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 Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer . However , because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses , concerns have been raised about these findings . We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer . METHODS We did this r and omised , open-label , phase 3 study at 47 institutions in Japan . Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were r and omly assigned ( 1:1 ) to receive prophylactic cranial irradiation ( 25 Gy in ten daily fractions of 2·5 Gy ) or observation . All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment . R and omisation was done by computer-generated allocation sequence , with age as a stratification factor and minimisation by institution , Eastern Cooperative Oncology Group performance status , and response to initial chemotherapy . The primary endpoint was overall survival , analysed in the intention-to-treat population . This trial is registered with the UMIN Clinical Trials Registry , number UMIN000001755 , and is closed to new participants . FINDINGS Between April 3 , 2009 , and July 17 , 2013 , 224 patients were enrolled and r and omly assigned ( 113 to prophylactic cranial irradiation and 111 to observation ) . In the planned interim analysis on June 18 , 2013 , of the first 163 enrolled patients , Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011 % , result ing in early termination of the study because of futility . In the final analysis , median overall survival was 11·6 months ( 95 % CI 9·5 - 13·3 ) in the prophylactic cranial irradiation group and 13·7 months ( 10·2 - 16·4 ) in the observation group ( hazard ratio 1·27 , 95 % CI 0·96 - 1·68 ; p=0·094 ) . The most frequent grade 3 or worse adverse events at 3 months were anorexia ( six [ 6 % ] of 106 in the prophylactic cranial irradiation group vs two [ 2 % ] of 111 in the observation group ) , malaise ( three [ 3 % ] vs one [ < 1 % ] ) , and muscle weakness in a lower limb ( one [ < 1 % ] vs six [ 5 % ] ) . No treatment-related deaths occurred in either group . INTERPRETATION In this Japanese trial , prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer .  Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up . FUNDING The Ministry of Health , Labour and Welfare of Japan OBJECTIVE To evaluate the effect of prophylactic cranial irradiation ( PCI ) on overall survival ( OS ) in patients with extensive small cell lung cancer ( ESCLC ) . METHODS Between April 2005 and May 2014 , 204 patients with ESCLC who had any response ( according to RECIST 1.1 ) to initial chemotherapy were review ed . All patients had undergone appropriate imaging tests to exclude brain metastases before initial chemotherapy . PCI was performed on 45 patients ( 22.1 % ) and the remaining patients ( 77.9 % ) received no such treatment ( control group ) . Primary endpoint was OS . The incidence of brain metastases , brain metastases-free survival ( BMFS ) , and adverse effects were also evaluated . RESULTS Survival data of the 204 patients were analyzed statistically . PCI significantly prolonged median OS from 12.6 to 16.5 months as compared to the control group ( hazard ratio , HR , 0.63 ; 95 % confidence interval , CI , 0.41 to 0.96 ; p = 0.033 ) . PCI significantly lowered the risk of brain metastases ( HR 0.48 ; 95 % CI 0.30 to 0.76 ; p = 0.001 ) . The 1‑year incidence of brain metastases was 17.1 and 55.9 % in the PCI and control group , respectively . PCI significantly correlated with the increased median BMFS ( p = 0.002 ) . Additionally , multivariate analyses demonstrated that PCI was a favorable independent predictor of OS , BMFS , and the incidence of brain metastases . Acute and chronic adverse effects were generally low grade and well tolerated in patients receiving PCI . CONCLUSION PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND AND PURPOSE : Diffusion tensor imaging ( DTI ) will show abnormal fractional anisotropy ( FA ) in the normal-appearing brain after prophylactic cranial irradiation ( PCI ) . These abnormalities will be more accentuated in patients with underlying vascular risk factors . MATERIAL S AND METHODS : A prospect i ve study by use of DTI and conventional T2-weighted MR images was performed with a 1.5 T unit with 16 patients with small cell lung cancer and undergoing PCI .  All of the T2-weighted images were evaluated with respect to abnormalities in signal intensity of white matter as markers of radiation damage . Measurements of FA were performed before , at the end of , and 6 weeks after radiation therapy . On the FA maps , the bifrontal white matter , the corona radiata , the cerebellum , and the brain stem were evaluated . FA values were compared with respect to age , demographic , and vascular risk factors . Statistical analyses ( Friedman test , Wilcoxon test , and Mann-Whitney U test ) were performed . RESULTS : Fractional anisotropy decreased significantly in supratentorial and infratentorial normal-appearing white matter from the beginning to the end of PCI ( P < .01 ) . A further decline in FA occurred 6 weeks after irradiation ( P < .05 ) . A stronger reduction in FA was observed in patients with more than 1 vascular risk factor . There was an age-related reduction of white matter FA .  Patients 65 years and older showed a trend toward a stronger reduction in FA . CONCLUSION : During the acute phase , after PCI , patients with many vascular risk factors showed stronger damage in the white matter compared with patients with only 1 risk factor Introduction : Conflicting data from r and omized clinical trials incite the debate over the appropriate use of prophylactic cranial irradiation ( PCI ) for patients with extensive‐stage SCLC ( ES‐SCLC ) who achieve clinical response to systemic chemotherapy . The current pattern of practice among U.S. radiation oncologists is unknown . Methods : We surveyed practicing U.S. radiation oncologists through a short online question naire . Respondents ' characteristics and their self‐rated knowledge base were analyzed for association with their treatment recommendations . Results : We received 473 responses from practicing U.S. radiation oncologists . More than half of the respondents had been practicing for more than 10 years after completing residency training , and 70 % had treated more than 10 patients with lung cancer per year . Of the respondents , 90 % recommended  brain magnetic resonance imaging ( MRI )  before initiation of PCI and 98 % recommended PCI for patients with ES‐SCLC after systemic chemotherapy . Half of the respondents followed their patients with brain MRI after completion of PCI . One‐third of the respondents prescribed memantine to patients undergoing PCI . Among the respondents , recent graduates ( p = 0.004 ) and physicians practicing in academic centers ( p = 0.005 ) were more likely to prescribe memantine . Self‐rated knowledge base was not associated with any treatment recommendations . Conclusions : Our analysis revealed that among the respondents , there was a very high adherence to current National Comprehensive Cancer Network guidelines , which recommend providing universal PCI and obtaining brain MRI before initiation of PCI for patients with ES‐SCLC with clinical response to systemic chemotherapy . These guidelines and practice patterns are not supported by clinical evidence because patients in the European Organization for Research and Treatment of Cancer trial did not undergo brain MRI before PCI and the Japanese r and omized trial has shown a possible detrimental effect of PCI  on overall survival when brain MRI was incorporated . A critical reevaluation of current guidelines is essential to determine the appropriate management of these patients BACKGROUND The optimum dose of prophylactic cranial irradiation ( PCI ) for limited-stage small-cell lung cancer ( SCLC ) is unknown . A meta- analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses . This r and omised clinical trial compared the effect of st and ard versus higher PCI doses on the incidence of brain metastases . METHODS Between September , 1999 , and December , 2005 , 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were r and omly assigned to a st and ard ( n=360 , 25 Gy in 10 daily fractions of 2.5 Gy ) or higher PCI total dose ( n=360 , 36 Gy ) delivered using either conventional ( 18 daily fractions of 2 Gy ) or accelerated hyperfractionated ( 24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h ) radiotherapy . All of the treatment schedules excluded weekends . R and omisation was stratified according to medical centre , age ( < /=60 and > 60 years ) , and interval between the start of induction treatment and the date of r and omisation ( < /=90 , 91 - 180 , and > 180 days ) . Eligible patients were r and omised blindly by the data centre of the Institut Gustave Roussy ( PCI99 - 01 and IFCT ) using minimisation , and by the data centres of EORTC ( EORTC ROG and LG ) and RTOG ( for CALGB , ECOG , RTOG , and SWOG ) , both using block stratification . The primary endpoint was the incidence of brain metastases at 2 years . Analysis was by intention-to-treat . This study is registered with Clinical Trials.gov number NCT00005062 . FINDINGS Five patients in the st and ard-dose group and four in the higher-dose group did not receive PCI ; nonetheless , all r and omised patients were included in the effectiveness anlysis . After a median follow-up of 39 months ( range 0 - 89 months ) , 145 patients had brain metastases ; 82 in the st and ard-dose group and 63 in the higher-dose group . There was no significant difference in the 2-year incidence of brain metastases between the st and ard PCI dose group and the higher-dose group , at 29 % ( 95 % CI 24 - 35 ) and 23 % ( 18 - 29 ) , respectively ( hazard ratio [ HR ] 0.80 [ 95 % CI 0.57 - 1.11 ] , p=0.18 ) . 226 patients in the st and ard-dose group and 252 in the higher-dose group died ; 2-year overall survival was 42 % ( 95 % CI 37 - 48 ) in the st and ard-dose group and 37 % ( 32 - 42 ) in the higher-dose group ( HR 1.20 [ 1.00 - 1.44 ] ; p=0.05 ) . The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality :  189 patients in the st and ard group versus 218 in the higher-dose group died of progressive disease . Five serious adverse events occurred in the st and ard-dose group versus zero in the higher-dose group . The most common acute toxic events were fatigue ( 106 [ 30 % ] patients in the st and ard-dose group vs 121 [ 34 % ] in the higher-dose group ) , headache ( 85 [ 24 % ] vs 99 [ 28 % ] ) , and nausea or vomiting ( 80 [ 23 % ] vs 101 [ 28 % ] ) . INTERPRETATION No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI , but there was a significant increase in mortality . PCI at 25 Gy should remain the st and ard of care in limited-stage SCLC . FUNDING Institut Gustave-Roussy , Association pour la Recherche sur le Cancer ( 2001 ) , Programme Hospitalier de Recherche Clinique ( 2007 ) . The European Organisation for Research and Treatment of Cancer ( EORTC ) 
    Output:
    
agent
***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 Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer . However , because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses , concerns have been raised about these findings . We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer . METHODS We did this r and omised , open-label , phase 3 study at 47 institutions in Japan . Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were r and omly assigned ( 1:1 ) to receive prophylactic cranial irradiation ( 25 Gy in ten daily fractions of 2·5 Gy ) or observation . All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment . R and omisation was done by computer-generated allocation sequence , with age as a stratification factor and minimisation by institution , Eastern Cooperative Oncology Group performance status , and response to initial chemotherapy . The primary endpoint was overall survival , analysed in the intention-to-treat population . This trial is registered with the UMIN Clinical Trials Registry , number UMIN000001755 , and is closed to new participants . FINDINGS Between April 3 , 2009 , and July 17 , 2013 , 224 patients were enrolled and r and omly assigned ( 113 to prophylactic cranial irradiation and 111 to observation ) . In the planned interim analysis on June 18 , 2013 , of the first 163 enrolled patients , Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011 % , result ing in early termination of the study because of futility . In the final analysis , median overall survival was 11·6 months ( 95 % CI 9·5 - 13·3 ) in the prophylactic cranial irradiation group and 13·7 months ( 10·2 - 16·4 ) in the observation group ( hazard ratio 1·27 , 95 % CI 0·96 - 1·68 ; p=0·094 ) . The most frequent grade 3 or worse adverse events at 3 months were anorexia ( six [ 6 % ] of 106 in the prophylactic cranial irradiation group vs two [ 2 % ] of 111 in the observation group ) , malaise ( three [ 3 % ] vs one [ < 1 % ] ) , and muscle weakness in a lower limb ( one [ < 1 % ] vs six [ 5 % ] ) . No treatment-related deaths occurred in either group . INTERPRETATION In this Japanese trial , prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer .  Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up . FUNDING The Ministry of Health , Labour and Welfare of Japan OBJECTIVE To evaluate the effect of prophylactic cranial irradiation ( PCI ) on overall survival ( OS ) in patients with extensive small cell lung cancer ( ESCLC ) . METHODS Between April 2005 and May 2014 , 204 patients with ESCLC who had any response ( according to RECIST 1.1 ) to initial chemotherapy were review ed . All patients had undergone appropriate imaging tests to exclude brain metastases before initial chemotherapy . PCI was performed on 45 patients ( 22.1 % ) and the remaining patients ( 77.9 % ) received no such treatment ( control group ) . Primary endpoint was OS . The incidence of brain metastases , brain metastases-free survival ( BMFS ) , and adverse effects were also evaluated . RESULTS Survival data of the 204 patients were analyzed statistically . PCI significantly prolonged median OS from 12.6 to 16.5 months as compared to the control group ( hazard ratio , HR , 0.63 ; 95 % confidence interval , CI , 0.41 to 0.96 ; p = 0.033 ) . PCI significantly lowered the risk of brain metastases ( HR 0.48 ; 95 % CI 0.30 to 0.76 ; p = 0.001 ) . The 1‑year incidence of brain metastases was 17.1 and 55.9 % in the PCI and control group , respectively . PCI significantly correlated with the increased median BMFS ( p = 0.002 ) . Additionally , multivariate analyses demonstrated that PCI was a favorable independent predictor of OS , BMFS , and the incidence of brain metastases . Acute and chronic adverse effects were generally low grade and well tolerated in patients receiving PCI . CONCLUSION PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND AND PURPOSE : Diffusion tensor imaging ( DTI ) will show abnormal fractional anisotropy ( FA ) in the normal-appearing brain after prophylactic cranial irradiation ( PCI ) . These abnormalities will be more accentuated in patients with underlying vascular risk factors . MATERIAL S AND METHODS : A prospect i ve study by use of DTI and conventional T2-weighted MR images was performed with a 1.5 T unit with 16 patients with small cell lung cancer and undergoing PCI .  All of the T2-weighted images were evaluated with respect to abnormalities in signal intensity of white matter as markers of radiation damage . Measurements of FA were performed before , at the end of , and 6 weeks after radiation therapy . On the FA maps , the bifrontal white matter , the corona radiata , the cerebellum , and the brain stem were evaluated . FA values were compared with respect to age , demographic , and vascular risk factors . Statistical analyses ( Friedman test , Wilcoxon test , and Mann-Whitney U test ) were performed . RESULTS : Fractional anisotropy decreased significantly in supratentorial and infratentorial normal-appearing white matter from the beginning to the end of PCI ( P < .01 ) . A further decline in FA occurred 6 weeks after irradiation ( P < .05 ) . A stronger reduction in FA was observed in patients with more than 1 vascular risk factor . There was an age-related reduction of white matter FA .  Patients 65 years and older showed a trend toward a stronger reduction in FA . CONCLUSION : During the acute phase , after PCI , patients with many vascular risk factors showed stronger damage in the white matter compared with patients with only 1 risk factor Introduction : Conflicting data from r and omized clinical trials incite the debate over the appropriate use of prophylactic cranial irradiation ( PCI ) for patients with extensive‐stage SCLC ( ES‐SCLC ) who achieve clinical response to systemic chemotherapy . The current pattern of practice among U.S. radiation oncologists is unknown . Methods : We surveyed practicing U.S. radiation oncologists through a short online question naire . Respondents ' characteristics and their self‐rated knowledge base were analyzed for association with their treatment recommendations . Results : We received 473 responses from practicing U.S. radiation oncologists . More than half of the respondents had been practicing for more than 10 years after completing residency training , and 70 % had treated more than 10 patients with lung cancer per year . Of the respondents , 90 % recommended  brain magnetic resonance imaging ( MRI )  before initiation of PCI and 98 % recommended PCI for patients with ES‐SCLC after systemic chemotherapy . Half of the respondents followed their patients with brain MRI after completion of PCI . One‐third of the respondents prescribed memantine to patients undergoing PCI . Among the respondents , recent graduates ( p = 0.004 ) and physicians practicing in academic centers ( p = 0.005 ) were more likely to prescribe memantine . Self‐rated knowledge base was not associated with any treatment recommendations . Conclusions : Our analysis revealed that among the respondents , there was a very high adherence to current National Comprehensive Cancer Network guidelines , which recommend providing universal PCI and obtaining brain MRI before initiation of PCI for patients with ES‐SCLC with clinical response to systemic chemotherapy . These guidelines and practice patterns are not supported by clinical evidence because patients in the European Organization for Research and Treatment of Cancer trial did not undergo brain MRI before PCI and the Japanese r and omized trial has shown a possible detrimental effect of PCI  on overall survival when brain MRI was incorporated . A critical reevaluation of current guidelines is essential to determine the appropriate management of these patients BACKGROUND The optimum dose of prophylactic cranial irradiation ( PCI ) for limited-stage small-cell lung cancer ( SCLC ) is unknown . A meta- analysis suggested that the incidence of brain metastases might be reduced with higher PCI doses . This r and omised clinical trial compared the effect of st and ard versus higher PCI doses on the incidence of brain metastases . METHODS Between September , 1999 , and December , 2005 , 720 patients with limited-stage SCLC in complete remission after chemotherapy and thoracic radiotherapy from 157 centres in 22 countries were r and omly assigned to a st and ard ( n=360 , 25 Gy in 10 daily fractions of 2.5 Gy ) or higher PCI total dose ( n=360 , 36 Gy ) delivered using either conventional ( 18 daily fractions of 2 Gy ) or accelerated hyperfractionated ( 24 fractions in 16 days with two daily sessions of 1.5 Gy separated by a minimum interval of 6 h ) radiotherapy . All of the treatment schedules excluded weekends . R and omisation was stratified according to medical centre , age ( < /=60 and > 60 years ) , and interval between the start of induction treatment and the date of r and omisation ( < /=90 , 91 - 180 , and > 180 days ) . Eligible patients were r and omised blindly by the data centre of the Institut Gustave Roussy ( PCI99 - 01 and IFCT ) using minimisation , and by the data centres of EORTC ( EORTC ROG and LG ) and RTOG ( for CALGB , ECOG , RTOG , and SWOG ) , both using block stratification . The primary endpoint was the incidence of brain metastases at 2 years . Analysis was by intention-to-treat . This study is registered with Clinical Trials.gov number NCT00005062 . FINDINGS Five patients in the st and ard-dose group and four in the higher-dose group did not receive PCI ; nonetheless , all r and omised patients were included in the effectiveness anlysis . After a median follow-up of 39 months ( range 0 - 89 months ) , 145 patients had brain metastases ; 82 in the st and ard-dose group and 63 in the higher-dose group . There was no significant difference in the 2-year incidence of brain metastases between the st and ard PCI dose group and the higher-dose group , at 29 % ( 95 % CI 24 - 35 ) and 23 % ( 18 - 29 ) , respectively ( hazard ratio [ HR ] 0.80 [ 95 % CI 0.57 - 1.11 ] , p=0.18 ) . 226 patients in the st and ard-dose group and 252 in the higher-dose group died ; 2-year overall survival was 42 % ( 95 % CI 37 - 48 ) in the st and ard-dose group and 37 % ( 32 - 42 ) in the higher-dose group ( HR 1.20 [ 1.00 - 1.44 ] ; p=0.05 ) . The lower overall survival in the higher-dose group is probably due to increased cancer-related mortality :  189 patients in the st and ard group versus 218 in the higher-dose group died of progressive disease . Five serious adverse events occurred in the st and ard-dose group versus zero in the higher-dose group . The most common acute toxic events were fatigue ( 106 [ 30 % ] patients in the st and ard-dose group vs 121 [ 34 % ] in the higher-dose group ) , headache ( 85 [ 24 % ] vs 99 [ 28 % ] ) , and nausea or vomiting ( 80 [ 23 % ] vs 101 [ 28 % ] ) . INTERPRETATION No significant reduction in the total incidence of brain metastases was observed after higher-dose PCI , but there was a significant increase in mortality . PCI at 25 Gy should remain the st and ard of care in limited-stage SCLC . FUNDING Institut Gustave-Roussy , Association pour la Recherche sur le Cancer ( 2001 ) , Programme Hospitalier de Recherche Clinique ( 2007 ) . The European Organisation for Research and Treatment of Cancer ( EORTC ) 
    Output:
    