RADIOTHERAPY IN BREAST CANCER PART 1 CONSERVATION GNTHER

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

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

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

BREAST CONSERVATION NON-INVASIVE CANCER RT in LCIS ?

BREAST CONSERVATION NON-INVASIVE CANCER RT in LCIS ? ÞNo solid data multicentricity (-88%) contralateral pos. biopsies (-59%) 10 -35% progression to invasive cancer after 20 – 25 years follow-up

BREAST CONSERVATION NON-INVASIVE CANCER RT in DCIS ?

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

BREAST CONSERVATION DCIS Omission of RT after breast conserving surgery for DCIS low risk = Diagnosis 2002 SEER data; Katz et al. ; J Clin Oncol, 2005 G 1, up to 2 cm G 2, up to 1 cm high risk = > 2 cm or G 3

BREAST CONSERVATION DCIS VAN NUYS PROGNOSTIC INDEX SIZE -15 mm 16 -40 mm >40 mm G low w/o necrosis low with necrosis high RR 10+mm 1 -9 mm <1 mm New: AGE >60 yrs 40 – 60 yrs <40 yrs 1 2 3

BREAST CONSERVATION DCIS LOCAL CONTROL: Multivariate analysis Silverstein, 2002 G Van Nuys series Age Size RR

BREAST CONSERVATION DCIS Prospective study for omission of RT in ‚good risk‘ (mammo-2. 5 cm; G 1/2; RR 10+mm) 12 % LR at 5 years ! Stopped early with 158 pts (/200) J Wong et al. , J Clin Oncol 2006

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

BREAST CONSERVATION DCIS LOCAL CONTROL: Multivariate analysis Silverstein, 2002 RT G Van Nuys series Age Size RR

Randomised studies in DCIS with or without radiotherapy Local control – Efficacy of RT Trial n f-up Op Op+RT HR p NSABP B 17 818 5 yr 16% 7% 0. 43 <0. 001 EORTC 10853 1010 10 yr 26% 15% 0. 53 <0. 0001 UKCCCR 1701 5 yr 14% 6% 0. 38 <0. 001 Risk reduction in all subgroups (to various degrees) RT with 50 Gy => As expected: no difference in overall survival!

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

BREAST CONSERVATION DCIS – Impact of boost?

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

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 , unpublished median: 60 Gy (± 1) Mastectomy median: 50 Gy (± 1) no RT

BREAST CONSERVATION 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 ≥ 10 mm? (CAVE: young patients! VAN NUYS: >=10 mm; <40 yrs: n=15!) Interdisciplinarity is very important !

BREAST CONSERVATION INVASIVE CANCER • BCT vs mastectomy ?

BREAST CONSERVATION % Milan I Trial (Mastectomy vs BCT) 20 yrs – Results p=0. 8 p=1. 0 Veronesi et al. , NEJM 2002

BREAST CONSERVATION % NSABP-06 Trial (Mastectomy vs BCT) 20 yrs – Results p=0. 95 p=0. 74 Fisher et al. , NEJM 2002

BREAST CONSERVATION CONCLUSION • BCT + Mastectomy equivalent !

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

BREAST CONSERVATION Local relapse: BC surgery +/- RT Studies Median Follow-up NSABP B-06 125 months Scottish Cancer Trial 68 months UppsalaÖrebro Study Group 106 months Ontario Cancer Inst. Milano III Op LR w/o RT LR with RT Lumpectomy Segmentectomy 35% 9% 24% 6% 22% 7% 91 months Lumpectomy 35% 11% 109 months Quadrantectomy 22% 5%

BREAST CONSERVATION EBCTCG 2000 RT metaanalysis, Lancet 12/05 % N 0 N+/N? n=6097 n=1214 p<0. 00001 p=0. 006 p<0. 00001 p<0. 01

BREAST CONSERVATION

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

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

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

BREAST CONSERVATION BC surgery +/- RT, p. T 1 a/p. T 1 b p. N 0 16. 5 p<0. 0001 9. 3 p=0. 01 2. 8 NSABP B-21, n=1009; JCO 2002

BREAST CONSERVATION Local relapse rates, p. T 1 a/p. T 1 b p. N 0 Age 70+ ? Therapy, -ies n LR TAM RT TAM+RT 43 59 57 3 (7%) 5 (8%) 0 RT vs. TAM => HR 1. 06 (0. 25 -4. 46) ! NSABP B-21, n=1009 JCO, 2002

BREAST CONSERVATION … in T 1, N 0, R 0, ER+ (in 97%), >70 yrs CALGB, RTOG, ECOG (Hughes et al. NEJM, 9/2004) n=636 (75+ years: 55%) median F-up: 5 J LOCAL RELAPSE with tamoxifen and RT 4% 1% p<0. 001

BREAST CONSERVATION T 1/T 2, >50 yrs: 769 randomised (of 1572 ‚eligible‘ pts. ) 5 yrs LR -2 cm, R 0, HR+ n=611 Tam + WB-RT 3. 2% 0. 4% (p<0. 001) -1 cm, R 0, HR+ n=263 Tam + WB-RT Files et al. , NEJM 2004 2. 6% 0% (p=0. 02)

BREAST CONSERVATION T 1/T 2, >50 yrs: 769 randomised (of 1572 ‚eligible‘ pts. ) 5 yrs LR + 3 J -2 cm, R 0, HR+ n=611 Tam + WB-RT x 5! 3. 2% 0. 4% (p<0. 001) -1 cm, R 0, HR+ n=263 Tam + WB-RT Files et al. , NEJM 2004 8 yrs LR 2. 6% 0% (p=0. 02) 15. 2% 3. 6%

BREAST CONSERVATION T 1/T 2, >50 yrs: 769 randomised (of 1572 ‚eligible‘ pts. ) 5 yrs LR + 3 J -2 cm, R 0, HR+ n=611 Tam + WB-RT x 5! 3. 2% 0. 4% (p<0. 001) -1 cm, R 0, HR+ n=263 Tam + WB-RT Files et al. , NEJM 2004 8 yrs LR 2. 6% 0% (p=0. 02) (B 21) 15. 2% (16. 5%) 3. 6% ( 2. 8%)

BREAST CONSERVATION postmenop. , T <3 cm, N 0, ER+ and/or PR+ ABCSG 8 (8 A) (Pötter et al. ASTRO, OEGRO, ECCO 13, 11/2005) n=826 (60+ years: about two thirds) median F-up: 42 mo LOCAL RELAPSE 5 yrs with Tamoxifen/AI and RT 4. 5% 0. 6% p=0. 001

BREAST CONSERVATION „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 > 5 yrs: RT !

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

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

BREAST CONSERVATION

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

BREAST CONSERVATION Local relapse out of ‚tu bearing quadrant‘ RANDOMISED STUDIES TRIAL NSABP-B 06 MAILAND UPPSALA ONTARIO f-up 125 39 64 43 Modified after Baglan et al. , 2001 OP 2. 7% 1. 5% 3. 5% OP+RT 3. 8% 0% 1. 0%

BREAST CONSERVATION Intraoperative Radiotherapy in Phase III

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

BREAST CONSERVATION

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

BREAST CONSERVATION Brachytherapy-Ballon (Mammosite ®) Registry Trial; n=1449; Median f-up: 14 mo 2 yrs local failure: 1. 2% (isolated LF 0. 8%) 2 yrs axillary failure: 1. 0% (isolated AF 0. 6%) Good/excellent cosmesis 6 mo 12 mo 18 mo 24 mo 95. 1% 93. 7% 91. 3% 93. 5% Vicini F et al. ASCO; 2006 36 mo 90. 4%

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

BREAST CONSERVATION PBI only William Beaumont Hospital n=199 (92% p. T 1), f-up: 65 mo HDR: 32 Gy / 8 fx / 4 d LDR: 50 Gy, 0. 52 Gy/h, 96 h actuarial LR (5 J) WB-RT: 1% PBI as good as WB-RT ! Vicini et al. , 2003

BREAST CONSERVATION PBI only Manchester Trial (Phase III); 1982 -87; n = 708; Breast + LN (4 MV; 40 Gy/15 fx) 11% Randomisation LOCAL REL. PBI (10 Me. V; 40 -42. 5 Gy/8 fx) 20% • no axillary diss. • no systemic therapy • no microscopic resection margin determination • in 42% no Tumor size determination

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

BREAST CONSERVATION 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 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 altered fractionation Stage I/II n=1234 R 42. 5 Gy/2. 65 Gy 22 days n=622 50 Gy/2 Gy 35 days n=612 median f-up : 69 months Whelan et al. , JNCI 94, 2002

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

BREAST CONSERVATION altered fractionation T 1 -3 N 0 -1 n=1410 R 42. 9 Gy/3. 3 Gy 5 wks n=466 39 Gy/3 Gy 5 wks n=474 median f-up : 9. 7 years Owen et al. , Lancet Oncol, 2006 50 Gy/2 Gy 5 wks n=470

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

BREAST CONSERVATION altered fractionation HR LR 5 yrs 10 yrs 50 Gy 1 7. 9% 12. 1% 42. 9 Gy 0. 86 7. 1% 9. 6% 39 Gy 1. 33 9. 1% 14. 8% => alpha/beta is 4 (95%CI 1 -7. 8); 41. 6 Gy/3. 2 Gy = 50 Gy/2 Gy! Owen et al. , Lancet Oncol, 2006

BREAST CONSERVATION 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 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 Local recurrences after BCS + RT BOOST versus NO BOOST no 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 % (16 Gy) 0. 53 p = 0. 13 n = 664 • EORTC 10801 5 y 6. 8 % n = 5569 3. 4 % (15 Gy) 0. 59 p = 0. 0001

BREAST CONSERVATION BREAST-RT +/- BOOST - 40 J (n=449) p=0. 002 51 -60 J (n=1803) p=0. 07 Bartelink et al. , NEJM 2001 41 -50 J (n=1334) p=0. 02 > 60 J (n=1732) p=0. 11

BREAST CONSERVATION Breast pain – randomised study p<0. 01 * RT * no RT Whelan et al. , Cancer 2000

BREAST CONSERVATION Skin reactions – randomised study p<0. 01 * RT * no RT Whelan et al. , Cancer 2000

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

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

BREAST CONSERVATION

BREAST CONSERVATION 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 (! <50 yrs !)

RT – BREAST CANCER ‚TIMING‘

RT – BREAST CANCER ‚TIMING‘

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

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

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

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

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

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

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

RT – BREAST CANCER ‚TIMING‘ ‚Ch. T => RT‘ vs , sim. Ch. T/RT‘ Ch. T= mitoxantrone, 5 -FU, cyclophosphamide; 6 cycles RT= 50 Gy/2 Gy; +/- 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 ! ! sim. Ch. T/RT: Significant more breast atrophy, subcutaneous fibrosis, teleangiectasia, skin pigmentation ! Toledano et al. ; Int J Radiat Oncol Biol Phys; 2006

RT – BREAST CANCER ‚TIMING‘ RT – Herceptin ®

RT – BREAST CANCER ‚TIMING‘ RT – Herceptin ® N 9831: AC->T->H vs AC->TH->H RT (after BCS or Mx 4+LN sim to H allowed) 1460 available for adverse events analyses median f-up: 1. 5 yrs 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) Þ Concurrent H-RT is not associated with acute RT adverse events Þ Further follow up is needed for late adverse events Halyard MY et al. ASCO; 2006

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

BREAST CONSERVATION TECHNIQUE / RT APPLICATION

BREAST CONSERVATION

BREAST CONSERVATION Planning-CT and 3 D-Planning

BREAST CONSERVATION

BREAST CONSERVATION

BREAST CONSERVATION Hurkmans et al. , 2001 HEART 42 mm

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

BREAST CONSERVATION IMRT

BREAST CONSERVATION IMRT

BREAST CONSERVATION IMRT n=306 R Standard 2 D 3 D IMRT 5 yrs – Differences in breast appearence (Photos) 60% 48% p=0. 06 (Qo. L no difference) Yarnold et al. , ECCO 13; 2005

BREAST CONSERVATION 6 MV + 12 e Lomax et al. IMRT Protons IMRT IJROBP 2003

BREAST CONSERVATION ‚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 SCHLUSSFOLGERUNG

RT – BREAST CANCER RE-IRRADIATION