Publications by authors named "Duncan McLaren"

32 Publications

The risks of solar geoengineering research.

Science 2021 Jun;372(6547):1161

Environmental Studies, Mount Holyoke College, South Hadley, MA 01075, USA.

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http://dx.doi.org/10.1126/science.abj3679DOI Listing
June 2021

Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance.

BMJ Open 2020 12 31;10(12):e041005. Epub 2020 Dec 31.

Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.

Introduction: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity.

Methods And Analysis: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.

Ethics And Dissemination: This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities.

Trial Registration Number: NCT02447549; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-041005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780718PMC
December 2020

Breath markers for therapeutic radiation.

J Breath Res 2020 10 24;15(1):016004. Epub 2020 Oct 24.

Centre for Analytical Science, Chemistry, Loughborough University, Loughborough, United Kingdom.

Radiation dose is important in radiotherapy. Too little, and the treatment is not effective, too much causes radiation toxicity. A biochemical measurement of the effect of radiotherapy would be useful in personalisation of this treatment. This study evaluated changes in exhaled breath volatile organic compounds (VOC) associated with radiotherapy with thermal desorption gas chromatography mass-spectrometry followed by data processing and multivariate statistical analysis. Further the feasibility of adopting gas chromatography ion mobility spectrometry for radiotherapy point-of-care breath was assessed. A total of 62 participants provided 240 end-tidal 1 dm breath samples before radiotherapy and at 1, 3, and 6 h post-exposure, that were analysed by thermal-desorption/gas-chromatography/quadrupole mass-spectrometry. Data were registered by retention-index and mass-spectra before multivariate statistical analyses identified candidate markers. A panel of sulfur containing compounds (thio-VOC) were observed to increase in concentration over the 6 h following irradiation. 3-methylthiophene (80 ng.m to 790 ng.m) had the lowest abundance while 2-thiophenecarbaldehyde(380 ng.m to 3.85 μg.m) the highest; note, exhaled 2-thiophenecarbaldehyde has not been observed previously. The putative tumour metabolite 2,4-dimethyl-1-heptene concentration reduced by an average of 73% over the same time. Statistical scoring based on the signal intensities thio-VOC and 3-methylthiophene appears to reflect individuals' responses to radiation exposure from radiotherapy. The thio-VOC are hypothesised to derive from glutathione and Maillard-based reactions and these are of interest as they are associated with radio-sensitivity. Further studies with continuous monitoring are needed to define the development of the breath biochemistry response to irradiation and to determine the optimum time to monitor breath for radiotherapy markers. Consequently, a single 0.5 cm breath-sample gas chromatography-ion mobility approach was evaluated. The calibrated limit of detection for 3-methylthiophene was 10 μg.m with a lower limit of the detector's response estimated to be 210 fg.s; the potential for a point-of-care radiation exposure study exists.
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http://dx.doi.org/10.1088/1752-7163/aba816DOI Listing
October 2020

Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial.

Lancet Oncol 2020 01 2;21(1):162-174. Epub 2019 Dec 2.

The Institute of Cancer Research, London, UK.

Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.

Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.

Findings: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.

Interpretation: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.

Funding: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
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http://dx.doi.org/10.1016/S1470-2045(19)30684-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941219PMC
January 2020

VOCCluster: Untargeted Metabolomics Feature Clustering Approach for Clinical Breath Gas Chromatography/Mass Spectrometry Data.

Anal Chem 2020 02 5;92(4):2937-2945. Epub 2020 Feb 5.

Pharmacology, Toxicology and Therapeutics Unit , University of Edinburgh , Edinburgh EH8 9YL , U.K.

Metabolic profiling of breath analysis involves processing, alignment, scaling, and clustering of thousands of features extracted from gas chromatography/mass spectrometry (GC/MS) data from hundreds of participants. The multistep data processing is complicated, operator error-prone, and time-consuming. Automated algorithmic clustering methods that are able to cluster features in a fast and reliable way are necessary. These accelerate metabolic profiling and discovery platforms for next-generation medical diagnostic tools. Our unsupervised clustering technique, VOCCluster, prototyped in Python, handles features of deconvolved GC/MS breath data. VOCCluster was created from a heuristic ontology based on the observation of experts undertaking data processing with a suite of software packages. VOCCluster identifies and clusters groups of volatile organic compounds (VOCs) from deconvolved GC/MS breath with similar mass spectra and retention index profiles. VOCCluster was used to cluster more than 15 000 features extracted from 74 GC/MS clinical breath samples obtained from participants with cancer before and after a radiation therapy. Results were evaluated against a panel of ground truth compounds and compared to other clustering methods (DBSCAN and OPTICS) that were used in previous metabolomics studies. VOCCluster was able to cluster those features into 1081 groups (including endogenous and exogenous compounds and instrumental artifacts) with an accuracy rate of 96% (±0.04 at 95% confidence interval).
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http://dx.doi.org/10.1021/acs.analchem.9b03084DOI Listing
February 2020

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness.

Eur Urol Oncol 2018 12 14;1(6):449-458. Epub 2018 Sep 14.

Gloucestershire Royal Hospital Foundation Trust, Gloucester, UK.

Background: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources.

Objective: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting.

Design, Setting, And Participants: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy.

Intervention: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m) was administered alongside SOC for six three-weekly cycles.

Outcome Measurements And Statistical Analysis: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs).

Results And Limitations: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled.

Conclusions: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available.

Patient Summary: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.
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http://dx.doi.org/10.1016/j.euo.2018.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692495PMC
December 2018

Radiological Response Heterogeneity Is of Prognostic Significance in Metastatic Renal Cell Carcinoma Treated with Vascular Endothelial Growth Factor-targeted Therapy.

Eur Urol Focus 2020 09 6;6(5):999-1005. Epub 2019 Feb 6.

Barts Cancer Institute, CRUK Experimental Cancer Medicine Centre, London, UK; Department of Oncology, Royal Free NHS Foundation Trust, London, UK. Electronic address:

Background: Response evaluation criteria in solid tumours (RECIST) is widely used to assess tumour response but is limited by not considering disease site or radiological heterogeneity (RH).

Objective: To determine whether RH or disease site has prognostic significance in patients with metastatic clear-cell renal cell carcinoma (ccRCC).

Design, Setting, And Participants: A retrospective analysis was conducted of a second-line phase II study in patients with metastatic ccRCC (NCT00942877), evaluating 138 patients with 458 baseline lesions.

Intervention: The phase II trial assessed vascular endothelial growth factor-targeted therapy±Src inhibition.

Outcome Measurements And Statistical Analysis: RH at week 8 was assessed within individual patients with two or more lesions to predict overall survival (OS) using Kaplan-Meier method and Cox regression model. We defined a high heterogeneous response as occurring when one or more lesion underwent a ≥10% reduction and one or more lesion underwent a ≥10% increase in size. Disease progression was defined by RECIST 1.1 criteria.

Results And Limitations: In patients with a complete/partial response or stable disease by RECIST 1.1 and two or more lesions at week 8, those with a high heterogeneous response had a shorter OS compared to those with a homogeneous response (hazard ratio [HR] 2.01; 95% confidence interval [CI]: 1.39-2.92; p<0.001). Response by disease site at week 8 did not affect OS. At disease progression, one or more new lesion was associated with worse survival compared with >20% increase in sum of target lesion diameters only (HR 2.12; 95% CI: 1.43-3.14; p<0.001). Limitations include retrospective study design.

Conclusions: RH and the development of new lesions may predict survival in metastatic ccRCC. Further prospective studies are required.

Patient Summary: We looked at individual metastases in patients with kidney cancer and showed that a variable response to treatment and the appearance of new metastases may be associated with worse survival. Further studies are required to confirm these findings.
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http://dx.doi.org/10.1016/j.euf.2019.01.010DOI Listing
September 2020

EPID-based in vivo dosimetry using Dosimetry Check™: Overview and clinical experience in a 5-yr study including breast, lung, prostate, and head and neck cancer patients.

J Appl Clin Med Phys 2019 Jan 7;20(1):6-16. Epub 2018 Dec 7.

Department of Oncology Physics, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.

Background: Independent verification of the dose delivered by complex radiotherapy can be performed by electronic portal imaging device (EPID) dosimetry. This paper presents 5-yr EPID in vivo dosimetry (IVD) data obtained using the Dosimetry Check (DC) software on a large cohort including breast, lung, prostate, and head and neck (H&N) cancer patients.

Material And Methods: The difference between in vivo dose measurements obtained by DC and point doses calculated by the Eclipse treatment planning system was obtained on 3795 radiotherapy patients treated with volumetric modulated arc therapy (VMAT) (n = 842) and three-dimensional conformal radiotherapy (3DCRT) (n = 2953) at 6, 10, and 15 MV. In cases where the dose difference exceeded ±10% further inspection and additional phantom measurements were performed.

Results: The mean and standard deviation of the percentage difference in dose obtained by DC and calculated by Eclipse in VMAT was: in brain, in H&N, and in prostate cancer. In 3DCRT, this was in brain, in breast, in bladder, in H&N, 2.60 ± 5.35% in lung and in prostate cancer. A total of 153 plans exceeded the ±10% alert criteria, which included: 88 breast plans accounting for 7.9% of all breast treatments; 28 H&N plans accounting for 4.4% of all H&N treatments; and 12 prostate plans accounting for 3.5% of all prostate treatments. All deviations were found to be as a result of patient-related anatomical deviations and not from procedural errors.

Conclusions: This preliminary data shows that EPID-based IVD with DC may not only be useful in detecting errors but has the potential to be used to establish site-specific dose action levels. The approach is straightforward and has been implemented as a radiographer-led service with no disruption to the patient and no impact on treatment time.
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http://dx.doi.org/10.1002/acm2.12441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333145PMC
January 2019

Terminal Pleistocene epoch human footprints from the Pacific coast of Canada.

PLoS One 2018 28;13(3):e0193522. Epub 2018 Mar 28.

University of Victoria, Victoria, British Columbia, Canada.

Little is known about the ice age human occupation of the Pacific Coast of Canada. Here we present the results of a targeted investigation of a late Pleistocene shoreline on Calvert Island, British Columbia. Drawing upon existing geomorphic information that sea level in the area was 2-3 m lower than present between 14,000 and 11,000 years ago, we began a systematic search for archaeological remains dating to this time period beneath intertidal beach sediments. During subsurface testing, we uncovered human footprints impressed into a 13,000-year-old paleosol beneath beach sands at archaeological site EjTa-4. To date, our investigations at this site have revealed a total of 29 footprints of at least three different sizes. The results presented here add to the growing body of information pertaining to the early deglaciation and associated human presence on the west coast of Canada at the end of the Last Glacial Maximum.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193522PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873988PMC
June 2018

Clinical and patient-reported outcomes of SPARE - a randomised feasibility study of selective bladder preservation versus radical cystectomy.

BJU Int 2017 11 29;120(5):639-650. Epub 2017 May 29.

The Institute of Cancer Research, London, UK.

Objectives: To test the feasibility of a randomised trial in muscle-invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy.

Patients And Methods: SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2-3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non-responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non-inferiority of SBP in terms of overall survival (OS) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient-reported quality of life, clinician assessed toxicity, loco-regional recurrence-free survival, and rate of salvage RC after SBP.

Results: Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC; 20 SBP). Non-compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT. Long-term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups.

Conclusions: Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn.
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http://dx.doi.org/10.1111/bju.13900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655733PMC
November 2017

Targeted SERS nanosensors measure physicochemical gradients and free energy changes in live 3D tumor spheroids.

Nanoscale 2016 Sep;8(37):16710-16718

EaStCHEM, School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.

Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.
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http://dx.doi.org/10.1039/c6nr06031eDOI Listing
September 2016

Correction: Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Analyst 2016 10;141(20):5900

School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.

Correction for 'Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors' by Victoria L. Camus, et al., Analyst, 2016, 141, 5056-5061.
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http://dx.doi.org/10.1039/c6an90079hDOI Listing
October 2016

Intertidal resource use over millennia enhances forest productivity.

Nat Commun 2016 08 30;7:12491. Epub 2016 Aug 30.

Hakai Institute, Calvert Island, PO Box 309, Heriot Bay, British Columbia, Canada BC V0P 1H0.

Human occupation is usually associated with degraded landscapes but 13,000 years of repeated occupation by British Columbia's coastal First Nations has had the opposite effect, enhancing temperate rainforest productivity. This is particularly the case over the last 6,000 years when intensified intertidal shellfish usage resulted in the accumulation of substantial shell middens. We show that soils at habitation sites are higher in calcium and phosphorous. Both of these are limiting factors in coastal temperate rainforests. Western redcedar (Thuja plicata) trees growing on the middens were found to be taller, have higher wood calcium, greater radial growth and exhibit less top die-back. Coastal British Columbia is the first known example of long-term intertidal resource use enhancing forest productivity and we expect this pattern to occur at archaeological sites along coastlines globally.
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http://dx.doi.org/10.1038/ncomms12491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013557PMC
August 2016

TRAPEZE: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of chemotherapy with zoledronic acid, strontium-89, or both, in men with bony metastatic castration-refractory prostate cancer.

Health Technol Assess 2016 07;20(53):1-288

Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.

Background: Bony metastatic castration-refractory prostate cancer is associated with a poor prognosis and high morbidity. TRAPEZE was a two-by-two factorial randomised controlled trial of zoledronic acid (ZA) and strontium-89 (Sr-89), each combined with docetaxel. All have palliative benefits, are used to control bone symptoms and are used with docetaxel to prolong survival. ZA, approved on the basis of reducing skeletal-related events (SREs), is commonly combined with docetaxel in practice, although evidence of efficacy and cost-effectiveness is lacking. Sr-89, approved for controlling metastatic pain and reducing need for subsequent bone treatments, is generally palliatively used in patients unfit for chemotherapy. Phase II analysis confirmed the safety and feasibility of combining these agents. TRAPEZE aimed to determine the clinical effectiveness and cost-effectiveness of each agent.

Methods: Patients were randomised to receive six cycles of docetaxel plus prednisolone: alone, with ZA, with a single Sr-89 dose after cycle 6, or with both. Primary outcomes were clinical progression-free survival (CPFS: time to pain progression, SRE or death) and cost-effectiveness. Secondary outcomes were SRE-free interval (SREFI), total SREs, overall survival (OS) and quality of life (QoL). Log-rank test and Cox regression modelling were used to determine clinical effectiveness. Cost-effectiveness was assessed from the NHS perspective and expressed as cost per additional quality-adjusted life-year (QALY). An additional analysis was carried out for ZA to reflect the availability of generic ZA.

Results:

Patients: 757 randomised (median age 68.7 years; Eastern Cooperative Oncology Group scale score 0, 40%; 1, 52%; 2, 8%; prior radiotherapy, 45%); median prostate-specific antigen 143.78 ng/ml (interquartile range 50.8-353.9 ng/ml). Stratified log-rank analysis of CPFS was statistically non-significant for either agent (Sr-89, p = 0.11; ZA, p = 0.45). Cox regression analysis adjusted for stratification variables showed CPFS benefit for Sr-89 [hazard ratio (HR) 0.845, 95% confidence interval (CI) 0.72 to 0.99; p = 0.036] and confirmed no effect of ZA (p = 0.46). ZA showed a significant SREFI effect (HR 0.76; 95% CI 0.63 to 0.93; p = 0.008). Neither agent affected OS (Sr-89, p = 0.74; ZA, p = 0.91), but both increased total cost (vs. no ZA and no Sr-89, respectively); decreased post-trial therapies partly offset costs [net difference: Sr-89 £1341; proprietary ZA (Zometa(®), East Hanover, NJ, USA) £1319; generic ZA £251]. QoL was maintained in all trial arms; Sr-89 (0.08 additional QALYs) and ZA (0.03 additional QALYs) showed slight improvements. The resulting incremental cost-effectiveness ratio (ICER) for Sr-89 was £16,590, with £42,047 per QALY for Zometa and £8005 per QALY for generic ZA.

Conclusion: Strontium-89 improved CPFS, but not OS. ZA did not improve CPFS or OS but significantly improved SREFI, mostly post progression, suggesting a role as post-chemotherapy maintenance therapy. QoL was well maintained in all treatment arms, with differing patterns of care resulting from the effects of Sr-89 on time to progression and ZA on SREFI and total SREs. The addition of Sr-89 resulted in additional cost and a small positive increase in QALYs, with an ICER below the £20,000 ceiling per QALY. The additional costs and small positive QALY changes in favour of ZA resulted in ICERs of £42,047 (Zometa) and £8005 for the generic alternative; thus, generic ZA represents a cost-effective option. Additional analyses on the basis of data from the Hospital Episode Statistics data set would allow corroborating the findings of this study. Further research into the use of ZA (and other bone-targeting therapies) with newer prostate cancer therapies would be desirable.

Study Registration: Current Controlled Trials ISRCTN12808747.

Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 53. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta20530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967809PMC
July 2016

Cyborgs in the Everyday: Masculinity and Biosensing Prostate Cancer.

Sci Cult (Lond) 2015 Oct 3;24(4):484-506. Epub 2015 Sep 3.

Edinburgh Cancer Centre, The University of Edinburgh , Edinburgh , UK.

An biosensor is a technology in development that will assess the biological activity of cancers to individualise external beam radiotherapy. Inserting such technology into the human body creates cybernetic organisms; a cyborg that is a human-machine hybrid. There is a gap in knowledge relating to patient willingness to allow automated technology to be embedded and to become cyborg. There is little agreement around what makes a cyborg and less understanding of the variation in the cyborgisation process. Understanding the viewpoint of possible beneficiaries addresses such gaps. There are currently three versions of 'cyborg' in the literature (i) a critical feminist STS concept to destabilise power inherent in dualisms, (ii) an extreme version of the human/machine in science-fiction that emphasises the 'man' in human and (iii) a prediction of internal physiological adaptation required for future space exploration. Interview study findings with 12 men in remission from prostate cancer show a fourth version can be used to describe current and future sub-groups of the population; 'everyday cyborgs'. For the everyday cyborg the masculine cyborg status found in the fictionalised human-machine related to issues of control of the cancer. This was preferred to the felt stigmatisation of being a 'leaker and bleeder'. The willingness to become cyborg was matched with a having to get used to the everyday cyborg's technological adaptations and risks. It is crucial to explore the everyday cyborg's sometimes ambivalent viewpoint. The everyday cyborg thus adds the dimension of participant voice currently missing in existing cyborg literatures and imaginations.
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http://dx.doi.org/10.1080/09505431.2015.1063597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894087PMC
October 2015

Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors.

Analyst 2016 08;141(17):5056-61

School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.

Multicellular tumour spheroids (MTS) are three-dimensional cell cultures that possess their own microenvironments and provide a more meaningful model of tumour biology than monolayer cultures. As a result, MTS are becoming increasingly used as tumor models when measuring the efficiency of therapies. Monitoring the viability of live MTS is complicated by their 3D nature and conventional approaches such as fluorescence often require fixation and sectioning. In this paper we detail the use of Surface Enhanced Raman Spectroscopy (SERS) to measure the viability of MTS grown from prostate cancer (PC3) cells. Our results show that we can monitor loss of viability by measuring pH and redox potential in MTS and furthermore we demonstrate that SERS can be used to measure the effects of fractionation of a dose of radiotherapy in a way that has potential to inform treatment planning.
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http://dx.doi.org/10.1039/c6an01032fDOI Listing
August 2016

Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

BJU Int 2017 04 10;119(4):522-529. Epub 2016 Jul 10.

University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

Objective: To evaluate the cost-effectiveness of adding zoledronic acid or strontium-89 to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC).

Patients And Methods: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2 × 2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the National Health Service in the UK and included expenditures for trial treatments, concomitant medications, and use of related hospital and primary care services. Quality-adjusted life-years (QALYs) were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument, which evaluates health status. Results are expressed as incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves.

Results: The per-patient cost for ZA was £12 667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group had on average 0.03 QALYs more than their counterparts in no ZA group. The ICER for this comparison was £8 005. Sr89 was associated with a cost of £13 230, £1365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16 884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively.

Conclusions: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources.
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http://dx.doi.org/10.1111/bju.13549DOI Listing
April 2017

Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

JAMA Oncol 2016 Apr;2(4):493-9

Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, England.

Importance: Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival.

Objective: To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival.

Design, Setting, And Participants: The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months.

Interventions: Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89.

Main Outcomes And Measures: Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS).

Results: Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91).

Conclusions And Relevance: Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy.

Trial Registration: isrctn.com Identifier: ISRCTN12808747.
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http://dx.doi.org/10.1001/jamaoncol.2015.5570DOI Listing
April 2016

INVITED REVIEW--IMAGE REGISTRATION IN VETERINARY RADIATION ONCOLOGY: INDICATIONS, IMPLICATIONS, AND FUTURE ADVANCES.

Vet Radiol Ultrasound 2016 Mar-Apr;57(2):113-23. Epub 2016 Jan 18.

Department of Oncology Physics, Edinburgh Cancer Centre, Western General Hospital, The University of Edinburgh, Edinburgh, UK.

The field of veterinary radiation therapy (RT) has gained substantial momentum in recent decades with significant advances in conformal treatment planning, image-guided radiation therapy (IGRT), and intensity-modulated (IMRT) techniques. At the root of these advancements lie improvements in tumor imaging, image alignment (registration), target volume delineation, and identification of critical structures. Image registration has been widely used to combine information from multimodality images such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to improve the accuracy of radiation delivery and reliably identify tumor-bearing areas. Many different techniques have been applied in image registration. This review provides an overview of medical image registration in RT and its applications in veterinary oncology. A summary of the most commonly used approaches in human and veterinary medicine is presented along with their current use in IGRT and adaptive radiation therapy (ART). It is important to realize that registration does not guarantee that target volumes, such as the gross tumor volume (GTV), are correctly identified on the image being registered, as limitations unique to registration algorithms exist. Research involving novel registration frameworks for automatic segmentation of tumor volumes is ongoing and comparative oncology programs offer a unique opportunity to test the efficacy of proposed algorithms.
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http://dx.doi.org/10.1111/vru.12342DOI Listing
November 2016

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

Lancet 2016 Mar 21;387(10024):1163-77. Epub 2015 Dec 21.

Department of Urology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK.

Background: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

Methods: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

Findings: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

Interpretation: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

Funding: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
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http://dx.doi.org/10.1016/S0140-6736(15)01037-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800035PMC
March 2016

Identifying radiotherapy target volumes in brain cancer by image analysis.

Healthc Technol Lett 2015 Oct 2;2(5):123-8. Epub 2015 Oct 2.

Department of Oncology Physics , Edinburgh Cancer Centre, Western General Hospital , Crewe Road South, Edinburgh EH4 2XU , UK ; School of Engineering , University of Edinburgh , King's Buildings, Mayfield Road, Edinburgh EH9 3JL , UK.

To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required.
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http://dx.doi.org/10.1049/htl.2015.0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625830PMC
October 2015

Identifying the dominant prostate cancer focal lesion using image analysis and planning of a simultaneous integrated stereotactic boost.

Acta Oncol 2015 23;54(9):1543-50. Epub 2015 Sep 23.

a Department of Oncology Physics , Edinburgh Cancer Centre, Western General Hospital , Crewe Road South, Edinburgh , UK.

Background: Prostate cancer is now the only solid organ cancer in which therapy is commonly applied to the whole gland. One of the main challenges in adopting focal boost or true focal therapy is in the accurate mapping of cancer foci defined on magnetic resonance (MR) images onto the computerised tomography (CT) images used for radiotherapy planning.

Material And Methods: Prostate cancer patients (n = 14) previously treated at the Edinburgh Cancer Centre (ECC) were selected for this study. All patients underwent MR scanning for the purpose of diagnosis and staging. Patients received three months of androgen deprivation hormone therapy followed by a radiotherapy planning CT scan. The dominant focal prostate lesions were identified on MR scans by a radiologist and a novel image analysis approach was used to map the location of the dominant focal lesion from MR to CT. An offline planning study was undertaken on suitable patients (n = 7) to investigate boosting of the radiation dose to the tumour using a stereotactic ablative body radiotherapy (SABR) technique.

Results: The non-rigid registration algorithm showed clinically acceptable estimates of the location of the dominant focal disease on all CT image data of patients suitable for a boost treatment. Standard rigid registration was found to produce unacceptable estimates of the dominant focal lesion on CT. A SABR boost dose of 47.5 Gy was delivered to the dominant focal lesion of all patients whilst meeting all dose-volume histogram (DVH) constraints. Normal tissue complication probability (NTCP) for the rectum decreased from 1.28% to 0.73% with this method.

Conclusions: These preliminary results demonstrate the potential of this image analysis method for reliably mapping dominant focal disease within the prostate from MR images onto planning CT images. Significant dose escalation using a simultaneous integrated SABR boost was achieved in all patients.
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http://dx.doi.org/10.3109/0284186X.2015.1063782DOI Listing
July 2016

Translational research will fail without surgical leadership: SCOTRRCC a successful surgeon-led Nationwide translational research infrastructure in renal cancer.

Surgeon 2015 Aug 30;13(4):181-6. Epub 2015 Apr 30.

Edinburgh Urological Cancer Group, University of Edinburgh, Edinburgh, UK; NHS Lothian, UK; School of Medicine, St. Andrews University, St. Andrews, UK.

Background: High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource.

Approach: In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond.

Conclusions: The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research.
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http://dx.doi.org/10.1016/j.surge.2015.03.001DOI Listing
August 2015

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019).

Eur Urol 2015 Jun 6;67(6):1028-1038. Epub 2014 Oct 6.

Medical Research Council Clinical Trials Unit at University College London, London, UK.

Background: Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort.

Objective: Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group.

Design, Setting, And Participants: STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014.

Outcome Measurements And Statistical Analysis: Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models.

Results And Limitations: A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population.

Conclusions: Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse.

Patient Summary: Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.
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http://dx.doi.org/10.1016/j.eururo.2014.09.032DOI Listing
June 2015

DNA strand breaks and hypoxia response inhibition mediate the radiosensitisation effect of nitric oxide donors on prostate cancer under varying oxygen conditions.

Biochem Pharmacol 2011 Jan 1;81(2):203-10. Epub 2010 Oct 1.

Prostate Research Group, Department of Urology, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK.

Prostate cancer cells can exist in a hypoxic microenvironment, causing radioresistance. Nitric oxide (NO) is a radiosensitiser of mammalian cells. NO-NSAIDs are a potential means of delivering NO to prostate cancer cells. This study aimed to determine the effect and mechanism of action of NO-sulindac and radiation, on prostate cancer cells and stroma, under normoxia (21% oxygen) and chronic hypoxia (0.2% oxygen). Using clonogenic assays, at a surviving fraction of 10% the sensitisation enhancement ratios of radiation plus NO-sulindac over radiation alone on PC-3 cells were 1.22 and 1.42 under normoxia and hypoxia, respectively. 3D culture of PC-3 cells revealed significantly reduced sphere diameter in irradiated spheres treated with NO-sulindac. Neither NO-sulindac nor sulindac radiosensitised prostate stromal cells under normoxia or hypoxia. HIF-1α protein levels were reduced by NO-sulindac exposure and radiation at 21 and 0.2% oxygen. Alkaline Comet assay analysis suggested an increased rate of single strand DNA breaks and slower repair of these lesions in PC-3 cells treated with NO-sulindac prior to irradiation. There was a higher level of γ-H2AX production and hence double strand DNA breaks following irradiation of NO-sulindac treated PC-3 cells. At all radiation doses and oxygen levels tested, treatment of 2D and 3D cultures of PC-3 cells with NO-sulindac prior to irradiation radiosensitised PC-3, with minimal effect on stromal cells. Hypoxia response inhibition and increased DNA double strand breaks are potential mechanisms of action. Neoadjuvent and concurrent use of NO-NSAIDs have the potential to improve radiotherapy treatment of prostate cancer under normoxia and hypoxia.
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http://dx.doi.org/10.1016/j.bcp.2010.09.022DOI Listing
January 2011

The relevance of a hypoxic tumour microenvironment in prostate cancer.

BJU Int 2010 Jan 4;105(1):8-13. Epub 2009 Nov 4.

Prostate Research Group, Department of Urology, University of Edinburgh, Western General Hospital, Edinburgh, UK.

Research into the hypoxic tumour microenvironment is accelerating and the reversal of hypoxia is increasingly being suggested as a mechanism for improving cancer treatment. Recent studies have suggested that hypoxia is also a feature in prostate cancer and is associated with a poor prognosis. Hypoxia has been shown to cause radio-resistance and hence hamper one of the major treatments for prostate cancer. However, unlike other solid tumours, such as cervical and head-and-neck cancer, there are inconsistencies and unanswered questions about the relevance of hypoxia in prostate cancer. This review outlines the role of low-oxygen conditions in prostate cancer and the areas where further studies are required.
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http://dx.doi.org/10.1111/j.1464-410X.2009.08921.xDOI Listing
January 2010

Characterisation of radiotherapy planning volumes using textural analysis.

Acta Oncol 2008 ;47(7):1303-8

Department of Oncology Physics, Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK.

Computer-based artificial intelligence methods for classification and delineation of the gross tumour volume (GTV) on computerised tomography (CT) and magnetic resonance (MR) images do not, at present, provide the accuracy required for radiotherapy applications. This paper describes an image analysis method for classification of distinct regions within the GTV, and other clinically relevant regions, on CT images acquired on eight bladder cancer patients at the radiotherapy planning stage and thereafter at regular intervals during treatment. Statistical and fractal textural features (N=27) were calculated on the bladder, rectum and a control region identified on axial, coronal and sagittal CT images. Unsupervised classification results demonstrate that with a reduced feature set (N=3) the approach offers significant classification accuracy on axial, coronal and sagittal CT image planes and has the potential to be developed further for radiotherapy applications, particularly towards an automatic outlining approach.
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http://dx.doi.org/10.1080/02841860802256467DOI Listing
October 2008

Late Relapse and Follow-up Protocols in Testicular Germ Cell Tumours: The Edinburgh Cancer Centre Experience and Review of the Literature.

Clin Med Oncol 2008 21;2:19-25. Epub 2008 Jan 21.

Department of Radiotherapy, University of Florence, Florence, Italy.

Aims: To identify clinicopathological features and outcomes in patients with late relapse (LR) of testicular germ cell tumours (GCTs) in order to guide follow-up policy.

Materials And Methods: The Edinburgh Cancer Centre (ECC) database identified all patients diagnosed with testicular GCT between 1988 and 2002. Of 703 patients, six relapsed more than 24 months after their initial treatment. A retrospective casenote review was performed to extract clinical, pathological, treatment and outcome data.

Results: Six patients (0.85%) underwent late relapse. All patients presented initially with stage I disease and five were classified as good risk (International Germ Cell Consensus Classification, IGCCC). Median time to LR was 31 months. Two patients had previously relapsed less than 24 months from initial diagnosis. Markers at the time of relapse were normal in all patients. In all cases of late relapse disease was confined to axial lymphadenopathy. Three patients were treated with chemotherapy alone, two patients underwent surgical resection and one patient received combined treatment. All patients obtained a complete response and all remain disease free with a median follow-up of 52 months.

Conclusions: The incidence of late relapse in this series is low. Chemo-naive patients with LR were successfully salvaged with chemotherapy alone and patients previously exposed to cisplatin-based chemotherapy were salvaged with complete surgical excision. The optimal length of follow-up in patients with testicular germ cell tumours is not known and practice varies widely. In this cohort of 703 patients, only one patient who relapsed was picked up by additional clinic follow-up between 5 and 10 years. Thus, on the basis of this small series, the authors suggest that follow-up after five years may not be justified.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161629PMC
http://dx.doi.org/10.4137/cmo.s321DOI Listing
November 2011

Image-guided radiotherapy of bladder cancer: bladder volume variation and its relation to margins.

Radiother Oncol 2007 Sep 9;84(3):307-13. Epub 2007 Aug 9.

Department of Medical Physics, Aarhus University Hospital, Aarhus, Denmark.

Background And Purpose: To control and account for bladder motion is a major challenge in radiotherapy (RT) of bladder cancer. This study investigates the relation between bladder volume variation and margins in conformal and image-guided RT (IGRT) for this disease.

Materials And Methods: The correlation between the relative bladder volume (RBV, defined as repeat scan volume/planning scan volume) and the margins required to account for internal motion was first studied using a series of 20 bladder cancer patients with weekly repeat CT scanning during treatment. Both conformal RT (CRT) and IGRT were simulated; in the latter translational movement of the bladder was accounted for by isocentre shifting. Further analysis of bladder volumes and margins was performed using a second series of eight patients with twice-weekly repeat CT scanning. In an attempt to control bladder volume variation these patients were given fluid intake restrictions on alternating weeks during treatment.

Results: IGRT gave the strongest correlation between the RBV and margin size (R(2)=0.75; p<0.001). Using IGRT, isotropic margins >10mm were required in only 1% of the situations when the RBV1, whereas isotropic margins >10mm were required in 55% of the situations when the RBV>1. Less marked correlation was found using CRT (R(2) in the range 0.43-0.53, p<0.001) for four different methods used to assess the margins required in the six directions, although a strong correlation was found for the superior margin (R(2)=0.63; p<0.001). Fluid intake restriction gave a small reduction in both bladder volume (average absolute volume reduced from 126 to 121cm(3); RBV from 0.83 to 0.80) and bladder volume variation, but not sufficient to translate into margin reduction.

Conclusions: The study showed the potential for a large margin reduction in bladder RT if the bladder volume is controlled and this potential was even greater for IGRT. An attempt to control the bladder volume by restricting fluid intake prior to the treatment session failed to give any reduction in the margins required.
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http://dx.doi.org/10.1016/j.radonc.2007.06.014DOI Listing
September 2007

A concomitant tumour boost in bladder irradiation: patient suitability and the potential of intensity-modulated radiotherapy.

Radiother Oncol 2006 Jul 28;80(1):98-105. Epub 2006 Jul 28.

Section of Oncology, Institute of Medicine, Medical Faculty, University of Bergen, Norway.

Background And Purpose: In radiotherapy (RT) of bladder cancer, dose escalation without increased adverse effects could be achieved with a concomitant bladder tumour boost. In this study we quantified (1) the fraction of patients suitable for this approach, and (2) the potential of intensity-modulated RT (IMRT) to achieve this boost while also sparing normal tissues.

Materials And Methods: The fraction of patients suitable for this boost approach was quantified using both a series of 30 radical therapy candidates, and a series of 15 consecutive RT patients. IMRT plans with 3, 5, 7 and 9 equi-spaced beams were set up for the patients in the RT series found suitable for a boost. Two sets of targets were defined, with (i) wide and (ii) narrow margins around both the tumour (prescribed 120% dose) and the non-involved bladder (prescribed 100% dose). The inverse planning optimisation minimised the dose deviation across the targets whilst fulfilling dose-volume histogram (DVH) constraints--based on what could be achieved with conformal RT (CRT)--for both the normal tissues and the targets.

Results: Fourteen of the 30 radical therapy candidates (47%) and 10 of the 15 RT patients (67%) were suitable for a boost. The 20% boost could be obtained while maintaining target coverage with at least one IMRT plan in 9 of 10 cases with wide margins and for all 10 cases with narrow margins. Using wide margins, all 3-field plans were unacceptable, the 5-field plans were acceptable for 5 of 10, and the 7- and 9-field plans for 9 of the 10 patients. The normal tissue volumes receiving doses >100% were on average reduced by a factor of 3-4 compared with CRT. The normal tissue volumes receiving intermediate doses (73-88%) decreased slightly, whereas volumes receiving the lowest doses (30-48%) increased with the number of beams. The use of narrow margins resulted in markedly lower normal tissue irradiation.

Conclusion: This study has shown bladder tumour boosting to be both clinically relevant and technically feasible using IMRT. This approach is ready for clinical implementation, although further improvement could be expected if integrated with target localisation techniques.
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http://dx.doi.org/10.1016/j.radonc.2006.06.015DOI Listing
July 2006
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