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Barnett G.C.,University of Cambridge | Barnett G.C.,Strangeways Research Laboratories | De Meerleer G.,Ghent University | Gulliford S.L.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | And 3 more authors.
Clinical Oncology | Year: 2011

Aims: A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate. Materials and methods: Patient- and treatment-related factors that are thought to influence the development of late toxicity were analysed in 788 patients who had received radical radiotherapy to the prostate in the Medical Research Council RT01 trial. Late toxicity data were recorded using the Radiation Therapy Oncology Group, Late Effects of Normal Tissues/Subjective, Objective, Management, Analytic, Royal Marsden Hospital and the University of California, Los Angeles, Prostate Cancer Index. Acute toxicity was measured using the Radiation Therapy Oncology Group grading system. Results: On multivariate analysis, acute bowel toxicity was statistically significantly associated with increased proctitis (hazard ratio = 1.63, 95% confidence interval 1.18, 2.24; P= 0.003) and increased stool frequency (hazard ratio = 1.77, 95% confidence interval 1.27, 2.46; P= 0.001). Hypertension was strongly associated with a decreased risk of poor urinary stream (hazard ratio = 0.25, 95% confidence interval 0.09, 0.71; P= 0.009). There was an increased risk of rectal bleeding with increased age (hazard ratio = 1.04 per year of age, 95% confidence interval 1.01, 1.08; P= 0.009). As expected, a higher prescribed dose increased the risk of several late toxicity end points. Although acute bladder toxicity was associated with the presence of bladder symptoms at 5 years, the effect disappeared for all symptoms except increased urinary frequency and haematuria when a change in bladder function from baseline was calculated. Patients with any pretreatment bladder symptoms were more likely to report increased urinary frequency (hazard ratio = 2.09, 95% confidence interval 1.48, 2.95; P<. 0.0005), increased urinary incontinence (hazard ratio = 4.22, 95% confidence interval 2.13, 8.35; P<. 0.0005) and decreased stream (hazard ratio = 2.64, 95% confidence interval 1.62, 4.31; P<. 0.0005), after treatment and before the most recent follow-up assessment. Conclusions: In this study, increased acute gastrointestinal and bladder symptoms and prescribed dose were associated with increased late radiation toxicity. The presence of hypertension seemed to be protective for the development of late effects. Baseline symptoms should be taken into account when radiation toxicity is analysed. © 2011 The Royal College of Radiologists. Source


Buettner F.,Institute of Cancer Research | Gulliford S.L.,Institute of Cancer Research | Webb S.,Institute of Cancer Research | Sydes M.R.,Cancer Group | And 2 more authors.
Radiotherapy and Oncology | Year: 2012

Purpose: Most studies investigating the dose-response of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal-sphincter region and radiation-induced side-effects were quantified. Materials and methods: Dose-surface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397). Results: Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53 Gy (p = 0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface. Conclusions: The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model. © 2012 Elsevier Ireland Ltd. All rights reserved. Source


Gulliford S.L.,Institute of Cancer Research | Partridge M.,Institute of Cancer Research | Sydes M.R.,Cancer Group | Andreyev J.,Foundation Medicine | Dearnaley D.P.,Institute of Cancer Research
Radiotherapy and Oncology | Year: 2010

Background and purpose: Accurate reporting of complications following radiotherapy is an important part of the feedback loop to improve radiotherapy techniques. The definition of toxicity is normally regarded as the maximum or peak (P) grade of toxicity reported over the follow-up period. An alternative definition (integrated longitudinal toxicity (ILT)) is proposed which takes into account both the severity and the duration of the complication. Methods and materials: In this work, both definitions of toxicity were used to derive dose-volume constraints for six specific endpoints of late rectal toxicity from a cohort of patients who received prostate radiotherapy in the MRC RT01 trial. The dose-volume constraints were derived using ROC analysis for 30, 40, 50, 60, 65 and 70 Gy. Results: Statistically significant dose-volume constraints were not derived for all dose levels tested for each endpoint and toxicity definition. However, where both definitions produced constraints, there was generally good agreement. Variation in the derived dose-volume constraints was observed to be larger between endpoints than between the two definitions of toxicity. For one endpoint (stool frequency (LENT/SOM)) statistically significant dose-volume constraints were only derived using ILT. Conclusions: The longitudinal definition of toxicity (ILT) produced results consistent with those derived using peak toxicity and in some cases provided additional information which was not seen by analysing peak toxicity alone. © 2010 Elsevier Ireland Ltd. All rights reserved. Source


Whelan J.S.,University College London | Jinks R.C.,Cancer Group | McTiernan A.,University College London | Sydes M.R.,Cancer Group | And 11 more authors.
Annals of Oncology | Year: 2012

Background: Neoadjuvant chemotherapy improves outcome in osteosarcoma. Determination of optimum regimens for survival, toxicity and prognostic factors requires randomised controlled trials to be conducted. Patients and methods: Between 1983 and 2002, the European Osteosarcoma Intergroup recruited 1067 patients with localised extremity osteosarcoma to three randomised controlled trials. Standard treatment in each was doxorubicin 75 mg/m2 and cisplatin 100 mg/m2. Comparators were addition of methotrexate (BO02/80831), a multidrug regimen (BO03/80861) and a dose-intense schedule (BO06/80931). Standard survival analysis methods were used to identify prognostic factors, temporal and other influences on outcome. Results: Five- and 10-year survival were 56% (95% confidence interval 53% to 59%) and 52%, respectively (49% to 55%), with no difference between trials or treatment arms. Median follow-up was 9.4 years. Age range was 3-40 years (median 15). Limb salvage was achieved in 69%. Five hundred and thirty-three patients received the standard arm, 79% completing treatment. Good histological response to preoperative chemotherapy, distal tumour location (all sites other than proximal humerus/femur) and female gender were associated with improved survival. Conclusions: Localised osteosarcoma will be cured in 50% of patients with cisplatin and doxorubicin. Large randomised trials can be conducted in this rare cancer. Failure to improve survival over 20 years argues for concerted collaborative international efforts to identify and rapidly test new treatments. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source


Mead G.M.,Southampton General Hospital | Fossa S.D.,Norwegian Radium Hospital | Oliver R.T.D.,St Bartholomews and the London Hospitals | Joffe J.K.,Royal Infirmary | And 5 more authors.
Journal of the National Cancer Institute | Year: 2011

Background From July 1, 1989, through March 31, 2001, 2466 patients with stage I seminoma were evaluated in three randomized noninferiority trials: the TE10, TE18, and TE19 trials. We analyzed mature results of these studies. Methods The TE10 trial randomly assigned 478 patients to para-aortic and ipsilateral iliac lymph node (dogleg field) or para-aortic only radiation therapy (total dose = 30 Gy). The TE18 trial randomly assigned 1094 patients to a total dose of 30 or 20 Gy of radiation therapy, predominantly to a para-aortic field. The TE19 trial randomly assigned 1477 patients to radiation therapy or a single injection of carboplatin at a dose of seven times the area under the curve. Time to relapse was determined from Kaplan-Meier curves, and such data were compared by use of Cox regression models. Noninferiority in TE18 and TE19 required the upper limit of the 90% confidence intervals (CIs) (reflecting the one-sided test for noninferiority at a 5% statistical significance level) to exclude a hazard ratio (HR) of greater than 2.0 and a doubling of the 5-year relapse rates observed in the control arm. The TE10 trial was not powered to exclude clinically relevant differences in overall relapse rates but was assessed against the same criteria. Results Median follow-up times were 6.4-12 years in the three trials. We identified the noninferiority of the following treatments: 20 Gy of radiation therapy in the TE18 trial (HR of relapse = 0.63, 90% CI = 0.38 to 1.04) and carboplatin in the TE19 trial (HR of relapse = 1.25, 90% CI = 0.83 to 1.89). Para-aortic radiation therapy in the TE10 trial was associated with a hazard ratio of relapse of 1.15 (90% CI = 0.54 to 2.44). Relapse occurred after 3 years in only four (0.2%) of all 2466 patients. Computed tomography scans had little impact on the detection of relapse after radiation therapy; seven of the 904 patients allocated radiation therapy in TE19 had a relapse detected by this method. Conclusion This large and mature dataset from three randomized trials has provided support for the use of either radiation therapy or carboplatin therapy as adjuvant treatment for stage I seminoma. © 2011 The Author. Source

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