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Barnett G.C.,University of Cambridge | Coles C.E.,University of Cambridge | Elliott R.M.,University of Manchester | Baynes C.,University of Cambridge | And 15 more authors.
The Lancet Oncology | Year: 2012

Background: Several studies have reported associations between radiation toxicity and single nucleotide polymorphisms (SNPs) in candidate genes. Few associations have been tested in independent validation studies. This prospective study aimed to validate reported associations between genotype and radiation toxicity in a large independent dataset. 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 (ISRCTN21474421, n=942) or in a prospective 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 (ISRCTN47772397, n=224) or in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (CHHiP) trial (ISRCTN97182923, n=413). Late toxicity was assessed 2 years after radiotherapy with a validated photographic technique (patients with breast cancer only), clinical assessment, and patient questionnaires. 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 clinically relevant effect. Continued recruitment of patients into studies within the Radiogenomics Consortium is essential so that sufficiently powered studies can be done and methodological 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 Midlands Innovation, the National Cancer Institute, Joseph Mitchell Trust, Royal Marsden NHS Foundation Trust, Institute of Cancer Research NIHR Biomedical Research Centre for Cancer. © 2012 Elsevier Ltd.


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.


Gulliford S.L.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | Partridge M.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | Sydes M.R.,Cancer Group | Webb S.,Institute of Cancer Research and Royal Marsden NHS Foundation Trust | And 2 more authors.
Radiotherapy and Oncology | Year: 2012

Background and purpose: The Normal Tissue Complication Probability (NTCP) for rectum is usually defined for late rectal bleeding. This study calculates NTCP parameter values for additional rectal toxicity endpoints observed in clinical practise. Materials and methods: 388 patients from the multicentre MRC-RT01 prostate conformal radiotherapy trial (ISRCTN 47772397) were used to derive independent Lyman Kutcher Burman model (LKB) parameters for five late rectal toxicity endpoints: rectal bleeding, proctitis, stool frequency, loose stools and rectal urgency. The parameters were derived using maximum likelihood estimation. Bootstrap and leave-one-out methods were employed to test the generalisability of the results for use in a general population. Results: A consistent pattern of increasing value of TD50(1) for Grade 2 toxicity only compared to Grades 1 and 2 toxicity was observed for all endpoints. Parameter values varied between endpoints (particularly for the volume parameter n). TD50(1), m and n were 68.5 Gy (95% CI)(66.8-70.8), 0.15 (0.13-0.17) and 0.13 (0.10-0.17), respectively, for G2 rectal bleeding. Bootstrap and leave-one-out results showed that the rectal bleeding and proctitis parameter fits were extremely robust. Conclusions: The variation between the values derived for different endpoints may indicate different patho-physiological responses of the rectum to radiation. Therefore different parameter sets would be required to predict specific rectal toxicity endpoints. © 2011 Elsevier Ireland Ltd. All rights reserved.


Gulliford S.L.,National Health Research Institute | Foo K.,Wollongong Hospital | Morgan R.C.,Cancer Group | Aird E.G.,Mount Vernon Hospital | And 11 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (≥50 Gy). Evidence is emerging that lower doses could also be important. Methods and Materials: Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity. Results: A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30≤80%, V40≤65%, V50≤55%, V60≤40%, V65≤30%, V70≤15%, and V75≤3%. Conclusion: Considering the entire dose distribution to the rectum by applying dose-volume constraints such as those tested here in the present will reduce the incidence of late rectal toxicity. © 2010 Elsevier Inc. All rights reserved.


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.


Syndikus I.,Clatterbridge Center for Oncology | Morgan R.C.,Cancer Group | Sydes M.R.,Cancer Group | Graham J.D.,Musgrove Park Hospital | Dearnaley D.P.,Royal Marsden Hospital
International Journal of Radiation Oncology Biology Physics | Year: 2010

Purpose: In men with localized prostate cancer, dose-escalated conformal radiotherapy (CFRT) improves efficacy outcomes at the cost of increased toxicity. We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects. Methods and Materials: The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer, who were treated for 6 months with neoadjuvant radiotherapy and were randomly assigned to either 64-Gy or 74-Gy CFRT. Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group (RTOG) grading, the Late Effects on Normal Tissue: Subjective, Objective, Management (LENT/SOM) scale, and Royal Marsden Hospital assessment scores. Patients regularly completed Functional Assessment of Cancer Therapy--Prostate (FACT-P) and University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI) questionnaires. Results: In the dose-escalated group, the hazard ratio (HR) for rectal bleeding (LENT/SOM grade ≥2) was 1.55 (95% CI, 1.17-2.04); for diarrhea (LENT/SOM grade ≥2), the HR was 1.79 (95% CI, 1.10-2.94); and for proctitis (RTOG grade ≥2), the HR was 1.64 (95% CI, 1.20-2.25). Compared to baseline scores, the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened. At 5 years, the cumulative incidence of patient-reported severe bowel problems was 6% vs. 8% (standard vs. escalated, respectively) and severe distress was 4% vs. 5%, respectively. Conclusions: There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT. This remains at clinically acceptable levels, and overall prevalence ultimately decreases with duration of follow-up. Crown Copyright © 2010.


Sydes M.R.,Cancer Group | Langley R.E.,Cancer Group | Langley R.E.,University of Sussex
The Lancet Oncology | Year: 2010

Randomised controlled trials are the gold standard method for developing evidence-based medicine. Good trial design and an awareness of some potential pitfalls are likely to maximise the chances of a successful trial with a conclusion that adds meaningfully to the evidence base. This paper is aimed at people early in their research careers and focuses on some common, usually avoidable, pitfalls in trial design. The areas covered include: assessing the scientific idea; trial design; size and duration of the trial; analysis; and reporting and presentation. © 2010 Elsevier Ltd.


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.


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.


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.

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