title: Timing of radiotherapy following breast-conserving surgery: outcome of 1393 patients at a single institution Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Postmastectomy radiation improves local-regional control and survival for selected patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and mastectomy. Prone accelerated partial breast irradiation after breast-conserving surgery: preliminary clinical results and dose-volume histogram analysis. The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-radiotherapy versus chemotherapy-surgery. Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial. Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. DEGRO Practical Guidelines for Radiotherapy of Breast Cancer II Retrospective analysis of locally advanced noninflammatory breast cancer from Chennai, South India, 1990-1999. Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study. Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: National guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group Effect of Primary Tumor Extirpation in Breast Cancer Patients Who Present With Stage IV Disease and an Intact Primary Tumor DEGRO practical guidelines: radiotherapy of breast cancer III—radiotherapy of the lymphatic pathways Breast conservation and prolonged chemotherapy for locally advanced breast cancer: the University of Michigan experience. Prognostic factors in inflammatory breast cancer and therapeutic implications. Prospective randomized trial of paclitaxel alone versus 5-fluorouracil/doxorubicin/cyclophosphamide as induction therapy in patients with operable breast cancer. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? Pattern of rash, diarrhea, and hepatic toxicities secondary to lapatinib and their association with age and response to neoadjuvant therapy: analysis from the NeoALTTO trial.
abstract: Background The role of postoperative radiotherapy in breast-conserving therapy is undisputed . However , optimal timing of adjuvant radiotherapy is an issue of ongoing debate . This retrospective clinical cohort study was performed to investigate the impact of a delay in surgery – radiotherapy intervals on local control and overall survival . Patients and methods Data from an unselected cohort of 1393 patients treated at a single institution over a 17-year period ( 1990–2006 ) were analyzed . Patients were assigned to two groups ( CT+/CT− ) according to chemotherapy status . A delay in the initiation of radiotherapy was defined as > 7 weeks ( CT− group ) and > 24 weeks ( CT+ group ) . Results The 10-year regional recurrence-free survival for the CT− and CT+ groups were 95.6 and 86.0 % , respectively . A significant increase in the median surgery – radiotherapy interval was observed over time ( CT− patients : median of 5 weeks in 1990–1992 to a median of 6 weeks in 2005–2006 ; CT+ patients : median of 5 weeks in 1990–1992 to a median of 21 weeks in 2005–2006 ) . There was no association between a delay in radiotherapy and an increased local recurrence rate ( CT− group : p = 0.990 for intervals 0–6 weeks vs. ≥ 7 weeks ; CT+ group : p = 0.644 for intervals 0–15 weeks vs. ≥ 24 weeks ) or decreased overall survival ( CT− group : p = 0.386 for intervals 0–6 weeks vs. ≥ 7 weeks ; CT+ group : p = 0.305 for intervals 0–15 weeks vs. ≥ 24 weeks ) . Conclusion In the present cohort , a delay of radiotherapy was not associated with decreased local control or overall survival in the two groups ( CT−/CT+ ) . However , in the absence of r and omized evidence , delays in the initiation of radiotherapy should be avoided . ZusammenfassungHintergrundDie zentrale Rolle der postoperativen Strahlentherapie i m Rahmen der brusterhaltenden Therapie ist mittlerweile unbestritten . Allerdings ist der optimale Zeitpunkt für den Beginn der adjuvanten Strahlentherapie weiterhin ungewiss . In dieser retrospektiven Kohortenstudie wurde die mögliche Auswirkung einer verzögerten Einleitung der postoperativen Strahlentherapie auf die lokale Kontrolle , sowie auf das Gesamtüberleben untersucht . Patienten und Method eInsgesamt wurden Date n von 1393 Patienten über einen 17-Jahres-Zeitraum ( 1990–2006 ) analysiert . In Abhängigkeit vom Chemotherapiestatus wurden getrennte Analysen durchgeführt ( CT+/CT− ) . Eine verzögerte Einleitung der Strahlentherapie wurde als ein Intervall von > 7 Wochen ( CT− ) , bzw . > 24 Wochen ( CT+ ) definiert . ErgebnisseDas lokale rezidivfreie Überleben für die CT− und CT+ Gruppe lag nach 10 Jahren bei 95,6 % bzw . 86,0 % . Über den gesamten Zeitraum konnte ein signifikanter Anstieg des medianen Intervalls zwischen Operation und Strahlentherapie festgestellt werden ( CT− : von median 5 Wochen von 1990–1992 auf median 6 Wochen von 2005–2006 ; CT+ : von median 5 Wochen von 1990–1992 auf median 21 Wochen von 2005–2006 ) . Eine Korrelation zwischen verzögertem Beginn der Strahlentherapie und einer erhöhten lokalen Rezidivrate ( CT− : p = 0,990 für Intervalle 0–6 Wochen vs. ≥ 7 Wochen ; CT+ : p = 0,644 für Intervalle 0–15 Wochen vs. ≥ 24 Wochen ) oder einem verringerten Gesamtüberleben ( CT− : p = 0,386 für Intervalle 0–6 Wochen vs. ≥ 7 Wochen ; CT+ : p = 0,305 für Intervalle 0–15 Wochen vs. ≥ 24 Wochen ) wurde nicht gefunden . SchlussfolgerungIn der vorliegenden Kohorte f and sich kein Hinweis auf eine erhöhte Lokalrezidivrate oder ein verringertes Gesamtüberleben bei verzögertem Beginn der Strahlentherapie . Dennoch sollte bei fehlender r and omisierter Evidenz eine Verzögerung bei der Initiierung der Strahlentherapie aufgrund radiobiologischer Erwägungen grundsätzlich vermieden werden BACKGROUND Studies with pertuzumab , a novel anti-HER2 antibody , show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy . We investigated the combination of pertuzumab or trastuzumab , or both , with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting . METHODS In this multicentre , open-label , phase 2 study , treatment-naive women with HER2-positive breast cancer were r and omly assigned ( 1:1:1:1 ) central ly and stratified by operable , locally advanced , and inflammatory breast cancer , and by hormone receptor expression to receive four neoadjuvant cycles of : trastuzumab ( 8 mg/kg loading dose , followed by 6 mg/kg every 3 weeks ) plus docetaxel ( 75 mg/m(2 ) , escalating , if tolerated , to 100 mg/m(2 ) every 3 weeks ; group A ) or pertuzumab ( loading dose 840 mg , followed by 420 mg every 3 weeks ) and trastuzumab plus docetaxel ( group B ) or pertuzumab and trastuzumab ( group C ) or pertuzumab plus docetaxel ( group D ) . The primary endpoint , examined in the intention-to-treat population , was pathological complete response in the breast . Neither patients nor investigators were masked to treatment . This study is registered with Clinical Trials.gov , number NCT00545688 . FINDINGS Of 417 eligible patients , 107 were r and omly assigned to group A , 107 to group B , 107 to group C , and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate ( 49 of 107 patients ; 45·8 % [ 95 % CI 36·1 - 55·7 ] ) compared with those given trastuzumab plus docetaxel ( group A ; 31 of 107 ; 29·0 % [ 20·6 - 38·5 ] ; p=0·0141 ) . 23 of 96 ( 24·0 % [ 15·8 - 33·7 ] ) women given pertuzumab plus docetaxel ( group D ) had a pathological complete response , as did 18 of 107 ( 16·8 % [ 10·3 - 25·3 ] ) given pertuzumab and trastuzumab ( group C ) . The most common adverse events of grade 3 or higher were neutropenia ( 61 of 107 women in group A , 48 of 107 in group B , one of 108 in group C , and 52 of 94 in group D ) , febrile neutropenia ( eight , nine , none , and seven , respectively ) , and leucopenia ( 13 , five , none , and seven , respectively ) . The number of serious adverse events was similar in groups A , B , and D ( 15 - 20 serious adverse events per group in 10 - 17 % of patients ) but lower in group C ( four serious adverse events in 4 % of patients ) . INTERPRETATION Patients given pertuzumab and trastuzumab plus docetaxel ( group B ) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel , without substantial differences in tolerability .  Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile . These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer . FUNDING F Hoffmann-La Roche PURPOSE To evaluate the efficacy of radiation in patients treated with neoadjuvant chemotherapy and mastectomy .  PATIENTS AND METHODS We retrospectively analyzed the outcomes of 542 patients treated on six consecutive institutional prospect i ve trials with neoadjuvant chemotherapy , mastectomy , and radiation .  These data were compared to those of 134 patients who received similar treatment in these same trials but without radiation .  RESULTS Irradiated patients had a lower rate of local-regional recurrence ( LRR ) ( 10-year rates : 11 % v 22 % , P = .0001 ) . Radiation reduced LRR for patients with clinical T3 or T4 tumors , stage > or = IIB disease ( AJCC 1988 ) , pathological tumor size > 2 cm , or four or more positive nodes ( P < or = .002 for all comparisons ) . Patients who presented with clinical ly advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of LRR , which was significantly reduced with radiation ( 10-year rates : 33 % v 3 % , P = .006 ) . Radiation improved cause-specific survival ( CSS ) in the following subsets : stage > or = IIIB disease , clinical T4 tumors , and four or more positive nodes ( P < or = .007 for all comparisons ) . On multivariate analyses of LRR and CSS , the hazard ratios for lack of radiation were 4.7 ( 95 % CI , 2.7 to 8.1 ; P < .0001 ) and 2.0 ( 95 % CI , 1.4 to 2.9 ; P < .0001 ) , respectively . CONCLUSION After neoadjuvant chemotherapy and mastectomy , comprehensive radiation was found to benefit both local control and survival for patients presenting with clinical T3 tumors or stage III-IV ( ipsilateral supraclavicular nodal ) disease and for patients with four or more positive nodes . Radiation should be considered for these patients regardless of their response to initial chemotherapy PURPOSE To report the clinical and dose-volume histogram results of the first 47 patients accrued to a protocol of accelerated partial breast irradiation .  Patients were treated in the prone position with three-dimensional conformal radiotherapy after breast-conserving surgery . METHODS AND MATERIAL S Postmenopausal women with Stage T1N0 breast cancer were eligible only after they had first refused to undergo 6 weeks of st and ard radiotherapy . Planning CT in the prone position was performed on a dedicated table . The postoperative cavity was defined as the clinical target volume , with a 1.5-cm margin added to determine the planning target volume . A total dose of 30 Gy at 6 Gy/fraction was delivered in five fractions within 10 days . RESULTS The median age of the patients was 67.5 years ( range , 51 - 88 years ) . The median tumor diameter was 9 mm ( range , 1.3 - 19 mm ) . In all patients , the prescribed dose encompassed the planning target volume . The mean volume of the ipsilateral breast receiving 100 % of the prescription dose was 26 % ( range , 10 - 45 % ) , and the mean volume contained within the 50 % isodose surface was 47 % ( range , 23 - 75 % ) . The lung and heart were spared by treating in the prone position . Acute toxicity was modest , limited mainly to Grade 1 - 2 erythema . With a median follow-up of 18 months , only Grade 1 late toxicity occurred , and no patient developed local recurrence . CONCLUSION These data suggest that this approach is well tolerated , with only mild acute side effects and sparing of the heart and lung BACKGROUND 5-year results of the UK St and ardisation of Breast Radiotherapy ( START ) trials suggested that lower total doses of radiotherapy delivered in fewer , larger doses ( fractions ) are at least as safe and effective as the historical st and ard regimen ( 50 Gy in 25 fractions ) for women after primary surgery for early breast cancer . In this prespecified analysis , we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens . METHODS From 1999 to 2002 , women with completely excised invasive breast cancer ( pT1 - 3a , pN0 - 1 , M0 ) were enrolled from 35 UK radiotherapy centres . Patients were r and omly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment ( where prescribed ) . R and omisation was computer-generated and stratified by centre , type of primary surgery ( breast-conservation surgery or mastectomy ) , and tumour bed boost radiotherapy . In START-A , a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks . In START-B , a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks . Eligibility criteria included age older than 18 years and no immediate surgical reconstruction . Primary endpoints were local-regional tumour relapse and late normal tissue effects . Analysis was by intention to treat . Follow-up data are still being collected . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N59368779 . FINDINGS START-A enrolled 2236 women . Median follow-up was 9·3 years ( IQR 8·0 - 10·0 ) , after which 139 local-regional relapses had occurred . 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups ( 6·3 % , 95 % CI 4·7 - 8·5 vs 7·4 % , 5·5 - 10·0 ; hazard ratio [ HR ] 0·91 , 95 % CI 0·59 - 1·38 ; p=0·65 ) or the 39 Gy ( 8·8 % , 95 % CI 6·7 - 11·4 ) and 50 Gy regimen groups ( HR 1·18 , 95 % CI 0·79 - 1·76 ; p=0·41 ) . In START-A , moderate or marked breast in duration , telangiectasia , and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group . Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups . START-B enrolled 2215 women . Median follow-up was 9·9 years ( IQR 7·5 - 10·1 ) , after which 95 local-regional relapses had occurred . The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group ( 4·3 % , 95 % CI 3·2 - 5·9 ) and the 50 Gy group ( 5·5 % , 95 % CI 4·2 - 7·2 ; HR 0·77 , 95 % CI 0·51 - 1·16 ; p=0·21 ) . In START-B , breast shrinkage , telangiectasia , and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group . INTERPRETATION Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer . The results support the continued use of 40 Gy in 15 fractions , which has already been adopted by most UK centres as the st and ard of care for women requiring adjuvant radiotherapy for invasive early breast cancer . FUNDING Cancer Research UK , UK Medical Research Council , UK Department of Health In a prospect i ve r and omized study , the efficacy of two combined modality approaches ( chemotherapy plus radiotherapy or chemotherapy plus mastectomy ) was tested in a total of 132 women with locally advanced breast cancer . Chemotherapy consisted of Adriamycin plus vincristine ( AV ) administered for three cycles before either local-regional modality and subsequently for seven additional cycles . Although a higher proportion of women achieved complete remission after mastectomy ( 100 % ) compared to women given radiotherapy ( 60 % ) , the total response rate at the end of combined modality was identical ( 75 % ) . There was no significant difference between the two treatment groups in terms of patterns of treatment failure , median duration of response , and total survival . Treatment was not influenced by menopausal or estrogen receptor status . Two patients of the surgical group showed Adriamycin-induced cardiomyopathy after cumulative doses less than 500 mg/m2 . The results of present study failed to indicate that surgery per se improved the overall results including local control , over radiotherapy in a combined modality setting We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer ( LABC ) . We now report disease-free survival ( DFS ) and overall survival ( OS ) in the context of pathologic response . 105 LABC patients ( White 46 % , Non-White 54 % ) were treated with paclitaxel ( 30 mg/m2 intravenously twice a week ) for 10–12 weeks . Daily radiotherapy was delivered to breast , axillary , and supraclavicular lymph nodes during weeks 2–7 of paclitaxel treatment , at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction . Pathological complete response ( pCR ) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response ( pPR ) as the persistence of < 10 microscopic foci of invasive carcinoma in breast or lymph nodes . Pathologic response ( pCR and pPR ) after neoadjuvant chemoradiation was achieved in 36/105 patients ( 34 % ) and was associated with significantly better DFS and OS . Pathological responders had a lower risk of recurrence or death ( HR = 0.35 , P = 0.01 ) and a longer OS ( HR = 4.27 , P = 0.01 ) compared with non-responders . Median DFS and OS were 57 and 84 months for non-responders , respectively , and have not yet been reached for responders . Importantly , pathologic response was achieved in 54 % of patients with HR negative tumors ( 26/48 ) . In conclusion , pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS . Half of the patients with HR negative tumors achieved a pathologic response PURPOSE To assess the long-term contribution of adjuvant chemotherapy ( CT ) and hormonal therapy ( HT ) in patients with locally advanced breast cancer , and to evaluate the impact of time of analysis on the results during accrual and up to 8 years after closure of a r and omized phase III trial . MATERIAL S AND METHODS In a trial using a factorial design , 410 patients were r and omized between radiotherapy ( RT ) alone , RT plus CT , RT plus HT , and RT plus HT plus CT .  RESULTS CT and HT each produced a significant prolongation of the time to locoregional tumor recurrence and to distant progression of disease , with the combined treatments providing the greatest therapeutic effect . At the time of trial closure , a significant improvement of survival was observed in patients who received CT ( P = .004 ) ; however , with a longer follow-up duration , this effect disappeared ( P > .05 ) . HT did not initially appear to improve survival ( P = .16 ) ; however , in the latest analysis with a long-term follow-up duration , a significant improvement of survival was seen ( P = .02 ) . A consistent 25 % reduction in the death hazards ratio has been seen at all evaluations since trial closure in patients who received HT . The best survival results were observed in patients who received RT , HT , and CT ( P = .02 ) , with a reduction of 35 % in the death hazards ratio . CONCLUSION An improvement in survival attributable to HT has been shown in patients with locally advanced breast cancer . The greatest therapeutic effect was seen in the treatment group that received both CT and HT . The improvement obtained with HT became apparent only after long-term follow-up evaluation PURPOSE To examine the importance of estrogen receptor ( ER ) , progesterone receptor ( PgR ) , human epidermal growth factor receptor 2 ( HER-2 ) , and constructed subtypes in a large study r and omly assigning patients to receive or not receive postmastectomy radiotherapy ( PMRT ) .  PATIENTS AND METHODS The present analysis included 1,000 of the 3,083 high-risk breast cancer patients r and omly assigned to PMRT in the Danish Breast Cancer Cooperative Group ( DBCG ) protocol 82 trials b and c. Tissue microarray sections were stained for ER , PgR , and HER-2 . Median follow-up time for patients alive was 17 years . End points were locoregional recurrence as isolated first event , distant metastases , and overall survival . For statistical analyses four subgroups were constructed from hormonal receptors ( Rec ) . Rec+ was defined as ER+ and /or PgR+ . Rec-as both ER- and PgR- . The four subgroups were Rec+/HER-2- , Rec+/HER-2 + , Rec-/HER-2-(triple negative ) , and Rec-/HER-2 + . RESULTS A significantly improved overall survival after PMRT was seen only among patients characterized by good prognostic markers such as hormonal receptor-positive and HER-2- patients ( including the two Rec+ subtypes ) . No significant overall survival improvement after PMRT was found among patients with an a priori poor prognosis , the hormonal receptor-negative and HER-2 + patients , and in particular the Rec-/HER-2 + subtype . Furthermore , comparing hazard ratios and 95 % CIs , significantly smaller improvements in locoregional recurrence control after PMRT were found for ER- and PgR-tumors compared with the ER+ and PgR+ tumors ( P = .003 and .04 , respectively ) , and for the triple-negative ( P = .02 ) , and the Rec-/HER-2 + subtypes ( P = .003 ) compared with the Rec+/HER-2-subtype . CONCLUSION Hormonal receptor status , HER-2 , and the constructed subtypes may be predictive of locoregional recurrence and survival after postmastectomy radiotherapy Background and Purpose : The aim of the present paper is to up date the practical guidelines for radiotherapy of breast cancer published in 2006 by the breast cancer expert panel of the German Society for Radiooncology ( DEGRO ) . These recommendations were complementing the S3 guidelines of the German Cancer Society ( DKG ) elaborated in 2004 . The present DEGRO recommendations are based on a revision of the DKG guidelines provided by an interdisciplinary panel and published in February 2008 . Methods : The DEGRO expert panel ( authors of the present manuscript ) performed a comprehensive survey of the literature . Data from lately published meta-analyses , recent r and omized trials and guidelines of international breast cancer societies , yielding new aspects compared to 2006 , provided the basis for defining recommendations referring to the criteria of evidence -based medicine . In addition to the more general statements of the DKG , this paper emphasizes specific radiooncologic issues relating to radiotherapy after mastectomy ( PMRT ) , locally advanced disease , irradiation of the lymphatic pathways , and sequencing of local and systemic treatment . Technique , targeting , and dose are described in detail . Results : PMRT significantly reduces local recurrence rates in patients with T3/T4 tumors and /or positive axillary lymph nodes ( 12.9 % with and 40.6 % without PMRT in patients with four or more positive nodes ) . The more local control is improved , the more substantially it translates into increased survival . In node-positive women the absolute reduction in 15-year breast cancer mortality is 5.4 % . Data referring to the benefit of lymphatic irradiation are conflicting . However , radiotherapy of the supraclavicular area is recommended when four or more nodes are positive and otherwise considered individually . Evidence concerning timing and sequencing of local and systemic treatment is sparse ; therefore , treatment decisions should depend on the dominating risk of recurrence . Conclusion : There is common consensus that PMRT is m and atory for patients with T3/T4 tumors and /or four or more positive axillary nodes and should be considered for patients with one to three involved nodes . Irradiation of the lymphatic pathways and the optimal time point for onset of radiotherapy are still under debate . Hintergrund und Ziel : Ziel der Arbeit ist eine Aktualisierung der 2006 publizierten Leitlinie der „ Expertengruppe Mammakarzinom “ der Deutschen Gesellschaft für Radioonkologie ( DEGRO ) . Diese war seinerzeit in Ergänzung zur interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft ( DKG ) von 2004 verfasst worden . Zwischenzeitlich erfolgten eine Überarbeitung und Aktualisierung der S3-Leitlinie der DKG , die i m Februar 2008 publiziert wurde . Method ik : Die Expertengruppe ( identisch mit den Autoren dieses Manuskripts ) führte eine umfassende Literaturrecherche durch . Aktuelle Metaanalysen und r and omisierte Studien , die neue Aspekte gegenüber 2006 ergaben , sowie Empfehlungen internationaler Fachgesellschaften wurden in die Bewertung von Therapieindikationen einbezogen . Diese orientieren sich an den Kriterien evidenzbasierter Medizin . In Ergänzung zu den eher allgemeinen Statements der DKG 2008 werden spezielle radiotherapeutische Fragestellungen beh and elt , die eine Strahlentherapie nach Mastektomie ( PMRT ) und/oder bei fortgeschrittenen Tumoren , die Bestrahlung der Lymphabflusswege und die Sequenz von Radio- und Systemtherapie betreffen . Zielvolumendefinition und Dosierung werden i m Detail beschrieben . Ergebnisse : Die PMRT senkt die Lokalrezidivrate bei Patientinnen mit hohem Rückfallrisiko ( T3/T4-Tumoren und/oder befallene axilläre Lymphknoten ; 12,9 % mit und 40,6 % ohne PMRT ) . Je ausgeprägter die durch die Radiotherapie bewirkte lokale Tumorkontrolle ist , desto stärker wirkt sich dies auf die Überlebenswahrscheinlichkeit aus . Bei lymphonodal positiven Patientinnen ergab sich eine absolute Verminderung der tumorspezifischen Sterblichkeit um 5,4 % nach 15 Jahren . Hinsichtlich des Nutzens einer Strahlentherapie der Lymphabflusswege ist die Date nlage widersprüchlich . Eine Bestrahlung der Supraklavikularregion ist jedoch bei vier oder mehr befallenen axillären Lymphknoten stets indiziert und sollte bei ein bis drei positiven Lymphknoten erwogen werden . Bezüglich der Sequenz von Radio- und Systemtherapie gibt es keine richtungweisenden Evidenzen zugunsten einer Therapiemodalität . Postoperativ sollte die Sequenz vom dominierenden Risiko abhängig gemacht werden . Schlussfolgerung : Nach Mastektomie ist die PMRT bei T3/T4-Tumoren , Resttumor und/oder axillären Lymphknotenmetastasen obligat . Die Bestrahlung der regionalen Lymphabflusswege und die Sequenz von Radio- und Systemtherapie bleiben bei unzureichender Date nlage Gegenst and interdisziplinärer Diskussionen PURPOSE This was a retrospective observational study to elicit the outcome of the therapeutic strategy of concurrent neoadjuvant chemoradiotherapy protocol for locally advanced breast cancer . METHODS AND MATERIAL S A large series of 1,117 consecutive cases of locally advanced breast cancer treated at the Cancer Institute ( WIA ) , in Chennai , South India , between 1990 and 1999 and followed through 2004 formed the basis for this study . Disease-free survival was the main outcome , and nodal and tumor downstaging were the intermediate outcome measures studied . RESULTS Primary tumor downstaging was observed in 45 % and nodal downstaging in 57.5 % . The disease-free survival rate of nodal downstaged patients at 5 , 10 , and 15 years was 75 % , 65 % , and 58 % , respectively . The corresponding rates for pre- and postoperative node-negative patients were 70 % , 60 % , and 59 % . The best survival was seen among those who were tumor and node negative postoperatively . Nodal downstaging halved the risk of disease recurrence and death compared with node positivity , irrespective of tumor sterility . CONCLUSIONS A r and omized trial using cyclophosphamide , methotrexate , and 5-fluorouracil vs. an anthracycline-based regimen in the setting of concurrent chemoradiotherapy appears indicated . Additional preoperative chemotherapy to maximize nodal and tumor downstaging should be investigated . A change in postoperative chemotherapy according to nodal status could also be explored One hundred thirteen evaluable patients with previously untreated stage III breast carcinoma were treated with three monthly cycles of cyclophosphamide ( CYC ) , doxorubicin ( DOX ) , 5-fluorouracil ( 5-FU ) , vincristine ( VCR ) , and prednisone ( PRED ) ( CAFVP ) . Subsequently , 91 ( 81 % ) were deemed operable . Patients were then r and omized to receive surgery or radiotherapy ( RT ) to determine which of these modalities afforded better local tumor control . All patients also received 2 additional years of CAFVP in a further attempt to eradicate local disease and systemic micrometastases . Forty-one of the r and omized patients have relapsed . Approximately half of the initial relapses in each arm were local . The overall duration of disease control was similar following either modality , with a median of 29.2 months for surgery patients and 24.4 months for RT patients . Similarly , there was no major difference in survival related to r and omized treatment with an overall median of 39 months ( median follow-up 37 months ) . Pre- or perimenopausal status and inflammatory disease were associated with shorter disease control and survival . Treatment was generally well tolerated and toxicity was acceptable . This study demonstrates that prolonged control of stage III breast carcinoma  can be achieved with combined modality therapy in which cytotoxic chemotherapy precedes and follows treatment directly primarily at the breast tumor , using either surgery or RT . Nevertheless , new regimens must be design ed if significant advances that may lead to the cure of this disease are to be achieved Abstract During the past decade planning of adjuvant radiotherapy ( RT ) of early breast cancer has changed from two-dimensional ( 2D ) to 3D conformal techniques . In the planning computerised tomography ( CT ) scan both the targets for RT and the organs at risk ( OARs ) are visualised , enabling an increased focus on target dose coverage and homogeneity with only minimal dose to the OARs . To ensure uniform RT in the national prospect i ve trials of the Danish Breast Cancer Cooperative Group ( DBCG ) , a national consensus for the delineation of clinical target volumes ( CTVs ) and OARs was required . Material and methods . A CT scan of a breast cancer patient after surgical breast conservation and axillary lymph node ( LN ) dissection was used for delineation . During multiple dummy-runs seven experienced radiation oncologists contoured all CTVs and OARs of interest in adjuvant breast RT . Two meetings were held in the DBCG Radiotherapy Committee to discuss the contouring and to approve a final consensus . The Dice similarity coefficient ( DSC ) was used to evaluate the delineation agreement before and after the consensus . Results . The consensus delineations of CTVs and OARs are available online and a table is presented with a contouring description of the individual volumes . The consensus provides recommendations for target delineation in a st and ard patient both in case of breast conservation or mastectomy . Before the consensus , the average value of the DSC was modest for most volumes , but high for the breast CTV and the heart . After the consensus , the DSC increased for all volumes . Conclusion . The DBCG has provided the first national guidelines and a contouring atlas of CTVs and OARs definition for RT of early breast cancer . The DSC is a useful tool in quantifying the effect of the introduction of guidelines indicating improved inter-delineator agreement . This consensus will be used by the DBCG in our prospect i ve trials Background Currently , therapy for breast cancer patients with stage IV disease and an intact primary tumor is metastasis directed ; the primary tumor is treated only when it causes symptoms . A recent review suggested that surgery may improve long-term survival in such patients . We evaluated the effect of surgery in such patients on long-term survival and disease progression . Methods We review ed the records of all breast cancer patients treated at our institution between 1997 and 2002 who presented with stage IV disease and an intact primary tumor . Information collected included demographics , tumor characteristics , site(s ) of metastases , type/ date of operation , use of radiotherapy , chemotherapy and hormonal therapy , disease progression ( time to progression and location of progression ) in the first year after diagnosis , and last follow-up . Overall and metastatic progression-free survival were compared between surgery and nonsurgery patients . Results Of 224 patients identified , 82 ( 37 % ) underwent surgical extirpation of the primary tumor ( segmental mastectomy in 39 [ 48 % ] and mastectomy in 43 [ 52 % ] ) , and 142 ( 63 % ) were treated without surgery . The median follow-up time was 32.1 months . After adjustment for other covariates , surgery was associated with a trend toward improvement in overall survival ( P = .12 ; relative risk , .50 ; 95 % confidence interval , .21–1.19 ) and a significant improvement in metastatic progression-free survival ( P = .0007 ; relative risk , .54 ; 95 % confidence interval , .38–.77 ) . Conclusions Removal of the intact primary tumor for breast cancer patients with synchronous stage IV disease is associated with improvement in metastatic progression-free survival . Prospect i ve studies are needed to vali date these findings Aim The purpose of this work is to up date the practical guidelines for adjuvant radiotherapy of the regional lymphatics of breast cancer published in 2008 by the breast cancer expert panel of the German Society of Radiation Oncology ( DEGRO ) . Methods A comprehensive survey of the literature concerning regional nodal irradiation ( RNI ) was performed using the following search terms : “ breast cancer ” , “ radiotherapy ” , “ regional node irradiation ” . Recent r and omized trials were analyzed for outcome as well as for differences in target definition . Field arrangements in the different studies were reproduced and superimposed on CT slices with individually contoured node areas . Moreover , data from recently published meta-analyses and guidelines of international breast cancer societies , yielding new aspects compared to 2008 , provided the basis for defining recommendations according to the criteria of evidence -based medicine . In addition to the more general statements of the German interdisciplinary S3 guidelines up date d in 2012 , this paper addresses indications , targeting , and techniques of radiotherapy of the lymphatic pathways after surgery for breast cancer . Results International guidelines reveal substantial differences regarding indications for RNI .  Patients with 1–3 positive nodes seem to profit from RNI compared to whole breast ( WBI ) or chest wall irradiation alone , both with regard to locoregional control and disease-free survival . Irradiation of the regional lymphatics including axillary , supraclavicular , and internal mammary nodes provided a small but significant survival benefit in recent r and omized trials and one meta- analysis . Lymph node irradiation yields comparable tumor control in comparison to axillary lymph node dissection ( ALND ) , while reducing the rate of lymph edema . Data concerning the impact of 1–2 macroscopically affected sentinel node ( SN ) or microscopic metastases on prognosis are conflicting . Conclusion Recent data suggest that the current restrictive use of RNI should be scrutinized because the risk – benefit relationship appears to shift towards an improvement of outcome .ZusammenfassungZielAktualisierung der DEGRO-Leitlinie von 2008 zur adjuvanten Strahlentherapie des regionalen Lymphabflusses bei Mammakarzinom und Ergänzung der allgemeinen Empfehlungen der interdisziplinären S3-Leitlinie der Deutschen Krebsgesellschaft von 2012 durch spezifisch radioonkologische Leitlinien zur Indikation , Zielvolumendefinition und Technik der postoperativen Radiotherapie . Method enDie DEGRO-Expertengruppe Mammakarzinom führte eine systematische Literaturrecherche nach r and omisierten Studien , Metaanalysen sowie internationalen Leitlinien durch , die nach 2008 publiziert wurden und sich an den Kriterien evidenzbasierter Medizin orientierten . Suchbegriffe waren „ breast cancer “ , „ radiotherapy “ und „ regional node irradiation “ . Die Studien wurden sowohl auf ihre Ergebnisse als auch hinsichtlich der Unterschiede in den Zielvolumina analysiert und auf 3-D-Planungsschnittbilder mit CT-konturierten Lymphabflussgebieten projiziert . ErgebnisseDie Indikation zur regionalen Lymphabflussbestrahlung ( RNI ) wird in internationalen Leitlinien unterschiedlich gestellt . Bei Patientinnen mit 1–3 befallenen axillären Lymphknoten wurden nach RNI i m Vergleich zur alleinigen Bestrahlung der Brust oder Brustw and Verbesserungen der lokoregionalen Kontrolle und des Überlebens beobachtet . Mehrere r and omisierte Studien und eine Metaanalyse zeigten nach RNI ( mit unterschiedlichen Zielvolumina ) eine zwar geringe , jedoch signifikante Verbesserung des Überlebens . Bei positivem Sentinel-Lymphknoten ( SN ) ist die Lymphabflussbestrahlung einer axillären Lymphonodektomie ( ALND ) gleichwertig in der lokalen Tumorkontrolle , geht aber mit einer deutlich geringeren Lymphödemrate einher . Zur Frage , ob ein solch limitierter Lymphknotenbefall und selbst eine Mikrometastasierung langfristig einen Einfluss auf die Prognose haben , ist die Date nlage widersprüchlich . SchlussfolgerungDie restriktive Indikationsstellung zur Lymphabflussbestrahlung muss angesichts neuer Date n aus r and omisierten Studien kritisch überdacht werden PURPOSE To determine whether breast conservation and prolonged neoadjuvant chemotherapy have efficacy in locally advanced breast cancer ( LABC ) , as measured by survival and rate of breast conservation . MATERIAL S AND METHODS Eighty-nine patients with stage III disease were enrolled at the University of Michigan ( UM ) onto a prospect i ve nonr and omized trial . Patients received nine 21-day cycles of neoadjuvant chemohormonal therapy that consisted of doxorubicin 30 mg/m2 and cyclophosphamide 750 mg/m2 intravenously on day 1 , conjugated estrogens 0.625 mg orally twice daily on days 6 to 8 , methotrexate 40 mg/m2 and fluorouracil 500 mg/m2 intravenously on day 8 , and tamoxifen 10 mg orally twice daily on days 9 to 14 . Patients with a negative biopsy received radiation only , while those with residual disease underwent mastectomy and postoperative radiotherapy . Eight more cycles of chemohormonal therapy were administered after local-regional therapy . RESULTS The clinical response rate to neoadjuvant therapy was 97 % , 28 % of patients had a complete pathologic response evaluated at biopsy . Five-year overall and disease-free survival probabilities were 54 % and 44 % , respectively . The median disease-free survival time was 2.4 years . The 5-year actuarial rates of local-regional control with local failure as only first failure were 82 % and 78 % following radiotherapy , and mastectomy and radiotherapy , respectively ( P = .99 ) . CONCLUSION Prolonged neoadjuvant chemohormonal therapy and biopsy-driven local therapy have efficacy in LABC , with 28 % of patients being c and i date s for breast conservation and a 5-year overall survival rate of 54 % 223 inflammatory breast cancer patients were diagnosed at the Institut Curie between 1977 and 1987 . Patients received chemotherapy and radiation treatment according to three consecutive r and omised trials . Five- and 10- year survival rates were 41 and 32 % , respectively . Disease-free interval rates were 25.5 % at 5 years and 19 % at 10 years . Parameters significantly linked with a pejorative prognosis in a multivariate analysis were : diffuse erythema , lymph node involvement , chest wall adherence , and age above 50 years . When therapeutic response parameters were included in the multivariate analysis , the five most important prognostic factors in order of significance were complete tumour regression after completion of induction treatment ( at 8 months ) , complete regression of inflammatory symptoms after 3 months of neoadjuvant chemotherapy , limited erythema at presentation and , less significantly , complete regression of inflammatory symptoms at 8 months and tumour regression at 3 months . In conclusion , patients who achieved a rapid and complete remission had a better prognosis than patients who had an incomplete response to chemotherapy . High-dose chemotherapy and reversal or prevention of drug resistance will be evaluated in future trials . Detailed information on the biology of this disease should allow the design of new strategies aim ing to improve patient management The objective of this study was to compare the antitumor activity of single-agent paclitaxel ( Taxol ; Bristol-Myers Squibb Company , Princeton , NJ ) with that of the 5-fluorouracil/doxorubicin/cyclophosphamide ( FAC ) combination by evaluating the extent of residual disease in the breast and regional lymph nodes of patients with breast cancer following four cycles of induction chemotherapy .  Patients with histologically confirmed invasive but noninflammatory carcinoma of the breast stages T2 - 3 , N0 - 1 , M0 were eligible to enter the study . Patients were treated with four cycles of either FAC or single-agent paclitaxel before local therapy . Following local therapy , treatment of the two arms was identical . Of 104 operable breast cancer patients who were treated with either regimen , 78 were evaluable for response to preoperative chemotherapy and had undergone local therapy . Age , TNM classification , and estrogen receptor status of the patients were similar in the two groups . Following induction chemotherapy , the extent of disease in the breast and the distribution and number of positive nodes were similar between the two treatment arms . Disease progressed in two patients in the FAC arm and in none in the paclitaxel arm during the induction phase of therapy . A higher fraction of patients had neutropenic fever during the paclitaxel treatment . Initial data from this ongoing r and omized study show that paclitaxel alone has comparable anticancer activity with FAC in patients with early breast cancer . The degree of cytoreduction was similar with both induction therapies PURPOSE This retrospective analysis aim ed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission ( cCR ) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery . PATIENTS AND METHODS One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospect ively maintained data base of 453 patients . Of these , 67 patients had undergone surgery as their primary locoregional therapy , and 69 patients had radiotherapy alone . Outcome was assessed in relation to local recurrence-free survival , disease-free survival , and overall survival . RESULTS Median follow-up was 63 months in the surgery group and 87 months in the no surgery group . Prognostic characteristics were well balanced between the two groups . For surgery and no surgery , respectively , there were no significant differences in disease-free survival or overall survival ( 5-year , 74 % v 76 % ; 10-year , 60 % v 70 % , P = .9 ) between the two groups . There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group ( 21 % v 10 % at 5 years ; P = .09 ) , but no long-term failures of local control . Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8 % . CONCLUSION In patients achieving a cCR to neoadjuvant chemotherapy , radiotherapy alone achieve survival rates as good as with surgery , but with higher local recurrence rates . Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospect i ve trial PURPOSE We investigated the pattern of rash , diarrhea , and hepatic adverse events ( AEs ) secondary to lapatinib and their association with age and pathologic complete response ( pCR ) in the Neoadjuvant Lapatinib and /or Trastuzumab Treatment Optimisation ( NeoALLTO ) phase III trial . PATIENTS AND METHODS Patients with HER2-positive early breast cancer were r and omly assigned to receive lapatinib ( Arm A ) , trastuzumab ( Arm B ) , or their combination ( Arm C ) for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery . We investigated the frequency and time to developing each AE according to age ( ≤ 50 v > 50 years ) and their association with pCR in a logistic regression model adjusted for age , hormone receptors , tumor size , nodal status , planned breast surgery , completion of lapatinib administration , and treatment arm . RESULTS Only patients r and omly assigned to arms A and C were eligible ( n = 306 ) . Younger patients ( ≤ 50 years ) experienced significantly more rash compared with older patients ( 74.4 % v 47.9 % ; P < .0001 ) . Diarrhea and hepatic AEs were observed in 78.8 % and 41.2 % of patients , respectively , with no differences in rate or severity or time of onset according to age . Early rash ( ie , before starting paclitaxel ) was independently associated with a higher chance of pCR , mainly in patients older than 50 years ( odds ratio [ OR ] = 3.76 ; 95 % CI , 1.69 to 8.34 ) but not in those ≤ 50 years ( OR = 0.92 ; 95 % CI , 0.45 to 1.88 ; P for interaction = .01 ) . No significant association was observed between pCR and diarrhea or hepatic AEs . CONCLUSION Our results indicate that the frequency and clinical relevance of lapatinib-related rash is largely dependent on patient age
target: In patients with a de novo diagnosis of breast cancer with synchronous distant metastases , surgery and radiotherapy result in considerably better locoregional tumor control .
  An improvement in survival has not been consistently proven , but may exist in subgroups of patients .
  Bei Patientinnen mit primärer Fernmetastasierung führt die lokale Beh and lung mittels Operation und/oder Strahlentherapie zur besseren lokalen Tumorkontrolle .
background: Aim The purpose of this work is to give practical guidelines for radiotherapy of locally advanced , inflammatory and metastatic breast cancer at first presentation .
  ZusammenfassungZielZiel der Arbeit ist die Entwicklung von Praxis-Leitlinien zur Strahlentherapie des lokal fortgeschrittenen einschließlich des inflammatorischen Mammakarzinoms sowie zur lokalen Therapie bei synchroner Fernmetastasierung .
  Ein Überlebensvorteil besteht wohl nicht , möglicherweise aber doch für einige Subgruppen der Patientinnen .