Adjuvant Radiotherapy

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Adjuvant Radiotherapy

2 Adjuvant Radiotherapy (RT) Versions : Souchon / Blohmer / Friedrichs / Göhring / / Janni / Möbus / Seegenschmiedt Version 2013: Souchon / Friedrichs

3 Adjuvant Radiotherapy open questions areas of controversies - ongoing clinical trials - what we (still) need to know Subgroups suitable for quitclaim any RT for DCIS or invasive carcinoma? DCIS/invasive cancer: no subgroup that does not benefit from RT in terms of decreased local recurrence: ongoing trials DCIS: impact of RT by the fact that recent data not showing survival benefit?: ongoing trials Subgroups suitable for (accelerated) partial breast irradiation / IORT after BCS? Comparative effectiveness of WBI vs. PBI or APBI? For which subgroup equal effectiveness is considered?: ongoing trials Used as definitive radiotherapy without external WBI? Limited to interstitial PBI (GEC-ESTRO)? Fraction size: hypofractionation (hf) vs standard fractionation (nf) regimens? Comparative effectiveness of fractionation regimens? Hf equivalent and also accepted to be a new standard? For which subgroup?: ongoing trials Hypofractionation even, when boost RT is indicated? Post-mastectomy irradiation (PMRT) of the thoracic wall: Risk factors? Who are at risk for developing relapse, particularly the intermediate risk subgroup (RR: 10-20%; T1-2 and N+(1-3), G3, vascular invasion, lobular subtype; >T2 N0)?: ongoing trials In patients with positive SNB but no axilla dissection? Positive margins but no further surgery? After pathological (complete?) response to preoperative chemotherapy (NACT)? Boost RT to the tumor bed following BCS? No subgroup that does not benefit from boost RT in terms of decreased local recurrence? Simultaneously integrated boost RT (SIB) Should SIB replace sequential PBI boost in the context of WBI? Which locoregional lymphatics have to be irradiated? Post surgery: which nodal areas? Axilla, periclavicular, mammaria interna lymphatics? Post PST, even, if primary tumor is responsive to primary systemic treatment: no data from RCT; RCT urgently needed! Impact of advanced technologies? External beam conformal RT techniques: 3D-CRT, IMRT, Tomotherapy, VMAT, Protons, IGRT, SIB Improvement of risk stratification of patients and thus to select individualized optimal radiooncological treatment for each individual

4 EBCTCG-Metaanalysis: MRM+AxD +/- RT 5th Cycle (2000/1/1 - events to 2006/9/30; 20 trials) updated 2009 pn0 = 1.296(16%), pn+(1-3 n) = 3.222(39%), pn+(4/> n) = 2.794(34%) Gains /Treatment(s) Local Relapses No of Pos. Lymph Nodes (n) BC Mortality No Pts 5-y gain due to RT 4.7% pn Logrank 2p 15-y gain due to RT pn0 0.3% 0.1; ns 15-y: M+AxD, no RT 9.4% pn0 26.4% 15-y: M+AxD + RT 3.2% pn0 26.1% 5-y gain due to RT 16.1% pn1(1-3 n) y gain due to RT pn1(1-3 n) 8.1% y: M+AxD, no RT 25.9% pn1(1-3 n) 51.4% 15-y: M+AxD + RT 5.7% pn1(1-3 n) 43.3% 5-y gain due to RT 22.5% pn+(4/> n) y gain due to RT pn+(4/> n) 7.3% y: M+AxD, no RT 40.8% pn+(4/> n) 76.3% 15-y: M+AxD + RT 12.9% pn+(4/> n) 69.0% Darby S, on behalf of the Early Breast Cancer Trialists' Collaborative Group University of Oxford, GB. Overview of the randomised trials of radiotherapy in early breast cancer. SABCS 2009 [MS3-1]

5 Postmastectomy Radiotherapy (PMRT)* to the Chest Wall Oxford / AGO LoE / GR > 3 tumor infiltrated lymph nodes (Lnn.) 1a A tumor infiltrated lymph nodes (Lnn.) 1a A + (depending on patients age) T3 / T4 1a A ++ pt3 pn0 R0 (and no additional risk factors) 2b B +/- If R0 is impossible to reach 1a A ++ After neoadjuvant chemotherapy (NACT) based on the initial stage prior to NACT (cn+, ct3/4a-d) 2a A + In young pts with high risk features 2b C ++ Omission of radiotherapy in case of pcr (breast and nodes) after NACT 3b C +/- Additional RT of supra-/infraclav. region in >3 +Lnn. 1a A ++ * Indications for PMRT are independent of adjuvant systemic treatment 1a A ++

6 Postmastectomy Radiotherapy (PMRT) in pn0 Patients Locoregional relapse risk (LRR; 10 yrs) depending on the number of risk factors (lymphatic vessel invasion, grading G3, tumor >2 cm, close resection margin (cave: different definitions!), premenopausal status, age < 50 yrs.): 0 risk factor: 5% 1 risk factor: 10% 2 risk factors: 15% Metaanalysis of 3 randomized trials: PMRT: decreasing LRR by 83% PMRT: increasing OS by 16% Rowell NP. Radiother Oncol 2009;91:23-32 Consider effects of modern adjuvant systemic cytotoxic treatment Updated (2011/2012) recommendations of NCCN, French Group, NZGG, Belgian KCE (2012): Indication for PMRT in pn0 patients depending on one or more risk factors; Abi-Raab R et al. IJROBP 2011;81:e151-7; ypt0, ypn0: Le Scodan et al. Int J Radiat Oncol Biol Phys 2012;82:e1-7

7 EBCTCG-Metaanalysis: BCS+AxD +/- RT EBCTCG Metaanalysis 2011 Actual Aspects Covering 17 randomized clinical trials Limited to patients after BCS Included 9 x updates of previous trials 7 new trials, 6 of them included cohorts with low risk patients exclusively Compared with 2005, number of patients nearly doubled: n = : pn0 = 7.287, pn+ = 1.050, Nx = any recurrence instead of local recurrence 10 year recurrence 15 year breast cancer death Comparison of EBCTCG metaanalyses: trends : Absolute gain in OS probability by use of RT is unequivocal, however, the amount in the group all patients slightly decreased: -1.6% in the node-negative cohort decreased: -1.8% in the node-positive cohort improved: +1.4% (cancer specific) and +2.5% (OS) Proportional 10 y-recurrence risk reduction (any) by RT improved in all pats. up to 10.7% EBCTCG, Lancet 2011;378: and webappendix

8 EBCTCG-Metaanalysis: BCS+AxD +/- RT Events to 2006/9/30; 17 Trials; Published 2011 pn0 Patients (n = 7.287) and pn+ Patients (n = 1.050) pn0-cohort Netto gain by use of RT in pn0-patients (n = 7.287) due to: reduction in breast cancer mortality: 15-y-gain: - 3.3% (Logrank 2p = 0.005) risk reduction regarding any first recurrence : 10-y-gain: % (Logrank 2p = ) pn+ cohort Netto gain by use of RT in pn+-patients (n = 1.050) due to: reduction in breast cancer mortality: 15-y-gain: - 8.5% (Logrank 2p = 0.01) risk reduction regarding any first recurrence : 10-y-gain: % (Logrank 2p < )

9 EBCTCG-Metaanalysis: BCS+AxD +/- RT Comparison of Mortality Rates 2005 vs. 2011: All Patients (n=10.801) EBCTCG Metaanalyses 2011 vs Breast cancer mortality BCS vs. BCS + RT 2005: 35.9% vs. 30.5% 15-y gain: 5.4% (Logrank 2p = ) Breast cancer mortality BCS vs. BCS + RT 2011: 25.2% vs. 21.4% 15-y gain: 3.8% (Logrank 2p = ) 2011 vs. 2005: Netto gain with RT decreased due to slight reduction in Breast cancer mortality: - 1.6% Any death: - 2.3% 2011 vs. 2005: Overall survival improved due to reduction of: Breast cancer mortality: -5.3% with RT, -10.7% without RT Any death: -0.6% with RT, - 2.9% without RT

10 EBCTCG-Metaanalysis: BCS+AxD +/- RT Comparison of Mortality Rates 2005 vs. 2011: Node Positive Patients (n = 1.050) EBCTCG Metaanalyses 2011 vs Breast cancer mortality BCS vs. BCS + RT 2005: 55.0 % vs % 15-y gain: 7.1 % (Logrank 2p = 0.01) Breast cancer mortality BCS vs. BCS + RT 2011: 51.3 % vs % 15-y gain: 8.5 % (Logrank 2p = 0.01) 2011 vs. 2005: Netto gain with RT increased due to improved reduction of: Breast cancer mortality: + 1.4% Any death: + 2.5% 2011 vs. 2005: Overall survival improved due to improved reduction of: Breast cancer mortality: -3.7% without RT, -10.7% with RT Any death: -0.3% without RT, - 2.8% with RT

11 EBCTCG-Metaanalysis: BCS+AxD+/- RT Key Points Regarding Significant Clinical Benefits by Use of RT 16% absolute decrease (19 vs. 35%) in the risk of breast cancer relapse 4% absolute decrease (21% vs. 25%; p<0.0001) in the risk of dying from breast cancer RT led to a 50% proportional reduction in overall recurrence, which exceeds that from chemotherapy or endocrine therapy alone and is comparable to the benefits of trastuzumab in HER2-neu-positive patients After BCS there are clinically relevant rates of locoregional tumor remains depending on N status, tumor size, grading, age, ER-status RT is effective in eradication of much of those microscopic locoregional residuals that might still be present after BCS If no RT is given, this residuals can metastasise and increase the risk of dying from breast cancer Survival benefit with RT is dependent on several factors including: Tumor residuals must be located in the locoregional area, that has not been eradicated by surgery as well as adjuvant systemic treatment RT must be effective in eradication of this persistent tumor burden There are no distant micrometastases at the time of primary treatment surviving adjuvant systemic treatments Biologic subtype of breast cancer (RR reduction for ER-positive > ER-negative > triple negative pts.) Confirmation of 4:1 relation : for every 4 recurrences avoided by year 10, 1 breast cancer death is avoided by year 15 (which is an identical relation comparing benefits of postmastectomy-rt). Pts. with favourable biologic tumor characteristics, i.e. low number of positive lymph nodes, ER-positivity, have greatest survival benefit from locoregional relapse prevention Buchholz T, Lancet 2011;378:1680-2

12 RT of the Breast after Breast Conserving Surgery (BCS) Oxford / AGO LoE / GR Whole breast irradiation (WBI) 1a A ++ Standard fractionation 1a A ++ Hypofractionation for WBI 1a A ++ª Boost-irradiation (improves local control) 1a A + Absolute benefit depending on patient s age Dose-effect relationship independent of pts. age Boost-irradiation in node-negative tumors, endocrine responsive, complete resection 3a C +/- Simultaneously integrated boost irradiation (SIB) 2a C +/-* 1b 1b Intraoperative irradiation (IORT) As boost-irradiation followed by WBI 2b B + As sole radiotherapy modality 1b C -* * Study participation recommended

13 Boost RT after BCS in Invasive Carcinoma Oxford / AGO LoE / GR Improved local tumor control 1b A + All ages: LRR reduction (7 12%) 1b A + < 40 years: LRR reduction (10 29%) 1b A ++ High grade invasive ductal cancer 2b A + Additional boost RT does not impact survival

14 Simultaneously integrated Boost (SIB) RT after BCS in Invasive Carcinoma I Facts regarding SIB Applicable in low risk breast cancer Standard approach in the Netherlands Dose-reduction of normal tissue Shortening of treatment time Trend: lower total dose in the whole breast, enhanced dose in the tumor bed Acute toxicity similiar, no data on late toxicities Modern IMRT-boost techniques vs. photons/electrons Learning effects resulting from APBI techniques Caveat: changes in the breast tissue during radiation therapy Caveat: large boost-volumens after remodelling of the mamma: Relation between irradiated breast volume and late normal tissue complications (IMPORT-trials!)

15 Simultaneously integrated Boost (SIB) RT after BCS in Invasive Carcinoma II Statement of the German and the Austrian Societies of Radiooncology (DEGRO / ÖGRO) (elaborated by the Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO)) Is the simultaneously integrated boost (SIB) technique ready to be adopted for routine adjuvant radiotherapy? Summary Regarding radiobiological considerations normofractionated SIB seems to be in the therapeutic range, however, prospective data for longterm toxicity are not yet available. Normofractionated WBI plus sequential boost remain standard treatment, hypofractionated WBI plus sequential, normofractionated boost is an alternative for selected patients. Hypofractionated WBI plus SIB is discouraged outside clinical trials. Combination of SIB plus sequential boost is not recommended in the absence of respective data. Whenever modifications of the standard technique are used, an increase of normal tissue dose (especially lung, heart and contralateral breast) has strictly to be avoided. Long-term observation and documentation are mandatory. Sedlmayer F et al. Strahlenther Onkol 2013, 189:

16 Resection Margins: Do They Influence Effectiveness of RT for Invasive Ductal Cancer or DCIS? EORTC 22881/10882-Trials: Boost vs. No Boost-RT Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer Jones HA, Antonini N, Hart AA et al. JCO 2009;27:

17 Resection Margins: Do They Influence Effectiveness of RT for Invasive Ductal Cancer or DCIS? Metaanalysis: Impact of the resection margins and the effect of margin status on local recurrence after breast conserving surgery (BCS) and radiation therapy (RT) + EORTC 22881/10882-Trials: Boost vs. No Boost-RT Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer Houssami N et al Eur J Cancer 2010;46: Jones HA et al. JCO 2009;27: ; Lupe K et al. Int J Radiat Oncol Biol Phys 2011;81:e561-8

18 Side Effects of Radiotherapy (WBI) (Analysis of EORTC Trial after Median f/u of 10.7 yrs.) Independant prognostic factors (p< 0.01) of fibrosis with an increase of moderate/severe fibrosis rate from 13 to 28% Maximum irradiation dose: increasing risk with increasing maximum WBI dose Boost (26.9%) vs. no boost (12.6%): HR = 2.3, CI 95%: , p=0,0001 Boost technique, energy of electron boost (MeV) Concomitant CTX: increased with concomitant CTX Tamoxifen vs. no tamoxifen: increased in postmenopausal woman receiving adjuvant tamoxifen Postsurgery complication: increased for pts. with postoperative breast edema or haematoma Note: Side effects of radiotherapy are Independent of age Decreased, if WBI was delivered with >6 MV photons EORTC trial; Collette S et al. Eur J Cancer 2008;44:

19 Fraction Size in RT for Breast Conservation in Early Breast Cancer Prospective randomised trials comparing different concepts of hypofractionation versus standard fractionated adjuvant radiotherapy following breast conserving surgery update 2012 Standard Hypofractionation p (to standard) p (to standard) Study n f/u Local Local relapse Local Survival Late Dose # of yrs relapse % relapse effects (Gy) fractions Canadian a RMH/GOC b RMH/COG b START A * Locoregional relapses: year f/u START B * Locoregional relapses: year f/u Total n.s. n.s. n.s n.s. n.s worse n.s. n.s. n.s ,3 7,4% ,3 6,3 n.s. n.s. n.s ,3 8,8 n.s n.s better ,9 5, ,9 4,3 n.s better n.s a: Whelan T et al. J Natl Cancer Inst 2002; 94: ; b: Owen JR et al. Lancet Oncol 2006;7: ; c: START Trialists Group. Lancet Oncol 2008;9:331-41; d: START Trialists Group. Lancet 2008;371(9618): ; James ML et al. Cochrane Database Syst Rev Jul 16;(3):CD003860; : 1. James ML et al. Cochrane Database Syst Review, updated Nov 10,2010 (conclusions changed!). 2. Smith BD et al. ASTRO EbM-Guideline. Int J Radiat Oncol Biol Phys 2011;81, DEGRO Ko EC et al. Cancer Radiother 2011;15: : Herbert et al. IJROPB 2012;82: ; *UK START Trials update: 10 year-f/u safe and effective, SABCS 12;S4-1

20 Fraction Size in RT for Breast Conservation in Early Breast Cancer James ML, Lehman M, Hider PN, Jeffery M, Hickey BE, Francis DP. Cochrane Database Syst Rev Nov 10;11:CD003860: Two new studies have been published since the last version of the review, altering our conclusions. We have evidence from four low to medium quality randomised trials that using unconventional fractionation regimens (greater than 2 Gy per fraction) does not affect local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance or late toxicity for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins. Long-term follow up (>5 years) is available for a small proportion of the patients randomised. Longer follow up is required for a more complete assessment of the effect of altered fractionation. 1. UK START Trials-10-year-Update: Haviland JS, Agrawal R, Aird E, et al. on behalf of the START Trialists.. The UK START (Standardisation of Breast Radiotherapy) Trials: 10-Year follow-up results. SABCS 2012; S4-1 Hypofractionated radiotherapy is safe and effective at 10-year follow-up. A lower total radiation dose given in fewer slightly larger fractions and delivered over a shorter period of time was as safe and effective as the standard five-weeks schedule of radiotherapy. 2. Herbert et al. IJROPB 2012;82: : There is no evidence that hypofractionation is inferior to conventional fractionation for breast conserving therapy in patients with Grade 3 breast cancer in this large population-based series after 10 years of follow-up.

21 WBI versus APBI WBI non-invasive APBI short duration of treatment definitive pathology + resection status available widespread availability easier RT-techniques simpler QA issues treatment results are more uniforme better dose homogeneity better cosmetic outcome? quite a variety of techniques: external beam RT, IORT, interstitial multicatheter RT, intracavitary balloon brachyrt different sources applied for RT: electrons, photons, 50 kv-xrays different dose and fractionation schemes, target volumen definitions equieffectiveness of the various techniques is still unclear insufficient clinical and dosimetric data to determine optimal technique WBI = whole breast irradiation APBI = accelerated partial breast irradiation

22 Accelerated Partial Breast Irradiation (APBI) after BCS in Invasive Carcinoma Criteria for Decision Making I - ASTRO Consensus Statement from the American Society for Radiation Oncology (ASTRO) regarding APBI. Smith BD et al. IJROBP 2009;74:

23 Accelerated Partial Breast Irradiation (APBI) after BCS in Invasive Carcinoma Criteria for Decision Making II GEC-ESTRO Patient selection for accelerated partial-breast irradiation (APBI) after BCS: Recommendations of GEC-ESTRO. Polgar et al. Radiother Oncol 2010;94:264-73

24 Accelerated Partial Breast Irradiation (APBI) after BCS in Invasive Carcinoma RCTs Using EBRT with Selected Pats with Prognostically Favorable Factors Author/Trial Touboul et al. (22), 1999 Retrospective statistical analysis, Paris Liljegren et al. (23), 1999 Phase III Trial, Örebro Veronesi et al. (24), 2001 Phase III Trial, Milano Malstrom et al. (25), 2003 Multicentric Phase III trial Winzer et al. (26), 2004 Multicentric Phase III Trial Fyles et al. (27), 2004 Phase III Trial, Toronto Holli et al. (28), 2009 Multicentric Phase III Trial, Number of pts (n) Median follow-up (years) Local recurrences % (95% CI) (n) 528* 7,0 9.8 % ( ) (52/528) 184*/381 9,1 7.1 % ( ) (13/184) 294*/579 9,0 5.4 % ( ) (16/294) 591*/1178 5,1 4.4 % ( ) (26/591) 94*/347 6,3 4.3 % ( ) (4/94) 386*/769 5,6 7.0 % ( ) (27/386) 139*/264 12, % ( ) (16/139) Strnad et al. IJROBP 2011 Annual local recurrences % 1,40 0,77 0,60 0,86 0,78 1,25 0,92 Mean: 0.94% / year

25 Accelerated Partial Breast Irradiation (APBI) after BCS in Invasive Carcinoma APBI Brachytherapy Trials Using Stringent Patient Selection Criteria with Adequate (>5 yrs) f/u Author/Trial Polgar et al., 2009 Hungarian National Institute of Oncology, Phase II, Budapest Johansson et al., 2009 Örebro Med. Centre, Phase II, Örebro King, Kuske et al., 2000 Ochsner Clinic, Phase II, New Orleans Polgar et al, 2008 Hungarian National Institute of Oncology, Phase III, Budapest Arthur et al., 2008 Multicentric Phase II, RTOG Mark et al., 2009 J Arrington Cancer Center, Phase II, Lubbock Antonucci, Vicini et al., 2009 William Beaumont Hospital, Phase II, Detroit Strnad et al., 2010 Multicentric Phase II, German-Austrian Study,Erlangen, Leipzig, Vienna, Linz Number of pts (n) Median follow-up (years) Local recurrences % (95% CI)(n) 45 12,0 8.9 ( ) (4/45) 51 7,2 5.9 ( ) (3/51) 51 6, ( ) (1/51) 88*/258 6,8 4.6 ( ) (4/88) ( ) (6/99) 192 5,4 4.2 ( ) (8/192) 199 9,6 5.0 ( ) (10/199) 274 5, ( ) (8/274) Strnad et al. IJROBP 2011 Annual local recurrences % 0,80 0,82 0,32 0,66 0,87 0,78 0,52 0,55 Mean: 0.66% / year

26 Accelerated Partial Breast Irradiation (APBI) after BCS: IORT in Invasive Carcinoma Administered as Sole RT Modality Long-term data from RCT are sparse Update Targit A-Trial, Vaidya JS et al. SABCS 2012; Leonardi MC et al What are the minimal standards of intraoperative radiotherapy planning and dosimetry for invasive (as well as non-invasive) breast cancer? Different sources applied for RT: electrons, 50 kv-xrays Different dose and fractionation schemes, target volume definitions Equieffectiveness of the various techniques is still unclear Insufficient clinical and dosimetric data to determine optimal technique Criteria for patient selection are unclear Might be possible for patients in whom WBI is not possible

27 Key Points Regarding Accelerated Partial Breast Irradiation (APBI) Whole breast irradiation ( WBI) +/- boost remains the gold standard following BCS APBI carried out with a variety of techniques is feasible for anticipated or postoperative boost RT additional to WBI APBI alone might replace WBI for certain patients, but this approach is still experimental. For selected patients, early results of phase I/II trials look quite comparable to WBI, but there is a paucity of phase III data. Conclusive results of phase III trials will not be available for many years. Radiobiological equieffectiveness of the various techniques as well as distinct toxicities for different APBI approaches are unclear. Major questions for successful application of APBI: Patient selection, fractionation scheme, target volume definition, optimal dose and fractionation scheme, imaging and pathology, clinical trial evidence in terms of efficacy, QoL outcomes, cosmesis, costeffectiveness, long term toxicity.

28 Radiotherapy of the Axilla Oxford / AGO LoE / GR Tumor residuals after axillary dissection 2b B ++ Clinically involved (N1, N2a) and no or incomplete axillary clearing (<7 lnn removed)* 3b B ++ Sentinel node negative 1 B -- Axillary dissection not indicated** (e.g. SLN positive, see surgical chapter) 2a B - Extracapsular tumor spread (ECS) 2b B -- Axillary micrometastases or isolated cells found in regional lymph nodes 3b B -- *Consideration of nodal ratio of positive / total number of removed lymph nodes **Reduction of axillary surgery should not lead to extension of standard target volume for RT

29 Radiotherapy (RT) of Other Locoregional Lymph Node Areas Supra- / infraclavicular lymphatics irradiation: Oxford / AGO LoE / GR Level III involved 3b B + In case of irradiation of axilla 3b B + pn1a 2b* A + pn2a 1* A ++ (p)n3a-c 1* A ++ After NACT/NAT (if pretreatment nodal status was clinically positive)** 3 C +/- Axillary irradiation Following axillary clearing of level I + II 3b D - SNB - 4 D - In case of contraindication or patients withdrawal of sufficient axillary clearing 2b C +/- Internal mammary lymph node irradiation 2b C +/- * NCCN V **consider risk / benefit relationship of RT

30 Radiotherapy of Other Locoregional Lymph Node Areas Internal mammary lymph node irradiation*: 2b C -/+ Due to the lack of sufficient data individual decision in case of: N2b, N3b >pn1b (involvement of internal mammary lymph node detected by SNB) Oxford / AGO LoE / GR pn1c pn3 3b D +/- * The role of RT of internal mammary lymphatics is subject of ongoing clinical trials (French Group; EORTC 22922)

31 Key Points The best results for all clinical endpoints can be obtained by an optimal combination of surgery, systemic treatment and radiotherapy. This might be considered as a plea for dedicated breast cancer centers. Adjuvant systemic treatment has a positive effect on survival (LoE 1a). The influence of adjuvant systemic treatment on locoregional control is existing but not large enough to obviate the use of radiation therapy (LoE 1a). Both, adjuvant systemic treatment and radiotherapy should be started as soon as possible after surgery (LoE 2a). Combined chemotherapy and radiotherapy leads to a higher risk of especially late toxicity: the sequential administration is therefore preferred (LoE 2b). No robust evidence exists to suggest any impact of any particular sequence on overall survival. Thus, the sequence can be discussed on a patient per patient base depending on type (especially the duration) of treatment and the individual patients risk factors. However, RT should be administered within 7 months after surgery (LoE 2b, LoE 3).

32 Concomitant Use of Systemic Therapy with Radiotherapy Oxford / AGO LoE / GR Trastuzumab concurrent with radiotherapy 2b B + Tamoxifen concurrent with radiotherapy 3b C + AI (Letrozol) concurrent with radiotherapy 2a B +/-

33 Remaining Questions and Challenges Regarding the synergistic effects of new drugs and targeted therapies, based on new biological tools for treatment individualization, with ionizing radiation, rigorous prospective evaluation of combined therapy is important to ensure improved long-term benefit/risk ratio.