***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: The last quarter of the twentieth century has brought about sweeping changes in the loco-regional treatment of breast cancer . R and omised trials have consistently established that survival rates after conservation surgery and breast irradiation are equivalent to those observed after modified radical mastectomy [ 1 ] . Moreover , during the same period the use of mammography in asymptomatic women has led to a relative increase in small tumours , ideally suitable for breast conservation . As a consequence , the use of conservation surgery has risen progressively during the 1980s and 1990s , with a corresponding increase in the importance of breast irradiation . In addition , recent meta-analyses of r and omised trials have established that breast cancer mortality can be significantly reduced by loco-regional radiotherapy ( RT ) , and that the increased intercurrent mortality observed in older trials was caused by an excess in cardiovascular deaths , presumably avoidable , associated with the earlier techniques [ 2,3 ] . Newer trials of postmastectomy radiotherapy ( PMRT ) have demonstrated a clear survival improvement , without excess cardiac morbidity , leading to an increased confidence in the use of adjuvant loco-regional RT [ 4,5 ] . The extent of the swing to conservative surgery varies amongst geographical regions , depending , at least in part , on the availability of radiotherapy services . With the increasing diffusion of medical technology throughout Europe , this factor will probably assume a decreasing importance for the choice of primary breast cancer therapy . In urban areas with a high socio-economic st and ard , it is likely that mastectomy will come to be practised in a dwindling minority of patients . According to the Geneva Tumour Registry , the proportion of all curative breast operations that were conservative rose from 3 % before 1985 , to 51 % in 1990 , then to 67 % since 1998 ( Registre genevois des tumeurs , unpublished data , 2000 ) . As a consequence , patients currently requiring mastectomy are likely to have larger tumours and positive lymph nodes , and will frequently be considered for PMRT . In such a setting , a substantial majority of primary breast cancer patients will therefore receive RT as part of their initial treatment . These changes come at a time when the prevalence of breast cancer  is increasing significantly due , at least partly , to the ageing of the European population . For Geneva , an increase of more than 50 % in the number of new breast cancer cases is projected for the period between 2000 and 2010 ( Registre genevois des tumeurs , unpublished data , 1998 ) . The dem and for radiotherapy services required to treat breast cancer patients may thus be expected to increase substantially . Accordingly , the European Society of Mastology ( EUSOMA ) believes that a position paper regarding the use of RT in breast cancer is timely and useful . This document discusses the indications for adjuvant RT in operable breast cancer ( clinical stages T0 - 3 , N0 - 1 , M0 ) , the technical principles for its proper execution , and where possible , notions of its optimal co-ordination with other treatment modalities . As the breast cancer literature is vast , analysis was necessarily restricted to data having a high likelihood of being reliable , making every effort to draw conclusions likely to be pertinent PURPOSE To test for an association between in vitro fibroblast radiosensitivity and complication risk in a case-control study of breast cancer patients treated under st and ard conditions in a clinical trial of radiotherapy dose fractionation .  PATIENTS AND METHODS A cohort of patients participating in a r and omised clinical trial of radiotherapy dose fractionation was selected on the basis of treatment-induced changes in the breast several years later . Thirty-nine cases with marked normal tissue changes were matched on several variables with 65 controls with no changes attributable to radiotherapy  .  Dermal fibroblast strains were established from duplicate skin biopsies , and clonogenic cell survival assays performed in triplicate after both high ( approximately 1.6 Gy/min ) and low ( approximately 1 cGy/min ) dose-rate irradiation . Laboratory studies were blind to patient identity , treatment outcome and radiotherapy schedule . RESULTS Analysis of 1128 clonogenic survival curves confirmed significant inter-patient variation in fibroblast radiosensitivity as measured by clonogenic survival . However , no association between fibroblast radiosensitivity and the development of late radiotherapy normal tissue effects was detected . CONCLUSIONS Inter-individual variation in cellular radiosensitivity may not be the main determinant of complication risk in patients undergoing radiotherapy for breast cancer . Other biological and technical factors may be more important in explaining the marked inter-patient differences in normal tissue damage evident several years after curative radiotherapy PURPOSE Concurrent chemoradiation therapy ( CCRT ) for squamous cell carcinoma of the head and neck ( SCCHN ) increases local tumor control but at the expense of increased toxicity . We recently showed that several clinical /pretreatment factors were associated with the occurrence of severe late toxicity . This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity . METHODS AND MATERIAL S This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group ( RTOG ) trials of CCRT for locally advanced SCCHN ( RTOG trials 91 - 11 , 97 - 03 , and 99 - 14 ) .  Severe late toxicity was defined in this secondary analysis as chronic grade 3 - 4 pharyngeal/laryngeal toxicity and /or requirement for a feeding tube≥2 years after registration and /or potential treatment-related death ( eg , pneumonia ) within 3 years . Radiation dosimetry ( 2-dimensional ) analysis was performed central ly at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall ( superior oropharynx , inferior oropharynx , superior hypopharynx , and inferior hypopharynx ) . Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors . RESULTS A total of 154 patients were evaluable for this analysis , 71 cases ( patients with severe late toxicities ) and 83 controls ; thus , 46 % of evaluable patients had a severe late toxicity . On multivariate analysis , significant variables correlated with the development of severe late toxicity , including older age ( odds ratio , 1.062 per year ; P=.0021 ) and radiation dose received by the inferior hypopharynx ( odds ratio , 1.023 per Gy ; P=.016 ) . The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40 % rate of severe late toxicity compared with 56 % for patients receiving > 60 Gy . Oropharyngeal dose was not associated with this outcome . CONCLUSIONS Severe late toxicity following CCRT is common in long-term survivors . Age is the most significant factor , but hypopharyngeal dose also was associated BACKGROUND Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms ( SNPs ) in c and i date genes . Few associations have been tested in independent validation studies . This prospect i ve study aim ed to vali date reported associations between genotype and radiation toxicity in a large independent data set . METHODS 92 ( of 98 attempted ) SNPs in 46 genes were successfully genotyped in 1613 patients : 976 received adjuvant breast radiotherapy in the Cambridge breast IMRT trial ( IS RCT N21474421 , n=942 ) or in a prospect i ve study of breast toxicity at the Christie Hospital , Manchester , UK ( n=34 ) . A further 637 received radical prostate radiotherapy in the MRC RT01 multicentre trial ( IS RCT N47772397 , n=224 ) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer ( CHHiP ) trial ( IS RCT N97182923 , n=413 ) . Late toxicity was assessed 2 years after radiotherapy with a vali date d photographic technique ( patients with breast cancer only ) , clinical assessment , and patient question naires . Association tests of genotype with overall radiation toxicity score and individual endpoints were undertaken in univariate and multivariable analyses . At a type I error rate adjusted for multiple testing , this study had 99 % power to detect a SNP , with minor allele frequency of 0·35 , associated with a per allele odds ratio of 2·2 . FINDINGS None of the previously reported associations were confirmed by this study , after adjustment for multiple comparisons . The p value distribution of the SNPs tested against overall toxicity score was not different from that expected by chance . INTERPRETATION We did not replicate previously reported late toxicity associations , suggesting that we can essentially exclude the hypothesis that published SNPs individually exert a clinical ly relevant effect . Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and method ological challenges addressed . FUNDING Cancer Research UK , The Royal College of Radiologists , Addenbrooke 's Charitable Trust , Breast Cancer Campaign , Cambridge National Institute of Health Research ( NIHR ) Biomedical Research Centre , Experimental Cancer Medicine Centre , East Midl and s Innovation , the National Cancer Institute , Joseph Mitchell Trust , Royal Marsden NHS Foundation Trust , Institute of Cancer Research NIHR Biomedical Research Centre for Cancer BACKGROUND AND PURPOSE We have performed a case-control study among prostate cancer patients treated with three-dimensional conformational radiotherapy ( 3D-CRT )  in order to investigate the association between single nucleotide polymorphisms ( SNPs ) , treatment and patient features with gastrointestinal and genitourinary acute toxicity . MATERIAL AND METHODS A total of 698 patients were screened for 14 SNPs located in the ATM , ERCC2 , LIG4 , MLH1 and XRCC3 genes . Gastrointestinal and genitourinary toxicities were recorded prospect ively using the Common Terminology Criteria for Adverse Events v3.0 . RESULTS The XRCC3 SNP rs1799794 ( G/G OR=5.65 ; 95 % CI : 1.95 - 16.38 ; G/A OR=2.75 ; 95 % CI : 1.25 - 6.05 ; uncorrected p-value=2.8 × 10(-03 ) ; corrected p-value=0.03 ; FDR q-value=0.06 ) as well as the mean dose received by the rectum ( OR=1.06 ; 95 % CI : 1.02 - 1.1 ; uncorrected p-value=2.49 × 10(-03 ) ; corrected p-value=0.03 ; FDR q-value=0.06 ) were significantly associated with gastrointestinal toxicity after correction for multiple testing . Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity ( OR=0.38 ; 95 % CI : 0.18 - 0.71 ; uncorrected p-value=4.95 × 10(-03 ) ; corrected p-value=0.03 ; FDR q-value=0.08 ) . Our study excludes the possibility of a > 2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP , the rs1805386 and rs1805388 LIG4 markers , as well as all the SNPs evaluated in the ERCC2 , MLH1 and XRCC3 genes . CONCLUSIONS The XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT 
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In the sensitivity analyses , small studies did not show larger effects than large studies .
In addition , studies with high incidence of acute radiation injuries showed larger effects than studies with low incidence .
We also showed that the genetic effect of the rs1801516 polymorphism on acute radiation injuries was dependent on the incidence of the injury .