KONTROVERSEN IN DER RADIOTHERAPIE DES MAMMAKARZINOMS GUENTHER GRUBER Institut für Radio-Onkologie Klinik Hirslanden, Zuerich guenther.gruber @ hirslanden.ch

KONTROVERSEN - RT INDIKATION VOLUMINA RT - PLANUNG RT – APPLIKATION

Bei welchen Pat. kann auf eine RT nach KONTROVERSEN – RT BRUSTERHALTUNG Bei welchen Pat. kann auf eine RT nach Brusterhaltung verzichtet werden?

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

BREAST CONSERVATION

BREAST CONSERVATION CONCLUSION BC surgery: No omission of RT !

BREAST CONSERVATION INVASIVE CANCER Omission of RT in ‚low risk‘ ?

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

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

Local relapse rates, pT1a/pT1b pN0 BREAST CONSERVATION Local relapse rates, pT1a/pT1b pN0 Age 70+ ? Therapy,-ies n LR TAM 43 3 (7%) RT 59 5 (8%) TAM+RT 57 0 RT vs. TAM => HR 1.06 (0.25-4.46) ! NSABP B-21, n=1009 JCO, 2002

… in T1, N0, R0, ER+ (in 97%), >70yrs BREAST CONSERVATION … in T1, N0, R0, ER+ (in 97%), >70yrs CALGB, RTOG, ECOG (Hughes et al. NEJM, 9/2004) n=636 (75+ years: 55%) median F-up: 5J LOCAL RELAPSE with tamoxifen 4% with tamoxifen and RT 1% p<0.001

T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) BREAST CONSERVATION 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

T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) BREAST CONSERVATION T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) 5yrs LR 8yrs 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

T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) BREAST CONSERVATION T1/T2, >50yrs: 769 randomised (of 1572 ‚eligible‘ pts.) 5yrs LR 8yrs 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

postmenop., T <3cm, N0, ER+ and/or PR+ BREAST CONSERVATION postmenop., T <3cm, N0, ER+ and/or PR+ ABCSG 8 (8A) (Pötter et al. ASTRO, OEGRO, ECCO 13, 11/2005) n=826 (60+ years: about two thirds) median F-up: 42 mo LOCAL RELAPSE 5yrs with Tamoxifen/AI 4.5% with Tamoxifen/AI and RT 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 > 5yrs: RT !

BREAST CONSERVATION CONCLUSION BC surgery: No omission of RT ! No omission of RT in ‚low risk‘ !

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

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 42.5Gy/2.65Gy 22 days n=622 50Gy/2Gy 35 days n=612 median f-up : 69 months Whelan et al., JNCI 94, 2002

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

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

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

BREAST CONSERVATION CONCLUSION 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 Breast conserving surgery: Omission of RT ? Omission of RT in ‚low risk‘ ? PBI for ‚low risk‘ ? Altered fractionation? Increase of dose (boost) ?

Local recurrences after BCS + RT BOOST versus NO BOOST BREAST CONSERVATION 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) 0.59 p = 0.0001 n = 5569

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

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 (! <50yrs !)

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

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

RT – 6xCMF: ‚RT first‘ vs ,CMF first‘ RT – BREAST CANCER ‚TIMING‘ RT – 6xCMF: ‚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 – 6xCMF: ‚RT first‘ vs ,CMF first‘ RT – BREAST CANCER ‚TIMING‘ RT – 6xCMF: ‚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

‚ChT => RT‘ vs ,simChT/RT‘ RT – BREAST CANCER ‚TIMING‘ ‚ChT => RT‘ vs ,simChT/RT‘ 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 ! Toledano et al.; Int J Radiat Oncol Biol Phys; 2006

RT – BREAST CANCER ‚TIMING‘ RT – Herceptin ® 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 Halyard MY et al. ASCO; 2006

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

BREAST CONSERVATION TECHNIQUE / RT APPLICATION

BREAST CONSERVATION

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

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

BREAST CONSERVATION IMRT IMRT IMRT

5yrs – Differences in breast appearence (Photos) BREAST CONSERVATION IMRT n=306 R Standard 2D 3D IMRT 5yrs – Differences in breast appearence (Photos) 60% 48% p=0.06 (QoL no difference) Yarnold et al., ECCO 13; 2005

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

TARGET VOLUME ? SCHLUSSFOLGERUNG

MAMMARIA INTERNA – RT: SFRO trial TARGET VOLUME ? MAMMARIA INTERNA – RT: SFRO trial PATIENTS / METHODS RESULTS n=1281 (1/91 – 12/97); MI-RT+ MI-RT Median f-up: 65mo Death 19% 19% Mastectomy Cancer 11% 11% LR 4% 3% Meta 17% 20% CW+Supra CW+Supra+MI R

RT – BREAST CANCER RE-IRRADIATION