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Mukherjee S.,University of Oxford | Hurt C.N.,University of Cardiff | Gwynne S.,South West Wales Cancer Center | Sebag-Montefiore D.,St James's Hospital | And 15 more authors.
European Journal of Cancer | Year: 2017

Background Oxaliplatin-capecitabine (OxCap) and carboplatin-paclitaxel (CarPac) based neo-adjuvant chemoradiotherapy (nCRT) have shown promising activity in localised, resectable oesophageal cancer. Patients and methods A non-blinded, randomised (1:1 via a centralised computer system), ‘pick a winner’ phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of radiotherapy) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). Radiotherapy dose was 45 Gy/25 fractions/5 weeks. Both arms received induction OxCap chemotherapy (2 × 3 week cycles of oxaliplatin 130 mg/m2 day 1, capecitabine 625 mg/m2 bd days 1–21). Surgery was performed 6–8 weeks after nCRT. Primary end-point was pathological complete response (pCR). Secondary end-points included toxicity, surgical morbidity/mortality, resection rate and overall survival. Statistics Based on pCR ≤ 15% not warranting future investigation, but pCR ≥ 35% would, 76 patients (38/arm) gave 90% power (one-sided alpha 10%), implying that arm(s) having ≥10 pCR out of first 38 patients could be considered for phase III trials. ClinicalTrials.gov: NCT01843829. Funder: Cancer Research UK (C44694/A14614). Results Eighty five patients were randomised between October 2013 and February 2015 from 17 UK centres. Three of 85 (3.5%) died during induction chemotherapy. Seventy-seven patients (OxCapRT = 36; CarPacRT = 41) underwent surgery. The 30-d post-operative mortality was 2/77 (2.6%). Grade III/IV toxicity was comparable between arms, although neutropenia was higher in the CarPacRT arm (21.4% versus 2.6%, p = 0.01). Twelve of 41 (29.3%) (10 of first 38 patients) and 4/36 (11.1%) achieved pCR in the CarPacRT and OxcapRT arms, respectively. Corresponding R0 resection rates were 33/41 (80.5%) and 26/36 (72.2%), respectively. Conclusion Both regimens were well tolerated. Only CarPacRT passed the predefined pCR criteria for further investigation. © 2017 The Author(s)


Mason M.D.,University of Cardiff | Parulekar W.R.,Queen's University | Sydes M.R.,University College London | Kirkbride P.,Clatterbridge Cancer Center | And 18 more authors.
Journal of Clinical Oncology | Year: 2015

Purpose: We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. Patients and Methods: NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 μg/L or PSA of 20 to 40 μg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. Results: One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. Conclusion: This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer. © 2015 American Society of Clinical Oncology.


Gwynne S.,South West Wales Cancer Center | Gwynne S.,Cardiff Center | Jones G.,Cardiff Center | Jones G.,Velindre Cancer Center | And 14 more authors.
British Journal of Radiology | Year: 2016

Objective: We sought to develop a process that would allow us to perform a prospective review of outlining in trials using expert reviewers based in multiple centres. Methods: We implemented a specific information technology infrastructure and workflow that could serve all organizations involved in the radiotherapy quality assurance (RTQA) process. Results: Data were processed and packaged in the computational environment for radiotherapy research (CERR) binary format and securely transmitted to the expert reviewer at the designated remote organization. It was opened and reviewed using the distributed CERR-compiled application, and a standardized report was sent to the respective centre. Centres were expected to correct any unacceptable deviations and resubmit outlining for approval prior to commencing treatment. 75% of reviews were completed and fed back to centres within 3 working days. There were no delays in treatment start date. Conclusion: Our distributed RTQA review approach provides a method of prospective outlining review at multiple centres, without compromising the quality, delaying the start of treatment or the need for significant additional infrastructure resources. Future progress in the area of prospective individual case review will need to be supported by additional resources for clinician time to undertake the reviews. Advances in knowledge: Trial groups around the world have formulated different approaches to address the need for the prospective review of radiotherapy (RT) data with clinical trials, in line with available resources. We report a UK solution that has allowed the workload for outlining review to be distributed across a wider group of volunteer reviewers without the need for any additional infrastructure costs and has already been adopted within the UK RT trials community. © 2016 The Authors.


Mukherjee S.,University of Oxford | Hurt C.N.,University of Cardiff | Gwynne S.,South West Wales Cancer Center | Bateman A.,University of Southampton | And 15 more authors.
BMC Cancer | Year: 2015

Background: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK. Methods/Design: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m2 D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m2 Day 1,15,29; capecitabine 625 mg/m2 twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG. Discussion: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial. © Mukherjee et al.


PubMed | St Jamess Institute of Oncology, Velindre Cancer Center, Maastricht University, University of Southampton and 7 more.
Type: | Journal: BMC cancer | Year: 2015

Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II pick a winner trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK.Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), T3 and/or N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG.Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial.Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .


Carrington R.,University of Cardiff | Staffurth J.,Velindre Cancer Center | Warren S.,University of Oxford | Partridge M.,University of Oxford | And 5 more authors.
Radiation Oncology | Year: 2015

Purpose: Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach. Methods and materials: 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm3. The original 3D conformal plans (50Gy3D) were compared to newly created RapidArc plans of 50GyRA and 60GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared. Results: There was a significant increase in NTCP of the stomach wall when moving from the 50GyRA to the 60GyRA plans (11-17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60GyRA plans. Conclusion: Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60Gy. © 2015 Carrington et al.


Carrington R.,University of Cardiff | Spezi E.,University of Cardiff | Gwynne S.,South West Wales Cancer Center | Dutton P.,University of Cardiff | And 3 more authors.
Radiation Oncology | Year: 2016

Purpose: The first aim of this study was to assess plan quality using a conformity index (CI) and analyse its influence on patient outcome. The second aim was to identify whether clinical and technological factors including planning treatment volume (PTV) volume and treatment delivery method could be related to the CI value. Methods and materials: By extending the original concept of the mean distance to conformity (MDC) index, the OverMDC and UnderMDC of the 95 % isodose line (50Gy prescribed dose) to the PTV was calculated for 97 patients from the UK SCOPE 1 trial (ISCRT47718479). Data preparation was carried out in CERR, with Kaplan-Meier and multivariate analysis undertaken in EUCLID and further tests in Microsoft Excel and IBM's SPSS. Results: A statistically significant breakpoint in the overall survival data, independent of cetuximab, was found with OverMDC (4.4 mm, p < 0.05). This was not the case with UnderMDC. There was a statistically significant difference in PTV volume either side of the OverMDC breakpoint (Mann Whitney p < 0.001) and in OverMDC value dependent on the treatment delivery method (mean IMRT = 2.1 mm, mean 3D-CRT = 4.1 mm Mann Whitney p < 0.001). Re-planning the worst performing patients according to OverMDC from 3D-CRT to VMAT resulted in a mean reduction in OverMDC of 2.8 mm (1.6-4.0 mm). OverMDC was not significant in multivariate analysis that included age, sex, staging, tumour type, and position. Conclusion: Although not significant when included in multivariate analysis, we have shown in univariate analysis that a patient's OverMDC is correlated with overall survival. OverMDC is strongly related to IMRT and to a lesser extent with PTV volume. We recommend that VMAT planning should be used for oesophageal planning when available and that attention should be paid to the conformity of the 95 % to the PTV. © 2016 Carrington et al.


PubMed | Velindre Cancer Center, University of Oxford, University of Cardiff and South West Wales Cancer Center
Type: | Journal: Radiation oncology (London, England) | Year: 2015

Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach.10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm(3). The original 3D conformal plans (50 Gy3D) were compared to newly created RapidArc plans of 50 GyRA and 60 GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared.There was a significant increase in NTCP of the stomach wall when moving from the 50 GyRA to the 60 GyRA plans (11-17 %, Wilcoxon signed rank test, p=0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R=0.80 and R=0.82 respectively) for the 60 GyRA plans.Radiobiological modelling suggests that increasing the prescribed dose to 60 Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60 Gy.


PubMed | Velindre Cancer Center, University of Cardiff and South West Wales Cancer Center
Type: | Journal: Radiation oncology (London, England) | Year: 2016

The first aim of this study was to assess plan quality using a conformity index (CI) and analyse its influence on patient outcome. The second aim was to identify whether clinical and technological factors including planning treatment volume (PTV) volume and treatment delivery method could be related to the CI value.By extending the original concept of the mean distance to conformity (MDC) index, the OverMDC and UnderMDC of the 95 % isodose line (50Gy prescribed dose) to the PTV was calculated for 97 patients from the UK SCOPE 1 trial (ISCRT47718479). Data preparation was carried out in CERR, with Kaplan-Meier and multivariate analysis undertaken in EUCLID and further tests in Microsoft Excel and IBMs SPSS.A statistically significant breakpoint in the overall survival data, independent of cetuximab, was found with OverMDC (4.4 mm, p < 0.05). This was not the case with UnderMDC. There was a statistically significant difference in PTV volume either side of the OverMDC breakpoint (Mann Whitney p < 0.001) and in OverMDC value dependent on the treatment delivery method (mean IMRT = 2.1 mm, mean 3D-CRT = 4.1 mm Mann Whitney p < 0.001). Re-planning the worst performing patients according to OverMDC from 3D-CRT to VMAT resulted in a mean reduction in OverMDC of 2.8 mm (1.6-4.0 mm). OverMDC was not significant in multivariate analysis that included age, sex, staging, tumour type, and position.Although not significant when included in multivariate analysis, we have shown in univariate analysis that a patients OverMDC is correlated with overall survival. OverMDC is strongly related to IMRT and to a lesser extent with PTV volume. We recommend that VMAT planning should be used for oesophageal planning when available and that attention should be paid to the conformity of the 95 % to the PTV.

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