low grade DCIS. No Lobular CAThere 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 RT6 weeks (30 fractions)Homogeneous doseLogistical problem for patientsDifficult for frail, elderly, or chronically ill patientsInterferes with schedule of working womenSome BCT candidates will opt for mastectomy5 days (10 fractions)Dose is higher to tissue at greatest risk for sub-clinical malignant cellsReduction in skin, cardiac and lung doseIdeal for patients who live far from RT CenterConvenientMay increase number of women treated with BCT

66. Disadvantages of Breast Brachytherapy vs. External Beam RTNoninvasiveCan cover nodal regionsTreats multi-centric carcinomaLow complication rateLinear accelerators widely availableMost radiation oncologists experienced InvasiveNot useful for treatment of nodal basinsMay miss tumor foci in other quadrantsLow, but definite risk of infection and/or fat necrosisRequires special skills for performing; in placing catheters and dosimetry

67. MultiCatheter PBI:HDR/ LDR61 mo.5%89%61 y1.4 cm17.5%Average:

68. Breast BrachytherapyThere 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

69. MammoSite PBIMammosite® Breast Brachytherapy ApplicatorSimplified brachytherapy method for PBI

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

74. FDA approval May 2002

75. 5th Int. Meeting ISIORT Madrid, June 2008GTVPTVSkinVolume DefinitionPTV: GTV + 1.5 – 2.0 (clinical margin) + 0.5 (setup margin) excluding skin and chest wallSkin: 5 mm depth below skin surface

76. Difficulties with MammositeBalloon 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 MammositeBrachytherapyIsodose Lines50%80%100%120%140%200%Mammosite® balloon

78. Prescription Dose34 Gy

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 PBIAverage:4%0%83%64 y26 mo1 cm

86. Toxicities of MammositeSeroma 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. ConclusionThe MammoSite RTS is the most commonly used PBI techniqueMammoSite is minimally invasive, offers acceptable cosmetic results, and induces mild side effectsThe duration of treatment is only five days making it more convenient for patients The MammoSite RTS has criteria which prevent some patients from eligibilityNew devices such as SAVI, ClearPath, and Contura are overcoming those limitations

88. … and Mammosite begat ….ConturaClearPath™SAVI5th Int. Meeting ISIORT Madrid, June 2008

89. PBI: 3D-CRT Target definition

90. PBI: 3D-CRT Beam Arrangement3.85 Gy BID x 10 fractions

91. PBI: 3D-CRT Isodose Distribution3850 3752 3655 3557 3460axialsagittalcoronal

92. 3-DCRT PBISummary:27363210.9< 10

93. Accelerated Partial Breast Irradiation:SummaryAccelerated 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.

94. Stage 0, I-II breast cancer treated by lumpectomyRandomizationWBI50-50.4 Gy (1.8-2.0 Gy)Fractions to the whole breast followed by boost to 60 -66.6 GyPBI34 Gy in 3.4 Gy fxs bidMammosite® or Multicatheter brachytherapy OR 38.5 Gy in 3.85 Gy fxs bid3D-CRTNSABP B-39/RTOG 0413 TrialPhase III

95. EndpointsPrimary: in-breast tumor recurrence

96. Secondary:Distant disease-free survivalOverall survivalQOL: Cosmesis, fatigue, symptoms, burden of care

97. 5th Int. Meeting ISIORT Madrid, June 2008ZeissIntrabeam®50 kV x-ray source at the end of a 15 cm long, 3.5 mm diameter tube.

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

99. Dose rate of about 2 Gy/min at 1 cm in waterSpherical applicators1.5 to 5cm diameter in 0.5cm stepsUniform surface dose-rate

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 PBITARGIT 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?

106. Γιατί χρειαζόμαστε την IMRT ; Βελτιστοποίηση της ομοιογένειας της δόσης  καλύτερη κατανομή της δόσης ενδεχομένως συνοδεύεται από μικρότερη οξεία και χρόνια τοξικότητα (δέρμα, μαζικό παρέγχυμα) Μείωση των τμημάτων του πνεύμονα, της καρδιάς (σε όγκους αριστερού μαστού) και του ετερόπλευρου μαστού που λαμβάνουν υψηλές δόσεις. Σε εξειδικευμένες περιπτώσεις:

107. Μερική ακτινοβόληση μαστού