human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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 .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    