eligible patients were required to have histologically or cytologically proven inoperable stage iiia or iiib nsclc as defined in the tnm classification of malignant tumors ( 6th edition ) , no previous chemotherapy or radiation therapy , a performance status of 01 on the eastern cooperative oncology group scale , adequate bone marrow reserves , as well as normal liver and renal function . patients were excluded if they had malignant pleural or pericardial effusion , supraclavicular lymphnode metastasis , active secondary cancer , or a concomitant serious illness that contraindicated chemotherapy or pbt . for staging , all the patients underwent computed tomography ( ct ) of the thorax and either ct or magnetic resonance imaging ( mri ) of the brain . the dose escalation of pbt was decided based on consultation with the independent efficacy and safety evaluation committee . the total doses were 66 gy in arm 1 as the standard dose and 74 gy ( 12% higher ) in arm 2 as the elevated dose . the protocol was to treat three patients at a given dose of pbt and perform followup for at least 90 days , and then to escalate to the next level if no doselimiting toxicities ( dlt ) occurred . if one patient developed a dlt , then up to three additional patients were treated at the same dose . dose escalation was stopped if two or more dlt occurred at a given dose level among six patients , and a maximum tolerated dose and rd was determined at the previous dose level . if a dose of 74 gy ( relative biological effectiveness ; rbe ) did not cause dlt , then the actual maximum tolerated dose was not determined ; rather , 74 gy ( rbe ) was defined as the rd . adverse events were graded according to the national cancer institute common terminology criteria for adverse events , version 3.0 . dlt was defined as pbtrelated toxicities occurring within 190 days from the start of radiotherapy and included grade 3 nonhematologic toxicity , excluding nausea , vomiting and esophagitis , as well as grade 4 toxicity , excluding neutropenia . volumetric ct images at the end of the exhalation phase were obtained for treatment planning using a respiratory gating system . external respiratory signals were obtained by monitoring abdominal wall movement throughout simulation on ct , and carried out at every treatment session . each patient was positioned in an immobilization device in the treatment position on a flat table . the primary tumor and clinically positive lymph nodes , seen either on the planning ct ( shortaxis diameter > 1 cm ) or pretreatment positron emission tomography images , constituted the gross tumor volume . the total planning target volume ( ptv ) included the clinical target volume plus a total margin of at least 1.0 cm . pbt started on day 1 of the first cycle of chemotherapy and was delivered once daily for 5 days per week . the total dose of pbt was 66 gy ( rbe ) in 33 fractions in arm 1 and 74 gy ( rbe ) in 37 fractions in arm 2 . the volume of both lungs that received 20 gy ( rbe ) or more of pbt was kept below 30% of the total volume of the lungs , and brachial plexus doses were limited to below 66 gy ( rbe ) . the mean dose to the esophagus and heart were optimally kept below 34 gy ( rbe ) and 40 gy ( rbe ) , respectively . if the treatment volume is larger than the field size limit , ptv is divided into several ptv that are smaller than the maximum field size . treatment in eligible patients began with the administration of two cycles of concurrent chemoradiotherapy and two cycles of consolidation chemotherapy . this consisted of oral administration of s1 twice daily from day 1 to 14 , along with a 60min intravenous infusion of cddp ( 60 mg / m ) on day 1 and , thereafter , at 4week intervals . the patients received one of three fixed oral doses of s1 based on their body surface area . the three doses administered were 40 mg ( body surface area < 1.25 m ) , 50 mg ( body surface area , 1.251.50 m ) and 60 mg ( body surface area 1.50 m ) . the dose escalation of pbt was decided based on consultation with the independent efficacy and safety evaluation committee . the total doses were 66 gy in arm 1 as the standard dose and 74 gy ( 12% higher ) in arm 2 as the elevated dose . the protocol was to treat three patients at a given dose of pbt and perform followup for at least 90 days , and then to escalate to the next level if no doselimiting toxicities ( dlt ) occurred . if one patient developed a dlt , then up to three additional patients were treated at the same dose . dose escalation was stopped if two or more dlt occurred at a given dose level among six patients , and a maximum tolerated dose and rd was determined at the previous dose level . if a dose of 74 gy ( relative biological effectiveness ; rbe ) did not cause dlt , then the actual maximum tolerated dose was not determined ; rather , 74 gy ( rbe ) was defined as the rd . adverse events were graded according to the national cancer institute common terminology criteria for adverse events , version 3.0 . dlt was defined as pbtrelated toxicities occurring within 190 days from the start of radiotherapy and included grade 3 nonhematologic toxicity , excluding nausea , vomiting and esophagitis , as well as grade 4 toxicity , excluding neutropenia . volumetric ct images at the end of the exhalation phase were obtained for treatment planning using a respiratory gating system . external respiratory signals were obtained by monitoring abdominal wall movement throughout simulation on ct , and carried out at every treatment session . each patient was positioned in an immobilization device in the treatment position on a flat table . the primary tumor and clinically positive lymph nodes , seen either on the planning ct ( shortaxis diameter > 1 cm ) or pretreatment positron emission tomography images , constituted the gross tumor volume . the total planning target volume ( ptv ) included the clinical target volume plus a total margin of at least 1.0 cm . pbt started on day 1 of the first cycle of chemotherapy and was delivered once daily for 5 days per week . the total dose of pbt was 66 gy ( rbe ) in 33 fractions in arm 1 and 74 gy ( rbe ) in 37 fractions in arm 2 . the volume of both lungs that received 20 gy ( rbe ) or more of pbt was kept below 30% of the total volume of the lungs , and brachial plexus doses were limited to below 66 gy ( rbe ) . the mean dose to the esophagus and heart were optimally kept below 34 gy ( rbe ) and 40 gy ( rbe ) , respectively . if the treatment volume is larger than the field size limit , ptv is divided into several ptv that are smaller than the maximum field size . treatment in eligible patients began with the administration of two cycles of concurrent chemoradiotherapy and two cycles of consolidation chemotherapy . this consisted of oral administration of s1 twice daily from day 1 to 14 , along with a 60min intravenous infusion of cddp ( 60 mg / m ) on day 1 and , thereafter , at 4week intervals . the patients received one of three fixed oral doses of s1 based on their body surface area . the three doses administered were 40 mg ( body surface area < 1.25 m ) , 50 mg ( body surface area , 1.251.50 m ) and 60 mg ( body surface area 1.50 m ) . nine patients were enrolled in this study , six in arm 1 and three in arm 2 . the patient cohort consisted of five men and four women , with a median age of 72 years . patient characteristics and outcomes ad , adenocarcinoma ; awd , alive with disease ; dod , dead on disease ; ned , no evidence of disease ( recurrence ) ; nos , no specific ; os , overall survival ; pfs , progressionfree survival ; sq , squamous cell carcinoma ; m , male ; f , female ; ps , performance status . the median followup time was 43 months for surviving patients and the median progressionfree survival was 15 months . in arm 1 , grade 3 infection occurred in one patient who then stopped pbt at 60 gy ( rbe ) and chemotherapy at one cycle . no other dlt occurred in arm 1 . similarly , no dlt occurred in arm 2 . all patients without dlt in arm 1 , and all patients in arm 2 , completed their pbt up to the prescribed dose , together with four cycles of chemotherapy . however , one patient developed grade 3 esophageal fistula 9 months after the initiation of pbt ( fig . the maximum esophageal dose of pbt did not exceed 74 gy ( rbe ) , with the exception of the patient with esophageal fistula , who received a dose of 75.8 gy ( rbe ) . this patient also experienced recurrence in the primary tumor site , but not in the lymph nodes , and secondline chemotherapy ( docetaxel ) had started 1 month before the appearance of esophageal fistula . grade 3 esophageal fistula occurring in a patient 9 months after the initiation of pbt . upper middle : ( b ) ct image at 2 months after the initiation of pbt . upper right : ( c ) ct image at 9 months after the initiation of pbt . lower middle : ( e ) upper gi endoscopy at 9 months after the initiation of pbt . lower right : ( f ) bronchial endoscopy at 9 months after the initiation of pbt . overall toxicities experienced by patients following therapy to explain our results , we compared the pbt plans with those of 3dimensional conformal photon radiotherapy ( 3dcrt ) using the same targets and prescribed doses . for all patients , planning images and targets used in pbt were registered to the pinnacle treatment planning system ( phillips , milpitas , ca , usa ) . all plans were normalized such that 95% of the ptv received the same dose of pbt . the lung and heart doses are summarized in table 3 , and the esophageal doses for each patient are listed in table 4 . lung and heart doses for proton and photon radiotherapy lung v5 , relative lung volume irradiated more than 5 gy ; lung v20 , relative lung volume irradiated more than 20 gy ; mhd , mean heart dose ; mld , mean lung dose ; rbe , relative biological effectiveness . esophageal proton dose ( rbe ) and volume ( cc ) patient # 9 experienced esophageal fistula . rbe , relative biological effectiveness ; v66 , v70 and v74 , the esophageal volume irradiated more than 66 gy ( rbe ) , 70 gy ( rbe ) and v74 ( rbe ) , respectively . proton beam therapy has an advantage over other radiation therapies in that the dose drops off and it is , therefore , utilized to reduce the risk to surrounding structures , particularly the lowdose regions in critical structures such as the heart , lungs and esophagus.7 indeed , only radiation pneumonitis below grade 2 occurred in this pbt trial . in general , sparing of normal tissues in the lowtomoderate dose range is superior with proton therapy compared to photon therapy . however , we noted a case with severe esophageal toxicity resulting in a thoracoesophageal fistula without local recurrence in this lesion . first , the esophageal dose may have been too high to avoid a late toxicity probably because the esophagus was within the ptv of this patient , and was , hence , irradiated more than the prescribed dose . moreover , an adaptive planning strategy generally improves sparing of the esophagus;8 however , this was not performed in our study . a second potential reason for the observed toxicity is that combination with concurrent cddp and s1 chemotherapy was not feasible with highdose radiotherapy . a previous phase i study demonstrated that 74 gy photon radiotherapy , together with cddp and s1 , was feasible and promising.6 however , other reports regarding highdose thoracic radiotherapy adopted carboplatin and paclitaxel chemotherapy.4 , 5 , 9 , 10 . a third reason for the toxicity could be the secondline chemotherapy started 1 month before the esophageal fistula , which may have caused a recall phenomenon in the esophageal mucosa.11 after accounting for all possible factors , it is most likely that the high esophageal pbt dose is the main reason for this late esophageal toxicity . in fact , the esophageal dose in other patients without esophageal late toxicities did not exceed 74 gy ( rbe ) . for stage iii nsclc , lymphnodes are located in the mediastinum , which may lead to maximum esophagus doses to prescribed dose or more and it appears to be at a greater risk of severe esophageal toxicity . for the dose to serial organs in the mediatinum such as the esophagus and the bronchus , is a limiting factor in dose escalation . actually , a recent study comparing 74gy and 60gy photon radiotherapy showed no advantage in both local recurrence and overall survival.10 we assumed that overall toxicities were unacceptably high by photon 74 gy irradiation . in this study , the predefined dlt were toxicities occurring up to 90 days after proton beam therapy . when this study was planned , we thought that longer observation periods in the 66gy arm were not necessary to assess the need for dose escalation because 66 gy is considered a standard and safe dose . however , if we had set a period longer than 90 days for dlt observation , we could have detected late toxicity in arm 2 . future study should have a longer observation period so that the need for dose escalation can be properly assessed . in conclusion , considering these issues , we maintain that pbt at a dose of 66 gy ( rbe ) is more appropriate to reduce overall toxicity and improve therapeutic ratios , and identified this as the rd for future clinical trials .