radiation - induced sarcoma ( ris ) is a rare late event after radiation therapy ( rt ) , with a reported incidence of 0.03%- 0.2% in 5 years and overall up to 0.8% . it is known to have a worse prognosis than sporadic soft tissue sarcoma ( sts ) , with a 5-year disease - specific survival ( dss ) rate of 32%-58% in recent reports [ 3 - 5 ] . gladdy et al .   reported that ris had a worse dss than sporadic sts with a hazard ratio of 1.7 . dineen et al .   also recently reported a lower dss of ris than of sporadic sts . because ris arises in the previously treated area .   emphasized the low possibility of curative resection with data showing 62% r0 resection . in the study by neuhaus et al . , r0 - 1 resection was achieved in approximately 37% of the patients and was the only factor showing significant correlation with the dss . in addition , adjuvant rt for ris should be administered with caution because of the higher risk of rt - related toxicities . therefore , concerns about ris are emerging among cancer survivors because the survival rate and the survival time after cancer treatment are increasing as a result of advanced treatments including the use of targeted agents . most studies of ris in asia are case reports , and significantly under - reported compared to western countries . ris patients tend to be referred to a large tertiary center because of the surgical complexity , therefore we report herein the incidence and experience in management of ris at a single large tertiary referral center for 15 years . after receiving institutional review board approval , we retrospectively reviewed our institutional sarcoma registry from january 2000 to april 2014 . out of the 3,674 patients in the registry , we identified 33 patients who met the following criteria for ris , which were modifications of cahan s criteria : ( 1 ) pathologic confirmation of sarcoma that was histologically unique from the primary cancer , ( 2 ) occurrence of the sarcoma in the field of radiation , and ( 3 ) radiation exposure at least 6 months before development of the sarcoma . medical records were reviewed for the patients age , sex , primary cancer treatment , ris characteristics , ris treatment , and follow - up data . the radiographic image of ris and the histopathology report were assessed for identification of the tumor location , size , and histology . all available medical records from the follow - up were reviewed for evaluation of the disease status and toxicity . the toxicities from re - irradiation were evaluated using the common terminology criteria for adverse events ( ctcae ) ver . the overall survival rate was calculated from the time of the ris diagnosis until death . actuarial survival curves were plotted from the ris diagnosis using the kaplan - meier method . a p - value less than 0.05 was considered to indicate a statistically significant difference . the overall survival rate was calculated from the time of the ris diagnosis until death . actuarial survival curves were plotted from the ris diagnosis using the kaplan - meier method . a p - value less than 0.05 was considered to indicate a statistically significant difference . analyses were performed using pasw ver . 18.0 ( spss inc . , chicago , il ) . the number of cases increased from four cases in the years 2000 - 2003 to 14 cases in the years 2012 - 2014 with corresponding proportion of ris among sarcoma patients of 0.5% to 1.6% ( fig . the median age at the primary radiotherapy was 44 years ( range , 0 to 71 years ) . three patients were treated before age 20 ( for bilateral retinoblastoma , wilms tumor , and nasopharyngeal cancer ) , and 20 patients were treated in their 40s and 50s . the median age at the ris diagnosis was 55 years ( range , 22 to 85 years ) , and the median latency was 12.1 years ( range , 1.9 to 28.8 years ) . the most common type of primary cancer was breast cancer ( n=9 ) , followed by uterine cervical cancer ( n=8 ) , and head and neck cancer ( n=7 ) . all patients received a dose greater than 45 gy , with the exception of three patients with wilms tumor , retinoblastoma , and lymphoma treated with 10.8 gy , 36 gy , and 30 gy , respectively . four patients underwent intracavitary brachytherapy in addition to external - beam rt for treatment of cervical cancer ; 58% of patients underwent chemotherapy as their primary cancer treatment . ris was located in the trunk in 75.8% of the cases , and in the head and neck in 24.2% . the most common histology was osteosarcoma ( 36.4% ) , followed by malignant fibrous histiocytoma ( 33.3% ) and angiosarcoma ( 6.1% ) . the median tumor size was 4.8 cm ( range , 1.5 to 12.5 cm ) , and tumors were located deep in the muscle fascia in 27 cases ( 81.8% ) . the median follow - up period was 23.1 months ( range , 2.2 to 174.8 months ) . nineteen patients underwent surgery with curative intent , while 14 patients were treated conservatively . a list of the details of the treatment of 19 patients with curative surgery is shown in table 2 . the median overall survival period of all patients was 2.9 years , and their 5-year survival rate was 44.7% . in univariate and multivariate analyses , the age at diagnosis and the treatment aim showed association with the overall survival ( table 3 ) . the median duration of the overall survival period and the 5-year survival rate of patients treated with curative surgery were 9.6 years and 65% , respectively , and that of the conservatively treated patients , 0.7 years and 0% ( p=0.001 ) ( fig . local recurrence occurred in nine patients ( 47% ) , and distant metastasis , in seven patients ( 37% ) . four patients were misdiagnosed with bone metastasis from their primary tumor and underwent palliative rt before biopsy . three patients underwent palliative radiotherapy , one patient was treated with gamma knife surgery of the recurred mass , and one patient underwent adjuvant rt after curative surgery . five patients , including the familial retinoblastoma patient who developed grade 4 skin necrosis after re - irradiation , showed radiation toxicity after re - irradiation ( table 4 ) . the number of cases increased from four cases in the years 2000 - 2003 to 14 cases in the years 2012 - 2014 with corresponding proportion of ris among sarcoma patients of 0.5% to 1.6% ( fig . the median age at the primary radiotherapy was 44 years ( range , 0 to 71 years ) . three patients were treated before age 20 ( for bilateral retinoblastoma , wilms tumor , and nasopharyngeal cancer ) , and 20 patients were treated in their 40s and 50s . the median age at the ris diagnosis was 55 years ( range , 22 to 85 years ) , and the median latency was 12.1 years ( range , 1.9 to 28.8 years ) . the most common type of primary cancer was breast cancer ( n=9 ) , followed by uterine cervical cancer ( n=8 ) , and head and neck cancer ( n=7 ) . all patients received a dose greater than 45 gy , with the exception of three patients with wilms tumor , retinoblastoma , and lymphoma treated with 10.8 gy , 36 gy , and 30 gy , respectively . four patients underwent intracavitary brachytherapy in addition to external - beam rt for treatment of cervical cancer ; 58% of patients underwent chemotherapy as their primary cancer treatment . ris was located in the trunk in 75.8% of the cases , and in the head and neck in 24.2% . the most common histology was osteosarcoma ( 36.4% ) , followed by malignant fibrous histiocytoma ( 33.3% ) and angiosarcoma ( 6.1% ) . the median tumor size was 4.8 cm ( range , 1.5 to 12.5 cm ) , and tumors were located deep in the muscle fascia in 27 cases ( 81.8% ) . the median follow - up period was 23.1 months ( range , 2.2 to 174.8 months ) . a list of the details of the treatment of 19 patients with curative surgery is shown in table 2 . the median overall survival period of all patients was 2.9 years , and their 5-year survival rate was 44.7% . in univariate and multivariate analyses , the age at diagnosis and the treatment aim showed association with the overall survival ( table 3 ) . the median duration of the overall survival period and the 5-year survival rate of patients treated with curative surgery were 9.6 years and 65% , respectively , and that of the conservatively treated patients , 0.7 years and 0% ( p=0.001 ) ( fig . local recurrence occurred in nine patients ( 47% ) , and distant metastasis , in seven patients ( 37% ) . four patients were misdiagnosed with bone metastasis from their primary tumor and underwent palliative rt before biopsy . three patients underwent palliative radiotherapy , one patient was treated with gamma knife surgery of the recurred mass , and one patient underwent adjuvant rt after curative surgery . five patients , including the familial retinoblastoma patient who developed grade 4 skin necrosis after re - irradiation , showed radiation toxicity after re - irradiation ( table 4 ) . to the best of our knowledge , this is the first study reporting on the incidence and survival of ris in asia in a significant number of patients . our data showed that , although rare , the number of patients diagnosed with ris in our institution is consistently increasing with time . this may be due to the significant increase of rt usage in cancer therapy in south korea since the first cobalt-60 teletherapy installation in 1963 . the increased survival time of cancer patients could also be attributed to the increasing incidence of ris . investigated the question of whether or not a previous rt history is a worse prognosticator . in their analysis , a previous rt history was not a prognostic factor , but unlike sporadic sts , ris tended to occur in a central location and to be associated with incomplete surgery , which are known poor prognosticators in sarcoma . .   stated , previous rt might obscure the anatomic and tumor planes , which might make radical resection challenging . consistently in our data , only 57.6% of the patients could be treated with curative intent , and the survival outcome differed significantly according to the treatment aim . in addition , the adjuvant rt for ris is limited by the concern for possible complications regarding re - irradiation , which can hinder optimal ris management . an adjuvant rt of 42 - 63 gy is known to reduce local recurrence of sts after conservative surgery . however , as shown in this study , rt for ris results in a high rate of rt - related complications , which is inevitable in high - dose regions . due to the rarity and the histologic diversity within ris , it is difficult to analyze the efficacy of secondary adjuvant rt after curative resection of ris . extrapolating from sporadic sts , adjuvant rt should also be performed for ris , but care is required in the process of consultation with the patient , rt planning , and prescription of the rt dose . also , high - precision rt techniques with increased conformality , such as intensity - modulated radiation therapy ( imrt ) , should be used in such re - irradiation cases to minimize the toxicity . the question of whether or not the use of imrt , stereotactic body radiation therapy , or proton therapy would reduce ris incidence is yet to be determined . from the follow - up observation data on atomic bomb survivors who showed no excess of sarcoma after exposure to radiation of a few gy , we acknowledge that ris is less likely to arise in very low - dose regions , and more likely to arise in intermediate- to high - dose regions of above 5 gy , with some evidence of a dose - response relationship . however , as studies regarding ris , including this study , lack data on the initial dose prescribed for the ris lesion due to the loss or incompleteness of the topographic primary rt planning information , accurate dose - incidence evaluation is limited . increased conformality with high - precision rt techniques would reduce the high - dose region , but integral doses in irradiated regions can be increased . in this context , hall and wuu   insisted that imrt would double the incidence of secondary malignancy . on the contrary , in a risk estimation study , imrt or proton therapy did not increase the risk of secondary cancer , but it was assumed that proton therapy reduced the incidence . these findings should be demonstrated by clinical data in future studies . in this study , four ris patients misdiagnosed with bone metastasis underwent palliative rt before the biopsy , which is not an optimal treatment for ris . although rare , the possibility of ris must be considered when malignancy is suspected in the previously irradiated region , and pathologic confirmation must be considered before the treatment . in this respect , identifying predisposing factors for development of ris could be of clinical concern . in the us surveillance , epidemiology and end results analysis by berrington de gonzalez et al . , a higher standardized incidence ratio for subsequent primary sarcoma was observed for patients treated at a younger age than those treated at older ages . in addition , several studies reported multiplicative effects of radiotherapy and chemotherapy for the subsequent risk of sarcoma [ 18 - 21 ] . however , there is a limitation in explaining the occurrence of ris with these clinical factors giving way to the idea of possible genetic predisposition of a patient for development of ris . pointed out that in the early 2000s , there was no molecular or pathological marker that was helpful in accurately distinguishing ris from spontaneous sarcoma , and little has changed since then . a study by kacker et al . found that myc gene amplification was prevalent in ris . on the other hand , the study by kadouri et al . , investigating the role of p53 and brca mutation in ris development , found a higher frequency of brca mutation in ris patients , but was insignificant , thus they concluded that brca mutation should not be considered when making the treatment decision . an in vivo study by kansara et al .   reported evidence that rb1 is required for development of radiation - induced osteosarcoma . comparing the transcriptome of sporadic sarcoma with that of ris showed 135 gene signatures which could differentiate ris from sporadic sarcoma , which indicated mitochondrial dysfunction with a hallmark of chronic oxidative stress . however , studies on genetic factors related to ris are still in their early stage . future studies on the biological background of ris should be conducted in two major parts : that on the genetic susceptibility to ris to distinguish high - risk patients before rt , and that on the molecular  radiation signature  that can distinguish ris from sporadic sts beyond cahan s criteria . in this study , we found that 0.9% of the sarcoma patients in the registry of a large tertiary center met the ris criteria . although prognosis of ris is poorer than that of sporadic sts , a surgical approach with curative intent is needed if possible , from which we can expect a favorable survival outcome , as seen in this study . considering the aforementioned difficulties in ris treatment , future study should focus on selection of ris patient candidates using molecular markers before rt and should compare the risks and benefits of administering rt before the treatment . in addition , enhancing the precision of rt would contribute to the reduction of ris or related complications in the future , but warrants further investigation .