numerous randomized trials have clearly confirmed breast conserving surgery ( bcs ) followed by radiation therapy ( rt ) as a treatment modality comparable to mastectomy for early breast cancer . thus , bcs plus rt is widely accepted as standard therapy in patients with early breast cancer [ 1 - 3 ] . parallel - opposed tangential beams are the traditional rt technique for breast irradiation , covering the breast and chest wall . the lateral borders of the tangential fields are extended by 1 - 2 cm from the body surface to accommodate the setup errors and respiratory motion . intensity - modulated radiation therapy ( imrt ) is currently popular in clinical use due to improved conformity of breast targets , decreasing radiation dose to normal structures , and better outcomes than conventional techniques with regard to skin toxicity and cosmesis [ 4 - 7 ] . imrt using simultaneous integrated boost is able to reduce the number of fraction and overall treatment time . considering these imrt advantages , tomodirect could be a suitable radiation modality for whole breast irradiation without nodal irradiation . tomodirect is a non - rotational treatment option of the tomotherapy hi - art system ( accuray , sunnyvale , ca ) allowing for rt planning and delivery with a series of highly modulated linear beam paths . the couch is moved along the cranial - caudal axis past the fixed fan beam path during delivery of each field . tomodirect also can enable image - guided radiation therapy ( igrt ) using a megavoltage computed tomography ( ct ) scan just prior to radiation treatment and verify the setup error before rt . this technique makes it possible to correct setup error by using igrt , reducing treatment error . this study analyzes patient setup error in tomodirect treatment and assesses risk factors associated with extensive setup errors . one hundred and fifty - one breasts of 147 consecutive patients who underwent whole breast irradiation with tomodirect after bcs for early breast cancer in 2012 and 2013 were evaluated . eligibility criteria were as follows : ( 1 ) histologically proven invasive breast cancer ; ( 2 ) ptis or pt1 - 2 with node - negative stage according to the seventh edition of the american joint committee on cancer ( ajcc ) staging system . all patients were measured for their bust and underbust circumference on simulation day ( fig . when the difference between the bust and underbust circumference is below 10 cm , the breast is defined as small . a difference over 10 cm patients underwent ct scans for 3 mm - slice thickness from the lower neck to the mid abdomen . reference points were marked on the skin on the anterior chest and bilateral intercostal surfaces . according to the contouring guideline , the whole breast planning target volume ( ptv ) included breast palpable tissue and the tumor bed . beam angles were selected to minimize dose to normal tissues and avoid irradiation to the contralateral breast ( fig . a total of 50.4 gy and 57.4 gy in 28 fractions were prescribed to the whole breast ptv and tumor bed , respectively . the contour of ptv and lung were transmitted to digitally reconstructed images , from virtual simulation . for the setup process of radiation treatment , all patients were verified through coincidence between skin center and room laser . before treatment , we acquired megavoltage ct ( mvct ) image with a minimum of 5 cm above and below the level of ptv in the treatment position . the first mvct images were carried out and merged automatically into the kilovoltage ct treatment planning images , and the anterior - posterior , right - left , superior - inferior , and angle of gantry shifts ( i.e. , table angle correction for patient s trunk rotation during igrt ) were calculated by automatic image fusion for soft tissue matching . after automatic breast tissue matching between simulation ct and mvct , the scanned images were manually adjusted for the chest wall and surgical clip . the setup errors were verified by one clinician and one radiation therapist . in this study , systemic error (  ) was defined as the deviation of the geometry between fractionated treatment and simulation isocenter . random error (  ) was defined as the deviation that occurred by fraction - to fraction errors . in the study , extensive setup error was defined as 5 mm above margin along any directions ( fig . a chi - square test was used to evaluate the univariate significance of the association between setup uncertainty and several clinical factors including breast size , body mass index ( bmi ) , status of seroma , and extent of axillary lymph node sampling . null hypotheses of no difference were rejected if p - values were less than 0.05 , or , equivalently , if the 95% confidence intervals of risk point estimates excluded 1 . one hundred and fifty - one breasts of 147 consecutive patients who underwent whole breast irradiation with tomodirect after bcs for early breast cancer in 2012 and 2013 were evaluated . eligibility criteria were as follows : ( 1 ) histologically proven invasive breast cancer ; ( 2 ) ptis or pt1 - 2 with node - negative stage according to the seventh edition of the american joint committee on cancer ( ajcc ) staging system . all patients were measured for their bust and underbust circumference on simulation day ( fig . when the difference between the bust and underbust circumference is below 10 cm , the breast is defined as small . a difference over 10 cm patients underwent ct scans for 3 mm - slice thickness from the lower neck to the mid abdomen . reference points were marked on the skin on the anterior chest and bilateral intercostal surfaces . according to the contouring guideline , the whole breast planning target volume ( ptv ) included breast palpable tissue and the tumor bed . beam angles were selected to minimize dose to normal tissues and avoid irradiation to the contralateral breast ( fig . a total of 50.4 gy and 57.4 gy in 28 fractions were prescribed to the whole breast ptv and tumor bed , respectively . the contour of ptv and lung were transmitted to digitally reconstructed images , from virtual simulation . for the setup process of radiation treatment , all patients were verified through coincidence between skin center and room laser . before treatment , we acquired megavoltage ct ( mvct ) image with a minimum of 5 cm above and below the level of ptv in the treatment position . the first mvct images were carried out and merged automatically into the kilovoltage ct treatment planning images , and the anterior - posterior , right - left , superior - inferior , and angle of gantry shifts ( i.e. , table angle correction for patient s trunk rotation during igrt ) were calculated by automatic image fusion for soft tissue matching . after automatic breast tissue matching between simulation ct and mvct , the scanned images were manually adjusted for the chest wall and surgical clip . the setup errors were verified by one clinician and one radiation therapist . in this study , systemic error (  ) was defined as the deviation of the geometry between fractionated treatment and simulation isocenter . random error (  ) was defined as the deviation that occurred by fraction - to fraction errors . in the study , extensive setup error was defined as 5 mm above margin along any directions ( fig . a chi - square test was used to evaluate the univariate significance of the association between setup uncertainty and several clinical factors including breast size , body mass index ( bmi ) , status of seroma , and extent of axillary lymph node sampling . null hypotheses of no difference were rejected if p - values were less than 0.05 , or , equivalently , if the 95% confidence intervals of risk point estimates excluded 1 . one hundred and fifty - one breasts of 147 consecutive patients were included in this study . the median age was 50 years ( range , 25 to 83 years ) and median bmi was 24 ( range , 16.0 to 33.8 years ) . there were 77 ( 51% ) right breast lesions and 74 ( 49% ) left breast lesions . forty - nine patients ( 32.5% ) enrolled were diagnosed with ductal or lobular carcinoma in situ . eighty - seven ( 57.6% ) had t1 tumors and 15 ( 9.9% ) had t2 tumors . one hundred twenty - four lesions ( 82.1% ) were discovered in upper quadrants and 27 lesions ( 17.9% ) in lower quadrants . ninety - three patients ( 61.6% ) underwent axillary lymph node dissection , and 12 patients ( 7.9% ) had sentinel lymph node biopsy . significant seroma of  15 ml were observed in 26 patients ( 17.2% ) in simulation ct scan . the mean systemic anterior - posterior error was 1.98 mm , right - left was 2.02 , and superior - inferior 2.99 . the mean random anterior - posterior error was 1.87 mm , right - left 2.10 , and superior - inferior errors 2.82 . the mean angle of gantry shifts was 0.6. the mean 3-dimensional distance of systemic setup error was 4.67 mm , and random setup error was 2.06 mm . the univariate and multivariate analyses of extensive setup errors are summarized in table 3 . in the univariate analysis , breast size ( p=0.022 ) however , bmi , chemotherapy , tumor location , number of dissected lymph nodes , and seroma status were not associated with extensive setup error . additional multivariate logistic regression analysis showed that breast size ( odds ratio , 2.82 ; 95% confidence interval , 1.00 to 7.90 ; p=0.049 ) was significantly associated with extensive setup error . the change of weekly mean absolute 3-dimensional distance of setup errors during breast irradiation using tomodirect is summarized in table 4 . the significant biggest change of setup deviation was observed in first week and weekly setup errors decreased gradually over time ( p < 0.001 ) . the mean value of absolute 3-dimensional distance of setup error was 5.68 mm in the first week , and the mean width of change was within 5 mm after the second week . this study assessed the setup error in early breast cancer using tomodirect with weekly igrt . the average setup errors measured were within the 3 mm of anterior - posterior , right - left , and superior - inferior directions , 0.6 of gantry angle shift , and < 5 mm of absolute 3-dimensional distance . our study suggested that ptv margins from tumor bed target volume of 6 mm along all directions was adequate to cover setup error . the most significant setup error was observed in the first week despite the coincidence between the skin center and room laser . patients tend to get nervous on their first radiotherapy , and the resultant muscle tension and irregular respiration could contribute to the large setup errors . in addition , the radiation therapist is not used to the setup of an individual patient during the first week of breast radiation . the setup errors reflect the course of patient s adaptation to the environmental change during the first week . thus , radiation oncologists need to educate the patients for simulation and treatment process and deliver concrete setup information for breast size , respiration , arm position , and edema to the radiation therapists to minimize patient setup errors in the first week . breast size ( the difference between bust and underbust ) had a large effect on setup error . hence it is recommended that meticulous caution should be paid to large - breast patients on every fraction . other patient characteristics , including age , bmi , number of dissected lymph node , or presence of seroma , were not associated with extensive setup error in this study . in our previous study , patients with seroma after surgery had a significant volume reduction of 5% or greater in the tumor bed during conventional breast irradiation . accordingly , we anticipated that seroma was significant in volumetric change , but the presence of seroma had a marginal effect on setup error in this study . several studies analyzed the setup error with cone - beam ct ( cbct ) or electronic portal image devices ( epid ) for breast cancer . performed a prospective study to assess the precision and the reproducibility of the tangential breast irradiation technique with the help of on - line epid . this study demonstrated that day - to - day variations in tangential breast treatment setup were acceptable and within the 5-mm recognized acceptable limit . treated 20 breast cancer patients to quantify the differences in setup errors measured with the cbct and epid . epid registration underestimated the actual bony anatomy setup error in breast cancer patients by 20% to 50% , but using cbct decreased setup uncertainties significantly . tumors in the upper outer quadrant , chest wall thickness  2.0 cm for medial portals , and age over 40 for lateral portals were associated with extensive errors . in our study yang et al . reported that extensive error on the initial fraction had a high probability of extensive setup errors in both portals . in our analysis , the mean systemic anterior - posterior error was 1.98 mm , right - left was 2.02 , and superior - inferior errors was 2.99 mm . the absolute 3-dimensional distance of setup error was about 5 mm . in accord with our results , offerman et al .   in their evaluation of setup errors using helical tomotherapy , suggested that the mean random shift for all patients in the lateral direction was 2.7 mm , longitudinal was 3.1 , and vertical 3.2 mm . our results should be interpreted with the caution that there was no breathing control in our analysis . respiratory movements during normal breathing may be ignored for conventional whole breast irradiation . however , for imrt , respiratory movements are a matter of concern . the setup error for early breast cancer patients who receive weekly igrt using tomodirect , are within 3 mm . the biggest deviation of setup errors was observed in the first fraction during breast irradiation . however , patients with large breast size should be closely observed at all times , especially in the first week of treatment .
purposethis study investigated setup error and effectiveness of weekly image - guided radiotherapy ( igrt ) of tomodirect for early breast cancer.materials and methodsone hundred and fifty - one breasts of 147 consecutive patients who underwent breast conserving surgery followed by whole breast irradiation using tomodirect in 2012 and 2013 were evaluated . 
 all patients received weekly igrt . 
 the weekly setup errors from simulation to each treatment in reference to chest wall and surgical clips were measured . 
 random , systemic , and 3-dimensional setup errors were assessed . 
 extensive setup error was defined as 5 mm above the margin in any directions.resultsall mean errors were within 3 mm of all directions . 
 the mean angle of gantry shifts was 0.6. the mean value of absolute 3-dimensional setup error was 4.67 mm . in multivariate analysis , 
 breast size ( odds ratio , 2.82 ; 95% confidence interval , 1.00 to 7.90 ) was a significant factor for extensive error . 
 the largest significant deviation of setup error was observed in the first week of radiotherapy ( p < 0.001 ) and the deviations gradually decreased with time . 
 the deviation of setup error was 5.68 mm in the first week and within 5 mm after the second week.conclusionin this study , there was a significant association between breast size and significant setup error in breast cancer patients who received tomodirect . 
 the largest deviation occurred in the first week of treatment . 
 therefore , patients with large breasts should be closely observed on every fraction and fastidious attention is required in the first fraction of igrt .