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: PURPOSE The phase III PROCL AIM study evaluated overall survival ( OS ) of concurrent pemetrexed-cisplatin and thoracic radiation therapy ( TRT ) followed by consolidation pemetrexed , versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy . PATIENTS AND METHODS Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer r and omly received ( 1:1 ) pemetrexed 500 mg/m(2 ) and cisplatin 75 mg/m(2 ) intravenously every 3 weeks for three cycles plus concurrent TRT ( 60 to 66 Gy ) followed by pemetrexed consolidation every 3 weeks for four cycles ( arm A ) , or st and ard therapy with etoposide 50 mg/m(2 ) and cisplatin 50 mg/m(2 ) intravenously , every 4 weeks for two cycles plus concurrent TRT ( 60 to 66 Gy ) followed by two cycles of consolidation platinum-based doublet chemotherapy ( arm B ) . The primary objective was OS . The study was design ed as a superiority trial with 80 % power to detect an OS hazard ratio of 0.74 with a type 1 error of .05 . RESULTS Enrollment was stopped early because of futility . Five hundred ninety-eight patients were r and omly assigned ( 301 to arm A , 297 to arm B ) and 555 patients ( 283 in arm A , 272 in arm B ) were treated . Arm A was not superior to arm B in terms of OS ( hazard ratio , 0.98 ; 95 % CI , 0.79 to 1.20 ; median , 26.8 v 25.0 months ; P = .831 ) . Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events ( 64.0 % v 76.8 % ; P = .001 ) , including neutropenia ( 24.4 % v 44.5 % ; P < .001 ) , during the overall treatment period . CONCLUSION Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to st and ard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer BACKGROUND Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases ( N2 ) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival . We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with st and ard concurrent chemotherapy and definitive radiotherapy without resection . METHODS Patients with stage T1 - 3pN2M0 non-small-cell lung cancer were r and omly assigned in a 1:1 ratio to  concurrent induction chemotherapy  ( two cycles of cisplatin [ 50 mg/m(2 ) on days 1 , 8 , 29 , and 36 ] and etoposide [ 50 mg/m(2 ) on days 1 - 5 and 29 - 33 ] ) plus radiotherapy ( 45 Gy ) in multiple academic and community hospitals . If no progression , patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy . Two additional cycles of cisplatin and etoposide were given in both groups . The primary endpoint was overall survival ( OS ) . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00002550 . FINDINGS 202 patients ( median age 59 years , range 31 - 77 ) were assigned to group 1 and 194 ( 61 years , 32 - 78 ) to group 2 .  Median OS was 23.6 months ( IQR 9.0-not reached ) in group 1 versus 22.2 months ( 9.4 - 52.7 ) in group 2 ( hazard ratio [ HR ] 0.87 [ 0.70 - 1.10 ] ; p=0.24 ) . Number of patients alive at 5 years was 37 ( point estimate 27 % ) in group 1 and 24 ( point estimate 20 % ) in group 2 ( odds ratio 0.63 [ 0.36 - 1.10 ] ; p=0.10 ) . With N0 status at thoracotomy , the median OS was 34.4 months ( IQR 15.7-not reached ; 19 [ point estimate 41 % ] patients alive at 5 years ) . Progression-free survival ( PFS ) was better in group 1 than in group 2 , median 12.8 months ( 5.3 - 42.2 ) vs 10.5 months ( 4.8 - 20.6 ) , HR 0.77 [ 0.62 - 0.96 ] ; p=0.017 ) ; the number of patients without disease progression at 5 years was 32 ( point estimate 22 % ) versus 13 ( point estimate 11 % ) , respectively . Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 ( 77 [ 38 % ] and 20 [ 10 % ] , respectively ) and group 2 ( 80 [ 41 % ] and 44 [ 23 % ] , respectively ) . In group 1 , 16 ( 8 % ) deaths were treatment related versus four ( 2 % ) in group 2 . In an exploratory analysis , OS was improved for patients who underwent lobectomy , but not pneumonectomy , versus chemotherapy plus radiotherapy . INTERPRETATION Chemotherapy plus radiotherapy with or without resection ( preferably lobectomy ) are options for patients with stage IIIA(N2 ) non-small-cell lung cancer . FUNDING National Cancer Institute , Canadian Cancer Society , and National Cancer Institute of Canada 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 Based on clinical assessment alone , patients with stage II non-small cell lung cancer ( NSCLC ) comprise only 5 % of all patients with NSCLC . In addition , patients with stage II NSCLC represent a heterogeneous group , since stage II consists of patients with T1 - 2N1 or T3N0 tumors . By definition , patients with tumor invading the chest wall apex , mediastinum , diaphragm , or even the mainstem bronchus may all have T3 tumors . The extent of the data available regarding treatment of each of these different groups is therefore limited . The quality of the data is limited as well , because information often comes from small series of patients . Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization , since data from large , r and omized studies of adjuvant radiation therapy , chemotherapy , or a combination of the two are available for analysis . Superior sulcus tumors are discussed elsewhere in these guidelines OBJECTIVES Stage III non-small cell lung cancer ( NSCLC ) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable , bulky nodal disease . This review up date s the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients . METHODS Systematic search es were conducted through MEDLINE , Embase , and the Cochrane Data base for Systematic Review up to December 2011 , focusing primarily on r and omized trials , selected meta-analyses , practice guidelines , and review s. RESULTS For individuals with stage IIIA or IIIB disease , good performance scores , and minimal weight loss , treatment with combined chemoradiotherapy results in better survival than radiotherapy alone . Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported . Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation . Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy ; however , weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate . The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery . Postoperative radiotherapy  improves local control without improving survival . CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer . Variability in the patients included in r and omized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios . Future trials are needed to investigate the roles of individualized chemotherapy , surgery in particular cohorts or setting s , prophylactic cranial radiation , and adaptive radiation PURPOSE To evaluate the feasibility and efficacy of an intensive multimodality approach with combination chemotherapy , hyperfractionated accelerated chemoradiotherapy , and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB ( LAD-NSCLC ) . PATIENTS AND METHODS Following staging , including mediastinoscopy , 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy ( three courses of split-dose cisplatin and etoposide [ PE ] ) followed by concurrent chemoradiotherapy ( one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy ) . After repeat mediastinoscopy , patients underwent surgery 4 weeks postradiation . RESULTS Of 94 consecutive patients ( 52 stage IIIA [ > or = two lymph node levels involved ] and 42 stage IIIB [ no pleural effusion , no supraclavicular nodes ] ) , 62 ( 66 % ) completed induction and underwent surgery . Complete resection ( R0 ) was achieved in 50 ( 53 % of all patients ) and pathologic complete response ( PCR ) in 24 ( 26 % ) . After a median follow-up of 43 months , the median survival time was 20 months for IIIA , 18 months for IIIB , and 42 months for R0 patients . Calculated survival rates at 4 years were 31 % , 26 % , and 46 % . Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema ( n = 1 ) , stump insufficiency ( n = 2 ) , and cardiac failure ( n = 1 ) . Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy . CONCLUSION This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical BACKGROUND We aim ed to compare overall survival after st and ard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer . METHODS In this open-label r and omised , two-by-two factorial phase 3 study in 185 institutions in the USA and Canada , we enrolled patients ( aged ≥ 18 years ) with unresectable stage III non-small-cell lung cancer , a Zubrod performance status of 0 - 1 , adequate pulmonary function , and no evidence of supraclavicular or contralateral hilar adenopathy . We r and omly assigned ( 1:1:1:1 ) patients to receive either 60 Gy ( st and ard dose ) , 74 Gy ( high dose ) , 60 Gy plus cetuximab , or 74 Gy plus cetuximab . All patients also received concurrent chemotherapy with 45 mg/m(2 ) paclitaxel and carboplatin once a week ( AUC 2 ) ; 2 weeks after chemoradiation , two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( AUC 6 ) . R and omisation was done with permuted block r and omisation methods , stratified by radiotherapy technique , Zubrod performance status , use of PET during staging , and histology ; treatment group assignments were not masked . Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy . The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary . For patients assigned to receive cetuximab , 400 mg/m(2 ) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2 ) , and was continued through consolidation therapy . The primary endpoint was overall survival . All analyses were done by modified intention-to-treat . The study is registered with Clinical Trials.gov , number NCT00533949 . FINDINGS Between Nov 27 , 2007 , and Nov 22 , 2011 , 166 patients were r and omly assigned to receive st and ard-dose chemoradiotherapy , 121 to high-dose chemoradiotherapy , 147 to st and ard-dose chemoradiotherapy and cetuximab , and 110 to high-dose chemoradiotherapy 
    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: PURPOSE The phase III PROCL AIM study evaluated overall survival ( OS ) of concurrent pemetrexed-cisplatin and thoracic radiation therapy ( TRT ) followed by consolidation pemetrexed , versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy . PATIENTS AND METHODS Patients with stage IIIA/B unresectable nonsquamous non-small-cell lung cancer r and omly received ( 1:1 ) pemetrexed 500 mg/m(2 ) and cisplatin 75 mg/m(2 ) intravenously every 3 weeks for three cycles plus concurrent TRT ( 60 to 66 Gy ) followed by pemetrexed consolidation every 3 weeks for four cycles ( arm A ) , or st and ard therapy with etoposide 50 mg/m(2 ) and cisplatin 50 mg/m(2 ) intravenously , every 4 weeks for two cycles plus concurrent TRT ( 60 to 66 Gy ) followed by two cycles of consolidation platinum-based doublet chemotherapy ( arm B ) . The primary objective was OS . The study was design ed as a superiority trial with 80 % power to detect an OS hazard ratio of 0.74 with a type 1 error of .05 . RESULTS Enrollment was stopped early because of futility . Five hundred ninety-eight patients were r and omly assigned ( 301 to arm A , 297 to arm B ) and 555 patients ( 283 in arm A , 272 in arm B ) were treated . Arm A was not superior to arm B in terms of OS ( hazard ratio , 0.98 ; 95 % CI , 0.79 to 1.20 ; median , 26.8 v 25.0 months ; P = .831 ) . Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events ( 64.0 % v 76.8 % ; P = .001 ) , including neutropenia ( 24.4 % v 44.5 % ; P < .001 ) , during the overall treatment period . CONCLUSION Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to st and ard chemoradiotherapy for stage III unresectable nonsquamous non-small-cell lung cancer BACKGROUND Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases ( N2 ) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival . We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with st and ard concurrent chemotherapy and definitive radiotherapy without resection . METHODS Patients with stage T1 - 3pN2M0 non-small-cell lung cancer were r and omly assigned in a 1:1 ratio to  concurrent induction chemotherapy  ( two cycles of cisplatin [ 50 mg/m(2 ) on days 1 , 8 , 29 , and 36 ] and etoposide [ 50 mg/m(2 ) on days 1 - 5 and 29 - 33 ] ) plus radiotherapy ( 45 Gy ) in multiple academic and community hospitals . If no progression , patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy . Two additional cycles of cisplatin and etoposide were given in both groups . The primary endpoint was overall survival ( OS ) . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00002550 . FINDINGS 202 patients ( median age 59 years , range 31 - 77 ) were assigned to group 1 and 194 ( 61 years , 32 - 78 ) to group 2 .  Median OS was 23.6 months ( IQR 9.0-not reached ) in group 1 versus 22.2 months ( 9.4 - 52.7 ) in group 2 ( hazard ratio [ HR ] 0.87 [ 0.70 - 1.10 ] ; p=0.24 ) . Number of patients alive at 5 years was 37 ( point estimate 27 % ) in group 1 and 24 ( point estimate 20 % ) in group 2 ( odds ratio 0.63 [ 0.36 - 1.10 ] ; p=0.10 ) . With N0 status at thoracotomy , the median OS was 34.4 months ( IQR 15.7-not reached ; 19 [ point estimate 41 % ] patients alive at 5 years ) . Progression-free survival ( PFS ) was better in group 1 than in group 2 , median 12.8 months ( 5.3 - 42.2 ) vs 10.5 months ( 4.8 - 20.6 ) , HR 0.77 [ 0.62 - 0.96 ] ; p=0.017 ) ; the number of patients without disease progression at 5 years was 32 ( point estimate 22 % ) versus 13 ( point estimate 11 % ) , respectively . Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 ( 77 [ 38 % ] and 20 [ 10 % ] , respectively ) and group 2 ( 80 [ 41 % ] and 44 [ 23 % ] , respectively ) . In group 1 , 16 ( 8 % ) deaths were treatment related versus four ( 2 % ) in group 2 . In an exploratory analysis , OS was improved for patients who underwent lobectomy , but not pneumonectomy , versus chemotherapy plus radiotherapy . INTERPRETATION Chemotherapy plus radiotherapy with or without resection ( preferably lobectomy ) are options for patients with stage IIIA(N2 ) non-small-cell lung cancer . FUNDING National Cancer Institute , Canadian Cancer Society , and National Cancer Institute of Canada 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 Based on clinical assessment alone , patients with stage II non-small cell lung cancer ( NSCLC ) comprise only 5 % of all patients with NSCLC . In addition , patients with stage II NSCLC represent a heterogeneous group , since stage II consists of patients with T1 - 2N1 or T3N0 tumors . By definition , patients with tumor invading the chest wall apex , mediastinum , diaphragm , or even the mainstem bronchus may all have T3 tumors . The extent of the data available regarding treatment of each of these different groups is therefore limited . The quality of the data is limited as well , because information often comes from small series of patients . Studies of adjuvant therapy after complete resection of stage II NSCLC are an important exception to this generalization , since data from large , r and omized studies of adjuvant radiation therapy , chemotherapy , or a combination of the two are available for analysis . Superior sulcus tumors are discussed elsewhere in these guidelines OBJECTIVES Stage III non-small cell lung cancer ( NSCLC ) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable , bulky nodal disease . This review up date s the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients . METHODS Systematic search es were conducted through MEDLINE , Embase , and the Cochrane Data base for Systematic Review up to December 2011 , focusing primarily on r and omized trials , selected meta-analyses , practice guidelines , and review s. RESULTS For individuals with stage IIIA or IIIB disease , good performance scores , and minimal weight loss , treatment with combined chemoradiotherapy results in better survival than radiotherapy alone . Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported . Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation . Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy ; however , weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate . The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery . Postoperative radiotherapy  improves local control without improving survival . CONCLUSIONS Multimodality therapy is preferable in most subsets of patients with stage III lung cancer . Variability in the patients included in r and omized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios . Future trials are needed to investigate the roles of individualized chemotherapy , surgery in particular cohorts or setting s , prophylactic cranial radiation , and adaptive radiation PURPOSE To evaluate the feasibility and efficacy of an intensive multimodality approach with combination chemotherapy , hyperfractionated accelerated chemoradiotherapy , and definitive surgery in prognostically unfavorable subgroups of locally advanced non-small-cell lung cancer stages IIIA and IIIB ( LAD-NSCLC ) . PATIENTS AND METHODS Following staging , including mediastinoscopy , 94 patients with inoperable LAD-NSCLC were treated preoperatively with chemotherapy ( three courses of split-dose cisplatin and etoposide [ PE ] ) followed by concurrent chemoradiotherapy ( one course of PE combined with 45 Gy hyperfractionated accelerated radiotherapy ) . After repeat mediastinoscopy , patients underwent surgery 4 weeks postradiation . RESULTS Of 94 consecutive patients ( 52 stage IIIA [ > or = two lymph node levels involved ] and 42 stage IIIB [ no pleural effusion , no supraclavicular nodes ] ) , 62 ( 66 % ) completed induction and underwent surgery . Complete resection ( R0 ) was achieved in 50 ( 53 % of all patients ) and pathologic complete response ( PCR ) in 24 ( 26 % ) . After a median follow-up of 43 months , the median survival time was 20 months for IIIA , 18 months for IIIB , and 42 months for R0 patients . Calculated survival rates at 4 years were 31 % , 26 % , and 46 % . Two patients died of sepsis preoperatively and four died postoperatively of pleural empyema ( n = 1 ) , stump insufficiency ( n = 2 ) , and cardiac failure ( n = 1 ) . Other toxicities were acceptable-mainly hematologic during chemotherapy or chemoradiotherapy and esophagitis during chemoradiotherapy . CONCLUSION This intensive multimodality treatment is feasible and demonstrates high efficacy in prognostically unfavorable LAD-NSCLC subgroups with high R0 rates and improved long-term survival compared with historical BACKGROUND We aim ed to compare overall survival after st and ard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer . METHODS In this open-label r and omised , two-by-two factorial phase 3 study in 185 institutions in the USA and Canada , we enrolled patients ( aged ≥ 18 years ) with unresectable stage III non-small-cell lung cancer , a Zubrod performance status of 0 - 1 , adequate pulmonary function , and no evidence of supraclavicular or contralateral hilar adenopathy . We r and omly assigned ( 1:1:1:1 ) patients to receive either 60 Gy ( st and ard dose ) , 74 Gy ( high dose ) , 60 Gy plus cetuximab , or 74 Gy plus cetuximab . All patients also received concurrent chemotherapy with 45 mg/m(2 ) paclitaxel and carboplatin once a week ( AUC 2 ) ; 2 weeks after chemoradiation , two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel ( 200 mg/m(2 ) ) and carboplatin ( AUC 6 ) . R and omisation was done with permuted block r and omisation methods , stratified by radiotherapy technique , Zubrod performance status , use of PET during staging , and histology ; treatment group assignments were not masked . Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy . The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary . For patients assigned to receive cetuximab , 400 mg/m(2 ) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2 ) , and was continued through consolidation therapy . The primary endpoint was overall survival . All analyses were done by modified intention-to-treat . The study is registered with Clinical Trials.gov , number NCT00533949 . FINDINGS Between Nov 27 , 2007 , and Nov 22 , 2011 , 166 patients were r and omly assigned to receive st and ard-dose chemoradiotherapy , 121 to high-dose chemoradiotherapy , 147 to st and ard-dose chemoradiotherapy and cetuximab , and 110 to high-dose chemoradiotherapy 
    Output:
    