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 Locoregional recurrence is the dominant form of treatment failure in head and neck ( H&N ) cancer . The epidermal growth factor receptor ( EGFR ) is frequently amplified in this disease ( < or=80 % ) and can lead to activation of phosphatidylinositol-3-kinase ( PI3 K ) , both directly and indirectly through Ras . We have shown previously that radioresistance could be conferred via the Ras-PI3 K pathway . Here we investigate the contribution of EGFR to this pathway and its impact on treatment outcome . EXPERIMENTAL DESIGN In a series of 38 H&N cancer patients , overexpression of EGFR by immunohistochemical staining was assessed . PI3 K signaling was evaluated by staining for phosphorylated Akt ( P-Akt ) , a downstream target of PI3 K . Both EGFR and P-Akt were then related to outcome . Radiation survival was determined in the SQ20B cell line , a radioresistant squamous cell line derived from a recurrent laryngeal cancer , after pharmacological blockade of EGFR with Iressa , of Ras by the FTI L744,832 , or of PI3 K by LY294002 . RESULTS A significant association was found between P-Akt staining and local control in the patient series . Two-year local control was 100 % for patients staining 0 - 1 + for P-Akt as compared with 70.6 % for patients staining 2 - 3 + ( P = 0.04 ) . In our series of 38 H&N cancers , 30 ( 78.9 % ) of the specimens were strongly ( 3 + ) positive for EGFR , whereas 25 ( 65.8 % ) were moderately to strongly ( 2 - 3 + ) positive for P-Akt . Pharmacologically inhibiting EGFR , Ras , and PI3 K led to radiosensitization of SQ20B cells . CONCLUSIONS Evaluation of PI3 K activation by Akt phosphorylation might be a prognostic marker for response to therapy , and PI3 K could be a useful target for therapy . These results also suggest that signaling from EGFR to PI3 K can lead to radioresistance BACKGROUND Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2-year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS Patients with recurrent squamous cell carcinoma or a second primary arising in a previously irradiated field were eligible . Four weekly cycles of 5-fluorouracil 300 mg/m2 IV bolus and hydroxyurea 1.5 g by mouth were used with 60 Gy at 1.5 Gy twice-daily fractions . Toxicity was scored according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer ( RTOG/EORTC ) criteria . RESULTS Seventy-nine of the 86 patients enrolled were analyzable . The worst acute toxicity was grade 4 in 17.7 % and grade 5 in 7.6 % . Grade 3 and 4 late toxicities were found in 19.4 % and 3.0 % , respectively . The estimated cumulative incidence of grade 3 to 4 late effects occurring at > 1 year was 9.4 % ( 95 % confidence interval [ CI ] : 0 , 19.7 ) at 2 and 5 years . The 2- and 5-year cumulative incidence for grade 4 toxicity was 3.1 % ( 95 % CI : 0 , 9.3 ) . The estimated 2- and 5-year survival rates were 15.2 % ( 95 % CI : 7.3 , 23.1 ) and 3.8 % ( 95 % CI : 0.8 , 8.0 ) , respectively . Patients who entered the study at > 1 year from initial radiotherapy ( RT ) had better survival than did those who were < 1 year from prior RT ( median survival , 9.8 months vs 5.8 months ; p = .036 ) . No correlation was detected between dose received and overall survival . Three patients were alive at 5 years . CONCLUSION This is the first prospect i ve multi-institutional trial testing reirradiation plus chemotherapy for recurrent or second SCCHN . The approach is feasible with acceptable acute and late effects . The results serve as a benchmark for ongoing RTOG trials The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma ( HNC ) with a high risk of recurrence after salvage surgery PURPOSE Stereotactic body radiotherapy ( SBRT ) has emerged as a promising salvage strategy for unresectable , previously-irradiated recurrent squamous cell carcinomas of the head and neck ( rSCCHN ) . Here-in , we report the first prospect i ve evaluation of patient-reported quality -of-life ( PR-QoL ) following re-irradiation with SBRT±cetuximab for rSCCHN . MATERIAL S AND METHODS From November 2004 to May 2011 , 150 patients with unresectable , rSCCHN in a previously-irradiated field receiving > 40 Gy were treated  with SBRT to 40 - 50 Gy in 5 fractions ± concurrent cetuximab . PR-QoL was prospect ively acquired using the University of Washington Quality -of-Life Revised ( UW-QoL-R ) . RESULTS Overall PR-QoL , health-related PR-QoL , and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing ( p=0.025 ) , speech ( p=0.017 ) , saliva ( p=0.041 ) , activity ( p=0.032 ) and recreation ( p=0.039 ) . CONCLUSIONS Especially for patients surviving > 1-year , improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL result ing from rSCCHN . These improvements in PR-QoL transcend all measured domains in a vali date d PR-QoL assessment tool independent of age , use of cetuximab , tumor volume , and interval since prior irradiation BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab  ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . PURPOSE Recurrent squamous cell carcinoma of the head and neck ( SCCHN ) or new second primary tumor ( SPT ) in a previous radiation field , if not curable by surgery or radiation , is almost always fatal . Chemotherapy alone yields a median survival time ( MST ) of no more than 10 months and 1-year overall survival ( OS ) of 35 % at best . Concurrent reirradiation and chemotherapy is an alternative strategy . PATIENTS AND METHODS Eligibility for Radiation Therapy Oncology Group ( RTOG ) protocol 9911 stipulated recurrent SCCHN or SPT in a previous radiation field . Patients received twice-daily radiation ( 1.5 Gy per fraction bid x 5 days every 2 weeks x4 ) , plus cisplatin 15 mg/m2 intravenously ( IV ) daily x 5 and paclitaxel 20 mg/m2 IV daily x 5 every 2 weeks x4 . Granulocyte colony-stimulated factor was administered days 6 through 13 of each 2-week cycle . RESULTS One hundred five patients were enrolled from March 2000 through June 2003 ; 23 % had SPT . Oropharynx ( 40 % ) and oral cavity ( 27 % ) were the predominant primary sites . Median prior radiation dose was 65.4 Gy . Seventy-four percent of patients completed chemotherapy . Grade 4 or worse acute toxicity occurred in 28 % , grade 4 or worse acute hematologic toxicity in 21 % . Eight treatment-related deaths ( 8 % ) occurred : five in the acute setting , three late ( including two carotid hemorrhages ) . MST was 12.1 months , with estimated 1- and 2-year OS rates of 50.2 % and 25.9 % . CONCLUSION Despite a high incidence of grade 5 toxicity , 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone AIMS To investigate prospect ively the feasibility and efficacy of dose escalation using three-dimensional conformal radiotherapy ( 3D-CRT ) boost technique for locally recurrent nasopharyngeal carcinoma ( NPC ) in a r and omised study . MATERIAL S AND METHODS Thirty-six patients with locally recurrent NPC ( > 6 months interval from previous radical radiotherapy , no cervical lymph-node involvement and no distant metastasis ) were enrolled . Treatment included conventional external-beam radiotherapy to 54 Gy , followed by a 3D-CRT boost to the gross tumour region . Patients were r and omised to three boost dose levels : 16 Gy , 20 Gy and 24 Gy for groups I , II and III , respectively , with 12 patients in each group . All boost doses were delivered in 4-Gy fractions and 3 fractions per week . Median follow-up was 27 months ( range 14 - 44 months ) . RESULTS Three-year , local-recurrence-free survival rate was significantly higher ( 72 % ) for the high-dose group III than for groups I and II ( 37 % and 28 % , respectively , P = 0.047 ) . No significant difference was found in the 3-year overall survival rate among the three groups ( 72 % , 59 % and 82 % for groups I , II and III , respectively ) . Three-year distant metastases rates were 17 % , 0 % and 18 % , respectively . Skull-base invasion ( P = 0.017 ) and pathology ( P = 0.0006 ) correlated with overall survival . Treatment was well tolerated and no significant difference was observed among the three groups in acute and late toxicities ( grade III toxicity is minimal : 17 % , 17 % , 0 % of oral mucositis and 25 % , 17 % , 17 % of nasopharyngeal mucositis in groups I , II , III , respectively , and 8 % leukocytopenia only in group II ; no grade IV toxicity occurred in any of the groups except for a fatal bleeding in group III ) . CONCLUSIONS Re-irradiation with high-dose 3D-CRT boost technique results in high local control rate and acceptable toxicity in patients with recurrent NPC . Dose escalation to the boost volume to 78 Gy ( 54 Gy + 24 Gy boost ) results in improved recurrence-free survival compared with lower doses PURPOSE To prospect ively test the effectiveness of combined chemotherapy and radiation therapy for recurrent head and neck cancer . MATERIAL S AND METHODS In 32 patients ,  external-beam radiation therapy ( 2 Gy/d )  was administered as a 5-day course with simultaneous hydroxyurea ( 1.5 g/d orally ) and 5-fluorouracil ( 300 mg/m(2)/d bolus ) , followed by 9 days of rest . This cycle was repeated until a cumulative soft-tissue radiation dose of 110 Gy ( including prior radiation therapy ) was reached . RESULTS At a median follow 
    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 Locoregional recurrence is the dominant form of treatment failure in head and neck ( H&N ) cancer . The epidermal growth factor receptor ( EGFR ) is frequently amplified in this disease ( < or=80 % ) and can lead to activation of phosphatidylinositol-3-kinase ( PI3 K ) , both directly and indirectly through Ras . We have shown previously that radioresistance could be conferred via the Ras-PI3 K pathway . Here we investigate the contribution of EGFR to this pathway and its impact on treatment outcome . EXPERIMENTAL DESIGN In a series of 38 H&N cancer patients , overexpression of EGFR by immunohistochemical staining was assessed . PI3 K signaling was evaluated by staining for phosphorylated Akt ( P-Akt ) , a downstream target of PI3 K . Both EGFR and P-Akt were then related to outcome . Radiation survival was determined in the SQ20B cell line , a radioresistant squamous cell line derived from a recurrent laryngeal cancer , after pharmacological blockade of EGFR with Iressa , of Ras by the FTI L744,832 , or of PI3 K by LY294002 . RESULTS A significant association was found between P-Akt staining and local control in the patient series . Two-year local control was 100 % for patients staining 0 - 1 + for P-Akt as compared with 70.6 % for patients staining 2 - 3 + ( P = 0.04 ) . In our series of 38 H&N cancers , 30 ( 78.9 % ) of the specimens were strongly ( 3 + ) positive for EGFR , whereas 25 ( 65.8 % ) were moderately to strongly ( 2 - 3 + ) positive for P-Akt . Pharmacologically inhibiting EGFR , Ras , and PI3 K led to radiosensitization of SQ20B cells . CONCLUSIONS Evaluation of PI3 K activation by Akt phosphorylation might be a prognostic marker for response to therapy , and PI3 K could be a useful target for therapy . These results also suggest that signaling from EGFR to PI3 K can lead to radioresistance BACKGROUND Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2-year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS Patients with recurrent squamous cell carcinoma or a second primary arising in a previously irradiated field were eligible . Four weekly cycles of 5-fluorouracil 300 mg/m2 IV bolus and hydroxyurea 1.5 g by mouth were used with 60 Gy at 1.5 Gy twice-daily fractions . Toxicity was scored according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer ( RTOG/EORTC ) criteria . RESULTS Seventy-nine of the 86 patients enrolled were analyzable . The worst acute toxicity was grade 4 in 17.7 % and grade 5 in 7.6 % . Grade 3 and 4 late toxicities were found in 19.4 % and 3.0 % , respectively . The estimated cumulative incidence of grade 3 to 4 late effects occurring at > 1 year was 9.4 % ( 95 % confidence interval [ CI ] : 0 , 19.7 ) at 2 and 5 years . The 2- and 5-year cumulative incidence for grade 4 toxicity was 3.1 % ( 95 % CI : 0 , 9.3 ) . The estimated 2- and 5-year survival rates were 15.2 % ( 95 % CI : 7.3 , 23.1 ) and 3.8 % ( 95 % CI : 0.8 , 8.0 ) , respectively . Patients who entered the study at > 1 year from initial radiotherapy ( RT ) had better survival than did those who were < 1 year from prior RT ( median survival , 9.8 months vs 5.8 months ; p = .036 ) . No correlation was detected between dose received and overall survival . Three patients were alive at 5 years . CONCLUSION This is the first prospect i ve multi-institutional trial testing reirradiation plus chemotherapy for recurrent or second SCCHN . The approach is feasible with acceptable acute and late effects . The results serve as a benchmark for ongoing RTOG trials The purpose of this study was to analyze the tolerance and efficacy of full dose reirradiation combined with chemotherapy in patients with head and neck carcinoma ( HNC ) with a high risk of recurrence after salvage surgery PURPOSE Stereotactic body radiotherapy ( SBRT ) has emerged as a promising salvage strategy for unresectable , previously-irradiated recurrent squamous cell carcinomas of the head and neck ( rSCCHN ) . Here-in , we report the first prospect i ve evaluation of patient-reported quality -of-life ( PR-QoL ) following re-irradiation with SBRT±cetuximab for rSCCHN . MATERIAL S AND METHODS From November 2004 to May 2011 , 150 patients with unresectable , rSCCHN in a previously-irradiated field receiving > 40 Gy were treated  with SBRT to 40 - 50 Gy in 5 fractions ± concurrent cetuximab . PR-QoL was prospect ively acquired using the University of Washington Quality -of-Life Revised ( UW-QoL-R ) . RESULTS Overall PR-QoL , health-related PR-QoL , and select domains commonly affected by re-irradiation progressively increase following an initial 1-month decline with statistically significant improvements noted in swallowing ( p=0.025 ) , speech ( p=0.017 ) , saliva ( p=0.041 ) , activity ( p=0.032 ) and recreation ( p=0.039 ) . CONCLUSIONS Especially for patients surviving > 1-year , improved tumor control associated with SBRT re-irradiation may ameliorate decreased PR-QoL result ing from rSCCHN . These improvements in PR-QoL transcend all measured domains in a vali date d PR-QoL assessment tool independent of age , use of cetuximab , tumor volume , and interval since prior irradiation BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab  ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . PURPOSE Recurrent squamous cell carcinoma of the head and neck ( SCCHN ) or new second primary tumor ( SPT ) in a previous radiation field , if not curable by surgery or radiation , is almost always fatal . Chemotherapy alone yields a median survival time ( MST ) of no more than 10 months and 1-year overall survival ( OS ) of 35 % at best . Concurrent reirradiation and chemotherapy is an alternative strategy . PATIENTS AND METHODS Eligibility for Radiation Therapy Oncology Group ( RTOG ) protocol 9911 stipulated recurrent SCCHN or SPT in a previous radiation field . Patients received twice-daily radiation ( 1.5 Gy per fraction bid x 5 days every 2 weeks x4 ) , plus cisplatin 15 mg/m2 intravenously ( IV ) daily x 5 and paclitaxel 20 mg/m2 IV daily x 5 every 2 weeks x4 . Granulocyte colony-stimulated factor was administered days 6 through 13 of each 2-week cycle . RESULTS One hundred five patients were enrolled from March 2000 through June 2003 ; 23 % had SPT . Oropharynx ( 40 % ) and oral cavity ( 27 % ) were the predominant primary sites . Median prior radiation dose was 65.4 Gy . Seventy-four percent of patients completed chemotherapy . Grade 4 or worse acute toxicity occurred in 28 % , grade 4 or worse acute hematologic toxicity in 21 % . Eight treatment-related deaths ( 8 % ) occurred : five in the acute setting , three late ( including two carotid hemorrhages ) . MST was 12.1 months , with estimated 1- and 2-year OS rates of 50.2 % and 25.9 % . CONCLUSION Despite a high incidence of grade 5 toxicity , 1- and 2-year OS rates for split-course bid radiation therapy and concurrent cisplatin/paclitaxel exceed results generally seen with chemotherapy alone AIMS To investigate prospect ively the feasibility and efficacy of dose escalation using three-dimensional conformal radiotherapy ( 3D-CRT ) boost technique for locally recurrent nasopharyngeal carcinoma ( NPC ) in a r and omised study . MATERIAL S AND METHODS Thirty-six patients with locally recurrent NPC ( > 6 months interval from previous radical radiotherapy , no cervical lymph-node involvement and no distant metastasis ) were enrolled . Treatment included conventional external-beam radiotherapy to 54 Gy , followed by a 3D-CRT boost to the gross tumour region . Patients were r and omised to three boost dose levels : 16 Gy , 20 Gy and 24 Gy for groups I , II and III , respectively , with 12 patients in each group . All boost doses were delivered in 4-Gy fractions and 3 fractions per week . Median follow-up was 27 months ( range 14 - 44 months ) . RESULTS Three-year , local-recurrence-free survival rate was significantly higher ( 72 % ) for the high-dose group III than for groups I and II ( 37 % and 28 % , respectively , P = 0.047 ) . No significant difference was found in the 3-year overall survival rate among the three groups ( 72 % , 59 % and 82 % for groups I , II and III , respectively ) . Three-year distant metastases rates were 17 % , 0 % and 18 % , respectively . Skull-base invasion ( P = 0.017 ) and pathology ( P = 0.0006 ) correlated with overall survival . Treatment was well tolerated and no significant difference was observed among the three groups in acute and late toxicities ( grade III toxicity is minimal : 17 % , 17 % , 0 % of oral mucositis and 25 % , 17 % , 17 % of nasopharyngeal mucositis in groups I , II , III , respectively , and 8 % leukocytopenia only in group II ; no grade IV toxicity occurred in any of the groups except for a fatal bleeding in group III ) . CONCLUSIONS Re-irradiation with high-dose 3D-CRT boost technique results in high local control rate and acceptable toxicity in patients with recurrent NPC . Dose escalation to the boost volume to 78 Gy ( 54 Gy + 24 Gy boost ) results in improved recurrence-free survival compared with lower doses PURPOSE To prospect ively test the effectiveness of combined chemotherapy and radiation therapy for recurrent head and neck cancer . MATERIAL S AND METHODS In 32 patients ,  external-beam radiation therapy ( 2 Gy/d )  was administered as a 5-day course with simultaneous hydroxyurea ( 1.5 g/d orally ) and 5-fluorouracil ( 300 mg/m(2)/d bolus ) , followed by 9 days of rest . This cycle was repeated until a cumulative soft-tissue radiation dose of 110 Gy ( including prior radiation therapy ) was reached . RESULTS At a median follow 
    Output:
    