1. GÜNTHER GRUBER Institut für Radio-Onkologie guenther.gruber @ ksa.ch RADIOTHERAPY IN BREAST CANCER (PART 1: CONSERVATION)

2. AIMS OF RT Breast conservation Local control Overall survival Reduction of side effects

3. TOPICS Breast conserving therapy (BCT) RT after mastectomy Complications New trends

4. BREAST CONSERVATION NON-INVASIVE CANCER RT in LCIS ?

5. BREAST CONSERVATION NON-INVASIVE CANCER RT in LCIS ?  No solid data multicentricity (-88%) contralateral pos. biopsies (-59%) 10-35% progression to invasive cancer after 20 – 25 years follow-up

6. BREAST CONSERVATION NON-INVASIVE CANCER RT in DCIS ?

7. BREAST CONSERVATION NON-INVASIVE CANCER RT in DCIS ? Omission of RT ?

8. Omission of RT after breast conserving surgery for DCIS low risk = G1, up to 2cm G2, up to 1cm high risk = > 2cm or G3 SEER data; Katz et al.; J Clin Oncol, 2005 Diagnosis 2002 BREAST CONSERVATION DCIS

9. VAN NUYS PROGNOSTIC INDEX BREAST CONSERVATION DCIS SIZE-15mm1 16-40mm2 >40mm3 Glow w/o necrosis1 low with necrosis2 high3 RR10+mm1 1-9mm2 <1mm3 New: AGE >60yrs1 40 – 60yrs2 <40yrs3

10. LOCAL CONTROL: Multivariate analysis Silverstein, 2002 GAgeSizeRR BREAST CONSERVATION DCIS Van Nuys series

11. Prospective study for omission of RT in ‚good risk‘ (mammo-2.5cm; G1/2; RR 10+mm) BREAST CONSERVATION DCIS J Wong et al., J Clin Oncol 2006 12 % LR at 5 years ! Stopped early with 158 pts (/200)

12. Omission of RT in ‚good risk‘ BREAST CONSERVATION DCIS tamoxifen RTOG 9804 tamoxifen + RT

13. LOCAL CONTROL: Multivariate analysis Silverstein, 2002 GAgeSizeRR BREAST CONSERVATION DCIS Van Nuys series RT

14. Randomised studies in DCIS with or without radiotherapy Local control – Efficacy of RT Trial nf-upOp Op+RT HR p NSABP B17 8185yr16% 7% 0.43<0.001 EORTC 10853101010yr26% 15% 0.53<0.0001 UKCCCR17015yr14% 6% 0.38<0.001 Risk reduction in all subgroups (to various degrees) RT with 50Gy => As expected: no difference in overall survival!

15. Randomised studies in DCIS with or without radiotherapy Local control – Efficacy of RT

16. BREAST CONSERVATION DCIS – Impact of boost?

17. median 50 Gy (±1) median 60 Gy (±1) Omlin et al. Lancet Oncol, 2006 median: 60Gy (±1) median: 50Gy (±1) keine RT DCIS – Impact of boost? BREAST CONSERVATION …in young women (-45 years)

18. Gruber et al., unpublished DCIS – Impact of boost? BREAST CONSERVATION …in young women (-45 years) median: 60Gy (±1) median: 50Gy (±1) no RT Mastectomy

19. For which pts. with DCIS radiotherapy can be omitted after breast conserving surgery? Evidence-based medicine (3 published studies + 1 as abstract): NO OMISSION OF RT! Probably yes: clinging or micropapillary growth?; RR ≥ 10mm? (CAVE: young patients! VAN NUYS: >=10mm; <40yrs: n=15!) Interdisciplinarity is very important ! BREAST CONSERVATION

20. INVASIVE CANCER BCT vs mastectomy ? BREAST CONSERVATION

21. Milan I Trial (Mastectomy vs BCT) 20 yrs – Results % Veronesi et al., NEJM 2002 p=0.8 p=1.0 BREAST CONSERVATION

22. NSABP-06 Trial (Mastectomy vs BCT) 20 yrs – Results % Fisher et al., NEJM 2002 p=0.95 p=0.74 BREAST CONSERVATION

23. CONCLUSION BCT + Mastectomy equivalent ! BREAST CONSERVATION

24. INVASIVE CANCER BCT vs mastectomy ? Breast conserving surgery: Omission of RT ? BREAST CONSERVATION

25. StudiesMedian Follow-up OpLR w/o RT LR with RT NSABP B-06125 monthsLump- ectomy 35%9% Scottish Cancer Trial 68 monthsLump- ectomy 24%6% Uppsala- Örebro Study Group 106 monthsSegment- ectomy 22%7% Ontario Cancer Inst. 91 monthsLump- ectomy 35%11% Milano III109 monthsQuadrant- ectomy 22%5% Local relapse: BC surgery +/- RT BREAST CONSERVATION

26. EBCTCG 2000 RT metaanalysis, Lancet 12/05 % p<0.00001 p=0.006 p<0.00001 p<0.01 N0 N+/N? n=6097 n=1214 BREAST CONSERVATION

28. CONCLUSION BCT + Mastectomy equivalent ! BC surgery: No omission of RT ! BREAST CONSERVATION

29. INVASIVE CANCER BCT vs mastectomy ? Breast conserving surgery: Omission of RT ? Omission of RT in ‚low risk‘ ? BREAST CONSERVATION

30. BC surgery +/- RT Swedish Breast Cancer Group, EJC 2003 median tu-size: 12mm; n=1187; median F-up: 8J 14% 4% BREAST CONSERVATION

31. p=0.01 16.5 9.3 2.8 p<0.0001 NSABP B-21, n=1009; JCO 2002 BC surgery +/- RT, pT1a/pT1b pN0 BREAST CONSERVATION

32. Local relapse rates, pT1a/pT1b pN0 Age 70+ ? Therapy,-ies nLR TAM433 (7%) RT595 (8%) TAM+RT570 RT vs. TAM => HR 1.06 (0.25-4.46) ! NSABP B-21, n=1009JCO, 2002 BREAST CONSERVATION

33. CALGB, RTOG, ECOG (Hughes et al. NEJM, 9/2004) n=636 (75+ years: 55%) median F-up: 5J … in T1, N0, R0, ER+ (in 97%), >70yrs LOCAL RELAPSE with tamoxifen4% with tamoxifen and RT1% p<0.001 BREAST CONSERVATION

34. T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) 5yrs LR -2cm, R0, HR+ n=611 Tam 3.2% Tam + WB-RT 0.4% (p<0.001) -1cm, R0, HR+ n=263 Tam 2.6% Tam + WB-RT 0% (p=0.02) Files et al., NEJM 2004 BREAST CONSERVATION

35. T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) 5yrs LR8yrs LR -2cm, R0, HR+ n=611 Tam 3.2%15.2% Tam + WB-RT 0.4% (p<0.001) 3.6% -1cm, R0, HR+ n=263 Tam 2.6% Tam + WB-RT 0% (p=0.02) + 3J x 5 ! Files et al., NEJM 2004 BREAST CONSERVATION

36. T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) 5yrs LR8yrs LR -2cm, R0, HR+ n=611 (B21) Tam 3.2%15.2% (16.5%) Tam + WB-RT 0.4% (p<0.001) 3.6% ( 2.8%) -1cm, R0, HR+ n=263 Tam 2.6% Tam + WB-RT 0% (p=0.02) + 3J x 5 ! Files et al., NEJM 2004 BREAST CONSERVATION

37. ABCSG 8 (8A) (Pötter et al. ASTRO, OEGRO, ECCO 13, 11/2005) n=826 (60+ years: about two thirds) median F-up: 42 mo postmenop., T <3cm, N0, ER+ and/or PR+ LOCAL RELAPSE5yrs with Tamoxifen/AI4.5% with Tamoxifen/AI and RT0.6% p=0.001 BREAST CONSERVATION

38. „low risk“ – studies summary Follow up still too short ! No subgroup of pts. which does not profit from RT! IMPORTANT: Trade-offs ! If overall survival > 5yrs: RT ! BREAST CONSERVATION

39. CONCLUSION BCT + Mastectomy equivalent ! BC surgery: No omission of RT ! No omission of RT in ‚low risk‘ ! BREAST CONSERVATION

40. INVASIVE CANCER BCT vs mastectomy ? Breast conserving surgery: Omission of RT ? Omission of RT in ‚low risk‘ ? PBI for ‚low risk‘ ? BREAST CONSERVATION

42. RATIONALE for PBI small RT volume offers the possibility for higher single doses => Shorter treatment time (4-5 days vs 5 weeks) Socio-economic aspects small RT volume has likely less long-term complications RT of whole breast necessary ? BREAST CONSERVATION

43. ‚ Never change a winning team ! ‘ (whole breast irradiation) Less experience ! Target volume ? Residual tumor cells ? Patient selection ? BREAST CONSERVATION PROBLEMS for PBI

44. Local relapse out of ‚tu bearing quadrant‘ TRIAL f-upOP OP+RT NSABP-B06 1252.7%3.8% MAILAND 391.5% 0% UPPSALA 643.5% ONTARIO 433.5%1.0% Modified after Baglan et al., 2001 RANDOMISED STUDIES BREAST CONSERVATION

45. Intraoperative Radiotherapy in Phase III BREAST CONSERVATION in Phase III

46. Interstitial Brachytherapy (iBT) Most data in the literature are based on iBT ! in Phase III BREAST CONSERVATION

49. Brachytherapy-Ballon (Mammosite ®) In USA very frequent ! in Phase III BREAST CONSERVATION

50. Brachytherapy-Ballon (Mammosite ®) BREAST CONSERVATION Registry Trial; n=1449; Median f-up: 14 mo 2yrs local failure: 1.2% (isolated LF 0.8%) 2yrs axillary failure: 1.0% (isolated AF 0.6%) Good/excellent cosmesis 6mo12mo 18mo 24mo36mo 95.1%93.7% 91.3% 93.5%90.4% Vicini F et al. ASCO; 2006

51. 3D (IMRT; protons) percutaneous RT Few data ! in Phase III BREAST CONSERVATION

52. PBI only William Beaumont Hospital n=199 (92% pT1), f-up: 65mo HDR: 32 Gy / 8fx / 4d LDR: 50 Gy, 0.52Gy/h, 96h actuarial LR (5J) actuarial LR (5J) WB-RT: 1% PBI: 1% PBI as good as WB-RT ! Vicini et al., 2003 BREAST CONSERVATION

53. Manchester Trial (Phase III); 1982-87; n = 708; Breast + LN (4MV;40Gy/15fx) Randomisation PBI (10MeV; 40-42.5Gy/8fx) no axillary diss. no systemic therapy no microscopic resection margin determination in 42% no Tumor size determination 11% LOCAL REL. 20% PBI only BREAST CONSERVATION

54. „low risk“ – PBI? Summary (So far) no standard ! Phase III studies ongoing ! Anyway, only for ‚low risk‘ ! Expertise ? BREAST CONSERVATION

55. CONCLUSION BCT + Mastectomy equivalent ! BC surgery: No omission of RT ! No omission of RT in ‚low risk‘ ! The target is the whole breast ! BREAST CONSERVATION

56. INVASIVE CANCER BCT vs mastectomy ? Breast conserving surgery: Omission of RT ? Omission of RT in ‚low risk‘ ? PBI for ‚low risk‘ ? Altered fractionation? BREAST CONSERVATION

57. altered fractionation Whelan et al., JNCI 94, 2002 Stage I/II n=1234 median f-up : 69 months R 42.5Gy/2.65Gy 22 days n=622 50Gy/2Gy 35 days n=612 BREAST CONSERVATION

58. Whelan et al., JNCI 94, 2002 LRFS DFS 100% 95% altered fractionation BREAST CONSERVATION

59. altered fractionation Owen et al., Lancet Oncol, 2006 T1-3 N0-1 n=1410 median f-up : 9.7 years R 42.9Gy/3.3Gy 5 wks n=466 50Gy/2Gy 5 wks n=470 BREAST CONSERVATION 39Gy/3Gy 5 wks n=474

60. altered fractionation BREAST CONSERVATION Owen et al., Lancet Oncol, 2006

61. HRLR 5yrs10yrs altered fractionation BREAST CONSERVATION Owen et al., Lancet Oncol, 2006 50Gy 1 7.9% 12.1% 42.9Gy 0.86 7.1% 9.6% 39Gy 1.33 9.1% 14.8% => alpha/beta is 4 (95%CI 1-7.8); 41.6Gy/3.2Gy = 50Gy/2Gy!

62. CONCLUSION BCT + Mastectomy equivalent ! BC surgery: No omission of RT ! No omission of RT in ‚low risk‘ ! The target is the whole breast ! There are equivalent schedules ! BREAST CONSERVATION

63. INVASIVE CANCER BCT vs mastectomy ? Breast conserving surgery: Omission of RT ? Omission of RT in ‚low risk‘ ? PBI for ‚low risk‘ ? Altered fractionation? Increase of dose (boost) ? BREAST CONSERVATION

64. Local recurrences after BCS + RT BOOST versus NO BOOST no boost boost H.R. Lyon 5 y 4.5 % 3.6 % (10 Gy) 0.80 p = 0.044 n = 1024 French M.C. 5 y 6.8 % 3.6 % (16Gy) 0.53 p = 0.13 n = 664 EORTC 10801 5 y 6.8 % 3.4 % (15Gy) 0.59p = 0.0001 n = 5569 BREAST CONSERVATION

65. BREAST-RT +/- BOOST p=0.002 p=0.02 p=0.07p=0.11 - 40J (n=449)41-50J (n=1334) 51-60J (n=1803)> 60J (n=1732) Bartelink et al., NEJM 2001 BREAST CONSERVATION

66. Breast pain – randomised study Whelan et al., Cancer 2000 no RT RT * * p<0.01 BREAST CONSERVATION

67. Skin reactions – randomised study RT no RT Whelan et al., Cancer 2000 * * p<0.01 BREAST CONSERVATION

68. Breast cosmesis – randomised study Whelan et al., Cancer 2000 no RT RT BREAST CONSERVATION

69. Global score by boost treatment No boostBoost 0 20 40 60 80 100% Excellent/Good Fair/Poor 71% 29% 86% 14% BREAST CONSERVATION

71. CONCLUSION BCT + Mastectomy equivalent ! BC surgery: No omission of RT ! No omission of RT in ‚low risk‘ ! The target is the whole breast ! There are equivalent schedules ! Boost efficient (! <50yrs !) BREAST CONSERVATION

72. RT – BREAST CANCER ‚TIMING‘

73. ‚TIMING‘

74. ‚TIMING‘ RT – HT In vitro Radioresistence, Ø, by Tamoxifen In vivo Only 2 studies (Labrie et al.; Cancer Res. 1999; Int J Cancer 2003) RT – BREAST CANCER ‚TIMING‘

75. ‚TIMING‘ RT – HT ZR-75-1 human breast cancer cells (s.c. into nude mice) => average tumor-area 20mm 2 ; Strata: tumor size RT 15x2Gy EM-800 300ug/d (SERM) Day 1 21 156 ARM A ARM B CR: 62% vs. 22% CR: 62% (arm A) vs. 22% (arm B) R RT 15x2Gy EM-800 300ug/d (SERM) 24 mice RT – BREAST CANCER ‚TIMING‘

76. RT – Tamoxifen: simultaneous vs sequential Journal of Clinical Oncology, Vol 23, No 1, 2005 * 3 (small) retrospective studies LRFSOS z.B. Ahn et al, 2005 RT – BREAST CANCER ‚TIMING‘

77. Lokalrezidiv Bentzen, S. M. et al. JCO; 23:6266-6267 2005 RT – Tamoxifen: simultaneous vs sequential RT – BREAST CANCER ‚TIMING‘

78. RT – 6xCMF: ‚RT first‘ vs,CMF first‘ Bellon, J. R. et al. JCO; 23:1934-1940; 2005 DFS RT – BREAST CANCER ‚TIMING‘ Breast conservation; n=244 No significant difference!

79. RT – 6xCMF: ‚RT first‘ vs,CMF first‘ Bellon, J. R. et al. JCO; 23:1934-1940; 2005 DMFSDFS RT – BREAST CANCER ‚TIMING‘ Breast conservation; n=244 No significant difference!

80. RT – 6xCMF: ‚RT first‘ vs,CMF first‘ Bellon, J. R. et al. JCO; 23:1934-1940; 2005 No significant difference! Breast conservation; n=244 OSDMFSDFS RT – BREAST CANCER ‚TIMING‘

81. ‚ChT => RT‘ vs,simChT/RT‘ Toledano et al.; Int J Radiat Oncol Biol Phys; 2006 RT – BREAST CANCER ‚TIMING‘ ChT= mitoxantrone, 5-FU, cyclophosphamide; 6 cycles RT= 50Gy/2Gy; +/- boost ARCOSEIN III trial (n=214 for late toxicity) ! No difference in acute toxicity ! (skin, esophagus, infections, neutropenia) ! No statistical difference in grade 2 or higher breast edema, lymphedema, pain ! ! simChT/RT: Significant more breast atrophy, subcutaneous fibrosis, teleangiectasia, skin pigmentation !

82. RT – Herceptin ® RT – BREAST CANCER ‚TIMING‘

83. RT – Herceptin ® Halyard MY et al. ASCO; 2006 RT – BREAST CANCER ‚TIMING‘ N9831: AC->T->H vs AC->TH->H RT (after BCS or Mx4+LN sim to H allowed) 1460 available for adverse events analyses median f-up: 1.5yrs Skin reaction (p=0.78); pneumonitis (p=0.78), dyspnea (p=0.87) Cough (p=0.54); dysphagea (p=0.26); neutropenia (p=0.16)  Concurrent H-RT is not associated with acute RT adverse events  Further follow up is needed for late adverse events

84. Individual HT:simultaneous possible ChT:In most centers: ChT -> RT simultaneous RChT possible but more side effects! => Not recommended RT – BREAST CANCER ‚TIMING‘ How to combine RT with systemic therapies ? Herc: simultaneous possible

85. TECHNIQUE / RT APPLICATION BREAST CONSERVATION

87. Planning-CT and 3D-Planning BREAST CONSERVATION

90. Hurkmans et al., 2001 Hurkmans et al., 2001 42 mm HEART BREAST CONSERVATION

92. „Open“ homogeneous beam (OB) Intensity modulated beam (IMB) BREAST CONSERVATION IMRT

93. BREAST CONSERVATION IMRT

94. BREAST CONSERVATION

95. R Standard 2D3D IMRT 5yrs – Differences in breast appearence (Photos) 60%48% p=0.06 (QoL no difference) n=306 Yarnold et al., ECCO 13; 2005 BREAST CONSERVATION IMRT

96. 6MV + 12eProtons IMRT Lomax et al.IJROBP 2003 BREAST CONSERVATION

97. ‚Organ‘motion, n=20 ‚motion‘ within 1 fraction: 1.3 +/- 0.4 mm ‘motion’ between 2 fractions: 2.6 +/- 1.3 mm Kron et al., ESTRO 2004 BREAST CONSERVATION

98. SCHLUSSFOLGERUNG

99. RT – BREAST CANCER RE-IRRADIATION