Publications by authors named "Peter J Hoskin"

116 Publications

A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive sbladder cancer.

Br J Cancer 2021 Apr 12. Epub 2021 Apr 12.

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester, UK.

Background: miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer.

Methods: Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation.

Results: A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen-nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094-0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24-0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08-0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033).

Conclusion: A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
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http://dx.doi.org/10.1038/s41416-021-01326-9DOI Listing
April 2021

Dosimetric comparison of volumetric modulated arc therapy (VMAT) and high-dose-rate brachytherapy (HDR-BT) for superficial skin irradiation with significant curvature in one or more planes.

Strahlenther Onkol 2021 Mar 31. Epub 2021 Mar 31.

Mount Vernon Cancer Centre, East and North Hertfordshire NHS Trust, London, UK.

Purpose: This study compares the plan quality of high-dose-rate brachytherapy (HDR-BT) and volumetric modulated arc therapy (VMAT) for superficial irradiation of large areas of skin with significant curvature in one or more planes.

Methods: A total of 14 patients from two centres previously treated with either HDR-BT or VMAT were retrospectively replanned using the alternative technique. Sites included scalp and lower limbs. Identical computed tomography (CT) scans, clinical target volume (CTV) and organs at risk (OARs) and prescription were used for both techniques. Conformity, skin surface dose and OAR doses were compared.

Results: Conformity index was consistently better with VMAT than HDR-BT (p < 0.01). Maximum skin surface dose (D0.1cc) had a higher mean of 49.6 Gy with HDR-BT compared to 31.4 Gy for VMAT (p < 0.01). Significantly smaller volumes of healthy tissue were irradiated with VMAT than with HDR-BT. This can be seen in brain volumes receiving 10, 20 and 30 Gy EQD2 and in extremities receiving 5 and 10 Gy. When close to the volume, the lens received significantly lower doses with VMAT (p < 0.01).

Conclusion: In this small sample, VMAT gives equal coverage with lower OAR and skin surface doses than HDR-BT for both scalp and extremities. VMAT is a useful technique for treating large, superficial volumes with significant curvature in one or more planes.
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http://dx.doi.org/10.1007/s00066-021-01759-4DOI Listing
March 2021

Lost in application: Measuring hypoxia for radiotherapy optimisation.

Eur J Cancer 2021 Mar 20;148:260-276. Epub 2021 Mar 20.

Division of Cancer Sciences, The University of Manchester, Christie Hospital NHS Foundation Trust, Manchester, UK.

The history of radiotherapy is intertwined with research on hypoxia. There is level 1a evidence that giving hypoxia-targeting treatments with radiotherapy improves locoregional control and survival without compromising late side-effects. Despite coming in and out of vogue over decades, there is now an established role for hypoxia in driving molecular alterations promoting tumour progression and metastases. While tumour genomic complexity and immune profiling offer promise, there is a stronger evidence base for personalising radiotherapy based on hypoxia status. Despite this, there is only one phase III trial targeting hypoxia modification with full transcriptomic data available. There are no biomarkers in routine use for patients undergoing radiotherapy to aid management decisions, and a roadmap is needed to ensure consistency and provide a benchmark for progression to application. Gene expression signatures address past limitations of hypoxia biomarkers and could progress biologically optimised radiotherapy. Here, we review recent developments in generating hypoxia gene expression signatures and highlight progress addressing the challenges that must be overcome to pave the way for their clinical application.
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http://dx.doi.org/10.1016/j.ejca.2021.01.039DOI Listing
March 2021

Ultra-hypofractionated radiotherapy for low- and intermediate risk prostate cancer: High-dose-rate brachytherapy vs stereotactic ablative radiotherapy.

Radiother Oncol 2021 Feb 24;158:184-190. Epub 2021 Feb 24.

Mount Vernon Cancer Centre, Northwood, UK; Division of Cancer Sciences, Faculty of Biology Medicine and Health, University of Manchester, United Kingdom.

Purpose: To compare the biochemical control rates (BCRs), late gastrointestinal (GI) and genitourinary (GU) toxicities in patients with low- and intermediate risk prostate cancer (PCa) treated with high-dose-rate brachytherapy (HDR BT) of 19 Gy/1 fraction, 26 Gy/2 fractions, or stereotactic ablative radiotherapy (SABR) of 36.25 Gy/5 fractions.

Methods And Materials: Between August 2008 and December 2017, patients with low- and intermediate risk PCa who received single dose or 2-fraction HDR BT, or 5-fraction SABR at a single institution were included. BCR for the whole population and the individual treatment groups were calculated using the Phoenix definition. Post treatment GI and GU toxicities were evaluated according to the CTCAE v4.0 guidelines.

Results: 185 patients with low- and intermediate risk PCa were included in this study with a median follow up of 60.5 months. BCRs at 3 and 5 years were 95% and 85% for all patients. The 5-year BCRs were 69%, 95% and 92% for the 19 Gy/1 fraction, 26 Gy/2 fractions and 36.25 Gy/5 fractions groups respectively. The cumulative 5-year incidence rates of ≥grade 2 GI events in the 19 Gy/1fr, 26 Gy/2fr and 36.25 Gy/5fr groups were 0%, 2% and 4%, respectively. Incidence rates in those treated in the 5-fraction SABR arm were significantly higher (p < 0.05) than those treated in both HDR BT arms where no statistically significant difference between the two HDR BT groups was seen (p = 0.15). The cumulative 5-year incidence rates of ≥grade 2 GU events in the 19 Gy/1fr, 26 Gy/2fr and 36.25 Gy/5fr groups were 30%, 5% and 6%, respectively. No statistically significant difference was found between the 26 Gy/2fr and 36.25 Gy/5fr (p = 0.37) treatment arms but the incidence rate in the 26 Gy/2fr were significantly lower than those seen after 19 Gy/1fr (p < 0.05).

Conclusions: 26 Gy/2 fractions HDR BT provided equivalent BCR with lower toxicity compared to 36.25 Gy/5 fractions SABR. Both 2-fraction HBR BT and 5-fraction SABR achieved better BCRs than single dose 19 Gy HDR BT. The two-fraction HDR BT schedule should be considered as an important comparator in future clinical trials.
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http://dx.doi.org/10.1016/j.radonc.2021.02.028DOI Listing
February 2021

Excess dose-related parameters (Vex, Rex, and iRex): novel predictors and late toxicity correlations in cervical cancer image-guided adaptive brachytherapy.

J Contemp Brachytherapy 2020 Oct 30;12(5):441-453. Epub 2020 Oct 30.

Mount Vernon Cancer Centre, Northwood, United Kingdom.

Purpose: In this paper, excess dose is originally proposed to represent the dose outside the target volume that encompass only organs at risk (OARs), not the whole dose volume of isodose surface volume (ISV). By means of spatial consideration, excess dose-related parameters would also compensate inconsistent applicator positions and OARs motion, which may deviate the identical dose small-volume assumption of D. Late toxicity correlations of these parameters were investigated.

Material And Methods: A retrospective review was performed on cervical cancer high-dose-rate image-guided adaptive brachytherapy (HDR-IGABT). From ISVs of 60 to 100 Gy EQD (a/β = 3), excess dose-related parameters were derived as following: toxicity negligible volume (Vneg = V of toxicity negligible organs; high-risk clinical target volume - HR-CTV, uterus, and vagina), excess dose volume (Vex = ISV - Vneg), Vneg normalized parameters of excess dose volume ratio (Rex = Vex/Vneg), and indirect excess dose volume ratio (iRex = ISV/Vneg). Relationships between toxicity and these parameters were analyzed using a mean difference and a probit analysis method. Net reclassification indices (NRIs) were used to compare iRex60 and D gastrointestinal (GI) toxicity prediction.

Results: From 143 cases with an incidence of 34.9% and 10.5% of 3-year grade 2-4 GI and genitourinary (GU) toxicity, respectively, comparisons of means showed significant difference between grade 0-1 and 2-4 toxicities for late GI toxicity for all parameters, except ISV. There was a dose-response relationship with toxicity for each parameter across the range of 60-100 Gy EQD. ED of iRex60 and iRex70 were 2.1 and 1.2, respectively. By comparing iRex60 and D, additive and absolute NRIs were +6.45 and +7.69%, respectively. The reclassification significantly occurred in range of 65-75 Gy of rectum D.

Conclusions: Excess dose-related parameters, including Vex, Rex, and iRex, showed significant mean differences and parameter-toxicity relationships for late GI but not for GU toxicities. Positive NRIs suggest iRex60 utilization for spatial control of dose expansion, in addition to high-dose control with OAR small volumes. Further investigations are needed to define the optimum use of these predictors.
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http://dx.doi.org/10.5114/jcb.2020.100377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701922PMC
October 2020

Randomised trial of external-beam radiotherapy alone or with high-dose-rate brachytherapy for prostate cancer: Mature 12-year results.

Radiother Oncol 2021 Jan 2;154:214-219. Epub 2020 Oct 2.

Cancer Centre, Mount Vernon Hospital, Northwood, UK.

Background And Purpose: A randomised phase-III trial compared external beam radiotherapy (EBRT) alone with EBRT combined with high-dose-rate brachytherapy boost (HDR-BTb) in localised prostate adenocarcinoma. Previous analysis, at median follow up of 85 months, demonstrated improved relapse free survival (RFS) with EBRT + HDR-BTb. This data has now been updated with a median follow up of 131 months.

Materials And Methods: From December 1997 to August 2005, patients were assigned either to EBRT alone delivering 55 Gy in 20 fractions over 4 weeks or EBRT followed by a temporary high-dose-rate implant delivering 2 × 8·5 Gy over 24 h. The primary endpoint was RFS defined by a PSA rise ≥2.0 µg/l above nadir, clinical progression or death. Actuarial survival rates and Hazard Ratios (HRs) were calculated using the Kaplan-Meier method and Cox's Proportional Hazard Model, respectively. Secondary endpoints were overall survival (OS), urinary and bowel toxicity.

Results: One hundred and six patients received EBRT alone and 110 EBRT + HDR-BTb. Median time to relapse was 137 months in the HDR-BTb arm compared to 82 months for EBRT alone (p = 0·01). A 27% risk of recurrence with EBRT alone was observed (p = 0·001), resulting in a 21% improvement in RFS at 12 years with EBRT + HDR-BTb. In multivariate analysis treatment arm, risk category and no androgen deprivation therapy were significant covariates for risk of relapse. Differences in overall survival were not significant.

Conclusion: At 12 years there remains a significant improvement in RFS after EBRT + HDR-BTb; both treatments were equitoxic for severe late urinary and bowel events and urethral strictures.
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http://dx.doi.org/10.1016/j.radonc.2020.09.047DOI Listing
January 2021

The implementation of an empty bladder filling protocol for localised prostate volumetric modulated arctherapy (VMAT): early results of a single institution service evaluation.

Br J Radiol 2020 Oct 31;93(1114):20200548. Epub 2020 Jul 31.

Mount Vernon Cancer Centre, Northwood, Middlesex HA6 2RN, UK.

Objective: To examine the impact of an empty bladder filling protocol on patients receiving radical RT for localised prostate cancer on post RT toxicity and biochemical progression free survival (bPFS).

Methods And Materials: Records of patients receiving radical external beam RT (EBRT) for localised prostate cancer with a full or empty bladder were reviewed. These included the bladder size on planning CT, daily online image guided RT (IGRT) setup data, treatment time and post treatment follow up data.These included bPFS, gastrointestinal(GI) and genitourinary(GU) toxicity scoring post RT using the CTCAE v4.0 scoring system. All patients included in the study were planned and treated under the same departmental clinical protocol with VMAT and daily online IGRT corrections.

Results: 90 patients were treated with 60 Gy in 20 fractions with a median follow up of 48 months. At 4 years bPFS in the empty bladder group was 100 and 98% in the full bladder group ( = 0.27). There were no statistically significant differences in cumulative ≥Grade 2GU ( = 0.10) and GI ( = 0.27) toxicity rates between the two bladder filling protocols. No statistically significant differences in the IGRT setup between the two groups of patients. Although the median treatment times per fraction were not statistically different between the two groups ( = 0.47), patients in the full bladder filling group were required to spend a longer time in the RT department per treatment session for bladder filling.

Conclusion: An empty bladder filling protocol has non-inferior bPFS, GI and GU toxicities at 4 years in patients with localised prostate cancer using advanced RT techniques in comparison to a full bladder filling protocol. A longer follow up with a larger sample size is required to validate this approach.

Advances In Knowledge: This study suggests that an empty bladder filling protocol can be used in external beam EBRT for localised prostate cancer with non-inferior treatment outcomes.
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http://dx.doi.org/10.1259/bjr.20200548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548355PMC
October 2020

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia.

Br J Radiol 2020 Aug 2;93(1112):20190250. Epub 2020 Jun 2.

Faculty of Medicine, Imperial College, London, UK.

Objective: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation.

Methods: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions.

Results: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions.

Conclusion: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation.

Advances In Knowledge: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.
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http://dx.doi.org/10.1259/bjr.20190250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446001PMC
August 2020

Addition of Androgen-Deprivation Therapy or Brachytherapy Boost to External Beam Radiotherapy for Localized Prostate Cancer: A Network Meta-Analysis of Randomized Trials.

J Clin Oncol 2020 09 12;38(26):3024-3031. Epub 2020 May 12.

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.

Purpose: In men with localized prostate cancer, the addition of androgen-deprivation therapy (ADT) or a brachytherapy boost (BT) to external beam radiotherapy (EBRT) have been shown to improve various oncologic end points. Practice patterns indicate that those who receive BT are significantly less likely to receive ADT, and thus we sought to perform a network meta-analysis to compare the predicted outcomes of a randomized trial of EBRT plus ADT versus EBRT plus BT.

Materials And Methods: A systematic review identified published randomized trials comparing EBRT with or without ADT, or EBRT (with or without ADT) with or without BT, that reported on overall survival (OS). Standard fixed-effects meta-analyses were performed for each comparison, and a meta-regression was conducted to adjust for use and duration of ADT. Network meta-analyses were performed to compare EBRT plus ADT versus EBRT plus BT. Bayesian analyses were also performed, and a rank was assigned to each treatment after Markov Chain Monte Carlo analyses to create a surface under the cumulative ranking curve.

Results: Six trials compared EBRT with or without ADT (n = 4,663), and 3 compared EBRT with or without BT (n = 718). The addition of ADT to EBRT improved OS (hazard ratio [HR], 0.71 [95% CI, 0.62 to 0.81]), whereas the addition of BT did not significantly improve OS (HR, 1.03 [95% CI, 0.78 to 1.36]). In a network meta-analysis, EBRT plus ADT had improved OS compared with EBRT plus BT (HR, 0.68 [95% CI, 0.52 to 0.89]). Bayesian modeling demonstrated an 88% probability that EBRT plus ADT resulted in superior OS compared with EBRT plus BT.

Conclusion: Our findings suggest that current practice patterns of omitting ADT with EBRT plus BT may result in inferior OS compared with EBRT plus ADT in men with intermediate- and high-risk prostate cancer. ADT for these men should remain a critical component of treatment regardless of radiotherapy delivery method until randomized evidence demonstrates otherwise.
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http://dx.doi.org/10.1200/JCO.19.03217DOI Listing
September 2020

Single dose high-dose rate (HDR) brachytherapy (BT) as monotherapy for localised prostate cancer: Early results of a UK national cohort study.

Radiother Oncol 2020 02 7;143:95-100. Epub 2020 Feb 7.

Mount Vernon Cancer Centre, Northwood, UK; University of Manchester, Manchester, UK.

Background: HDR brachytherapy alone is effective for the treatment of localised prostate cancer when given in 2-4 or more fractions. Single dose treatment has been explored in small cohort studies to date. This paper reports a large patient population with localised prostate cancer treated with single dose HDR brachytherapy delivering 19 Gy providing early outcome data from this approach.

Patients And Methods: Seven centres across the UK collaborated in this national protocol to deliver 19 Gy to the PTV defined by the prostate capsule and a 3 mm expansion with clearly defined planning constraints for the urethra and rectum. Entry criteria allowed all risk groups provided PSA ≤40 µg/L and staging investigations were negative for metastases. The primary end point was biochemical relapse free survival (bRFS) defined using the Phoenix definition. Toxicity was measured using CTCAE v4.0.

Results: A total of 441 patients were entered with median follow up 26 months (range 2-56). Median age was 73 (range 54-84) and 10% were low risk, 65% intermediate risk and 25% high risk. ADT was received by 37.6% overall and 90% of high risk patients for a median period of 6 months. Three year bRFS was overall 88%: this was 100% in low risk, 86% in intermediate risk and 75% in high risk. Only Gleason score was an independent predictor of bRFS. Relapse in 25 patients was assessed radiologically and occurred in the prostate in 15 of these, 11 of whom had localised prostate relapse only. Acute toxicity was low with no grade 3 or 4 events; there were two cases of late urinary stricture and two grade 3 late rectal events.

Conclusion: This is the largest cohort of single dose HDR brachytherapy patients treated with a single dose published to date. It shows that with 19 Gy there is 100% bRFS at 3 years in low risk patients but results in intermediate and high risk groups are less encouraging falling to 86% and 75% at 3 years with relapse predominantly in the prostate. Limited by the short follow up period of this study, the long-term outcomes of this single dose HDR approach remains uncertain. It is important to have close ongoing surveillance of this cohort as the data matures.
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http://dx.doi.org/10.1016/j.radonc.2019.12.017DOI Listing
February 2020

Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial.

JAMA 2019 12;322(21):2084-2094

CRUK & UCL Cancer Trials Centre, London, United Kingdom.

Importance: Malignant spinal canal compression, a major complication of metastatic cancer, is managed with radiotherapy to maintain mobility and relieve pain, although there is no standard radiotherapy regimen.

Objective: To evaluate whether single-fraction radiotherapy is noninferior to 5 fractions of radiotherapy.

Design, Setting, And Participants: Multicenter noninferiority randomized clinical trial conducted in 42 UK and 5 Australian radiotherapy centers. Eligible patients (n = 686) had metastatic cancer with spinal cord or cauda equina compression, life expectancy greater than 8 weeks, and no previous radiotherapy to the same area. Patients were recruited between February 2008 and April 2016, with final follow-up in September 2017.

Interventions: Patients were randomized to receive external beam single-fraction 8-Gy radiotherapy (n = 345) or 20 Gy of radiotherapy in 5 fractions over 5 consecutive days (n = 341).

Main Outcomes And Measures: The primary end point was ambulatory status at week 8, based on a 4-point scale and classified as grade 1 (ambulatory without the use of aids and grade 5 of 5 muscle power) or grade 2 (ambulatory using aids or grade 4 of 5 muscle power). The noninferiority margin for the difference in ambulatory status was -11%. Secondary end points included ambulatory status at weeks 1, 4, and 12 and overall survival.

Results: Among 686 randomized patients (median [interquartile range] age, 70 [64-77] years; 503 (73%) men; 44% had prostate cancer, 19% had lung cancer, and 12% had breast cancer), 342 (49.8%) were analyzed for the primary end point (255 patients died before the 8-week assessment). Ambulatory status grade 1 or 2 at week 8 was achieved by 115 of 166 (69.3%) patients in the single-fraction group vs 128 of 176 (72.7%) in the multifraction group (difference, -3.5% [1-sided 95% CI, -11.5% to ∞]; P value for noninferiority = .06). The difference in ambulatory status grade 1 or 2 in the single-fraction vs multifraction group was -0.4% (63.9% vs 64.3%; [1-sided 95% CI, -6.9 to ∞]; P value for noninferiority = .004) at week 1, -0.7% (66.8% vs 67.6%; [1-sided 95% CI, -8.1 to ∞]; P value for noninferiority = .01) at week 4, and 4.1% (71.8% vs 67.7%; [1-sided 95% CI, -4.6 to ∞]; P value for noninferiority = .002) at week 12. Overall survival rates at 12 weeks were 50% in the single-fraction group vs 55% in the multifraction group (stratified hazard ratio, 1.02 [95% CI, 0.74-1.41]). Of the 11 other secondary end points that were analyzed, the between-group differences were not statistically significant or did not meet noninferiority criterion.

Conclusions And Relevance: Among patients with malignant metastatic solid tumors and spinal canal compression, a single radiotherapy dose, compared with a multifraction dose delivered over 5 days, did not meet the criterion for noninferiority for the primary outcome (ambulatory at 8 weeks). However, the extent to which the lower bound of the CI overlapped with the noninferiority margin should be considered when interpreting the clinical importance of this finding.

Trial Registration: ISRCTN Identifiers: ISRCTN97555949 and ISRCTN97108008.
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http://dx.doi.org/10.1001/jama.2019.17913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902166PMC
December 2019

Magnetic resonance-guided radiation therapy: A review.

J Med Imaging Radiat Oncol 2020 Feb 23;64(1):163-177. Epub 2019 Oct 23.

Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK.

Magnetic resonance-guided radiation therapy (MRgRT) is a promising approach to improving clinical outcomes for patients treated with radiation therapy. The roles of image guidance, adaptive planning and magnetic resonance imaging in radiation therapy have been increasing over the last two decades. Technical advances have led to the feasible combination of magnetic resonance imaging and radiation therapy technologies, leading to improved soft-tissue visualisation, assessment of inter- and intrafraction motion, motion management, online adaptive radiation therapy and the incorporation of functional information into treatment. MRgRT can potentially transform radiation oncology by improving tumour control and quality of life after radiation therapy and increasing convenience of treatment by shortening treatment courses for patients. Multiple groups have developed clinical implementations of MRgRT predominantly in the abdomen and pelvis, with patients having been treated since 2014. While studies of MRgRT have primarily been dosimetric so far, an increasing number of trials are underway examining the potential clinical benefits of MRgRT, with coordinated efforts to rigorously evaluate the benefits of the promising technology. This review discusses the current implementations, studies, potential benefits and challenges of MRgRT.
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http://dx.doi.org/10.1111/1754-9485.12968DOI Listing
February 2020

External Beam Radiation Therapy (EBRT) and High-Dose-Rate (HDR) Brachytherapy for Intermediate and High-Risk Prostate Cancer: The Impact of EBRT Volume.

Int J Radiat Oncol Biol Phys 2020 03 11;106(3):525-533. Epub 2019 Oct 11.

Mount Vernon Cancer Centre, Northwood, United Kingdom; University of Manchester, Manchester, United Kingdom. Electronic address:

Purpose: Whole pelvis radiation therapy (WPRT) may improve clinical outcomes over prostate-only radiation therapy (PORT) in high-risk prostate cancer patients by sterilization of micrometastatic nodal disease, provided there is optimal control of the primary site.

Methods And Materials: A prospective multicenter cohort study of eligible patients (stage ≥T2c, Gleason score ≥7 or presenting prostate-specific antigen ≥10) treated between 2009 and 2013 were enrolled in a United Kingdom national protocol delivering combined external beam radiation therapy and high-dose-rate brachytherapy. Centers elected to deliver WPRT, 46 Gy in 23 fractions or PORT 37.5 Gy in 15 fractions with 15 Gy single dose high-dose-rate brachytherapy. The primary endpoint was biochemical progression-free survival (bPFS). Secondary endpoints were overall survival, genitourinary, and gastrointestinal toxicity. This was not a randomized comparison and was subject to bias; the findings are therefore hypothesis generating, but not conclusive.

Results: Eight hundred and twelve patients were entered; 401 received WPRT and 411 received PORT. With a median follow-up of 4.7 years, 5-year bPFS rates for WPRT versus PORT arms were 89% versus 81% (P = .007) for all patients and 84% versus 77% (P = .001) for high-risk patients. Differences in bPFS remained significant after accounting for Gleason score, presenting prostate-specific antigen, T stage, and androgen deprivation therapy duration as covariates. There was no difference in overall survival. The overall post treatment toxicities across both cohorts were low with no greater than 1.5% of ≥grade 3 toxicities at any follow-up time point. WPRT increased both prevalence and cumulative incidence of acute genitourinary toxicity (P = .004) and acute gastrointestinal toxicity (P = .003). No difference in late radiation toxicity was observed.

Conclusions: A significant improvement in 5-year bPFS was seen in intermediate and high-risk prostate cancer treated with WPRT compared with PORT in a combined external beam radiation therapy and brachytherapy schedule with no increase in late radiation toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2019.09.044DOI Listing
March 2020

New approaches for effective and safe pelvic radiotherapy in high-risk prostate cancer.

Nat Rev Urol 2019 09 25;16(9):523-538. Epub 2019 Jul 25.

Mount Vernon Cancer Centre, Northwood, UK.

Radical radiotherapy for prostate cancer offers excellent long-term outcomes for patients with high-risk disease. The increased risk of pelvic nodal involvement in this cohort has led to the development of whole-pelvis radiotherapy (WPRT) with a prostate boost. However, the use of WPRT remains controversial. Data are mixed, but advanced radiotherapy techniques enable delivery of increased radiation to pelvic nodes with acceptable levels of toxicity. Contemporary imaging modalities with increased sensitivity for detecting subclinical lymph node disease will facilitate selection of patients most likely to benefit from WPRT. Using such modalities for image guidance of advanced radiotherapy techniques could also permit high-dose delivery to nodes outside the conventional Radiation Therapy Oncology Group volumes, where magnetic resonance lymphography and single-photon-emission CT imaging have mapped a high frequency of microscopic disease. With increased toxicity a concern, an alternative to WPRT would be selective irradiation of target nodal groups most likely to harbour occult disease. New image-based 'big data' mining techniques enable the large-scale comparison of incidental dose distributions of thousands of patients treated in the past. By using novel computing methods and artificial intelligence, high-risk regions can be identified and used to optimize WPRT through refined knowledge of the likely location of subclinical disease.
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http://dx.doi.org/10.1038/s41585-019-0213-3DOI Listing
September 2019

Single Fraction High-Dose-Rate Brachytherapy: Too Good to Be True?

Int J Radiat Oncol Biol Phys 2019 08;104(5):1054-1056

Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.

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http://dx.doi.org/10.1016/j.ijrobp.2019.04.036DOI Listing
August 2019

Organ preservation in bladder cancer: an opportunity for truly personalized treatment.

Nat Rev Urol 2019 09 13;16(9):511-522. Epub 2019 Jun 13.

Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK.

Radical treatment of many solid tumours has moved from surgery to multimodal organ preservation strategies combining systemic and local treatments. Trimodality bladder-preserving treatment (TMT) comprises maximal transurethral resection of the bladder tumour followed by radiotherapy and concurrent radiosensitizing treatment, thereby sparing the urinary bladder. From the patient's perspective, the choice of maintaining quality of life without a negative effect on the chances of cure and long-term survival is attractive. In muscle-invasive bladder cancer (MIBC), the evidence shows comparable clinical outcomes between patients undergoing radical cystectomy and TMT. Despite this evidence, many patients continue to be offered radical surgery as the standard-of-care treatment. Improvements in radiotherapy techniques with adaptive radiotherapy and advances in imaging translate to increases in the accuracy of treatment delivery and reductions in long-term toxicities. With the advent of novel biomarkers promising improved prediction of treatment response, stratification of patients for different treatments on the basis of tumour biology could soon be a reality. The future of oncological treatment lies in personalized medicine with the combination of technological and biological advances leading to truly bespoke management for patients with MIBC.
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http://dx.doi.org/10.1038/s41585-019-0199-xDOI Listing
September 2019

Hypoxia and angiogenic biomarkers in prostate cancer after external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb).

Radiother Oncol 2019 08 3;137:38-44. Epub 2019 May 3.

Mount Vernon Cancer Centre, Northwood, United Kingdom; University of Manchester, Manchester, United Kingdom. Electronic address:

Purpose: To investigate angiogenic and hypoxia biomarkers to predict outcome in patients receiving external beam radiotherapy (EBRT) alone or combined with high-dose-rate brachytherapy boost (HDR-BTb) for localised prostate cancer.

Methods: Prostate biopsy samples were collected prospectively in patients entered into a phase 3 randomised controlled trial of patients receiving EBRT or EBRT + HDR-BTb. Univariate and multivariate analyses using Cox proportional hazards model were performed to identify associations between immunohistochemical staining of hypoxia inducible factor 1 alpha (HIF1α), glucose transporter 1 (GLUT1), osteopontin (OPN) and microvessel density (MVD) using CD-34 antibody with clinical outcome. The primary endpoint was biochemical relapse free survival (BRFS) and secondary endpoint was distant metastasis free survival (DMFS).

Results: Immunohistochemistry was available for 204 patients. Increased OPN (Hazard ratio [HR] 2.38, 95% Confidence Interval [CI] 1.06-5.34, p < 0.036) and GLUT1 (HR 2.36, 95%CI 1.39-4.01, p < 0.001) expression were predictive of worse BRFS. Increased GLUT1 expression (HR 2.22, 1.02-4.84, p = 0.045) was predictive of worse DMFS. Increased MVD (CD-34) (HR 1.82, 95%CI 1.06-3.14, p = 0.03) and OPN (HR 1.82, 95%CI 1.06-3.14, p = 0.03) but reduced GLUT1 expression (HR 0.40, 95%CI 0.20-0.79, p = 0.009) were predictive of improved BRFS in patients receiving EBRT + HDR-BTb.

Conclusion: Our data suggest angiogenic and hypoxia biomarkers may predict outcome and benefit of dose escalation, however further validation in prospective studies including hypoxia modification is needed. Trial registration number ISRCTN98241100, registered with ISRCTN at http://www.controlled-trials.com/isrctn/.
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http://dx.doi.org/10.1016/j.radonc.2019.04.019DOI Listing
August 2019

MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer.

Int J Radiat Oncol Biol Phys 2019 07 15;104(4):809-818. Epub 2019 Mar 15.

CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, United Kingdom. Electronic address:

Purpose: Organ-confined muscle-invasive bladder cancer is treated with cystectomy or bladder preservation techniques, including radiation therapy. There are currently no biomarkers to inform management decisions and aid patient choice. Previously we showed high levels of MRE11 protein, assessed by immunohistochemistry (IHC), predicted outcome after radiation therapy, but not cystectomy. Therefore, we sought to develop the MRE11 IHC assay for clinical use and define its relationship to clinical outcome in samples from 2 major clinical trials.

Methods And Materials: Samples from the BCON and BC2001 randomized controlled trials and a cystectomy cohort were stained using automated IHC methods and scored for MRE11 in 3 centers in the United Kingdom.

Results: Despite step-wise creation of scoring cards and standard operating procedures for staining and interpretation, there was poor intercenter scoring agreement (kappa, 0.32; 95% confidence interval, 0.17-0.47). No significant associations between MRE11 scores and cause-specific survival were identified in BCON (n = 132) and BC2001 (n = 221) samples. Reoptimized staining improved agreement between scores from BCON tissue microarrays (n = 116), but MRE11 expression was not prognostic for cause-specific survival.

Conclusions: Manual IHC scoring of MRE11 was not validated as a reproducible biomarker of radiation-based bladder preservation success. There is a need for automated quantitative methods or a reassessment of how DNA-damage response relates to clinical outcomes.
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http://dx.doi.org/10.1016/j.ijrobp.2019.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588678PMC
July 2019

Predictive Biomarkers for Muscle-invasive Bladder Cancer: The Search for the Holy Grail Continues.

Eur Urol 2019 07 4;76(1):69-70. Epub 2019 Feb 4.

Manchester Cancer Research Centre, Division of Cancer Science, School of Medical Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

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http://dx.doi.org/10.1016/j.eururo.2019.01.040DOI Listing
July 2019

Outcomes of radiosensitisation in elderly patients with advanced bladder cancer.

Radiother Oncol 2018 12 2;129(3):499-506. Epub 2018 Jun 2.

Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, United Kingdom. Electronic address:

Introduction: There is little evidence to guide treatment in elderly patients with muscle invasive bladder cancer (MIBC). We evaluated the efficacy and tolerability of concurrent radical radiotherapy with gemcitabine radiosensitisation (GemX) in elderly patients with MIBC and compared outcomes to those from the bladder carbogen and nicotinamide (BCON) phase III trial.

Materials And Methods: Data were retrospectively analysed for patients who received GemX from two oncology centres in the UK. Elderly was defined as aged ≥75 at the start of GemX. Following transurethral resection of bladder tumour, patients received neo-adjuvant platinum-based chemotherapy followed by radiotherapy concurrently with weekly gemcitabine. A separate, age-specific analysis was performed in the BCON cohort. Overall survival (OS), disease specific survival (DSS) and local progression free survival (LPFS) were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression.

Results: Out of 167 patients who received GemX, 61 were elderly (36.5%) with a median age of 78 years. Elderly patients had worse performance status (p = 0.020) and co-morbidities (p = 0.030). A similar proportion of patients received planned dose radiotherapy in both groups (p = 0.260), although fewer elderly patients received all four cycles of concurrent chemotherapy (p = 0.017) due to toxicity. For OS, age had some prognostic power; HR 1.04 (95% CI 1.00-1.08; p = 0.068). Overall survival and LPFS in elderly patients were comparable between CON and GemX (HR 1.13, 95% CI 0.69-1.85; p = 0.616 and HR 0.85, 95% CI 0.41-1.74; p = 0.659 respectively).

Discussion: Radiosensitisation is safe and effective and should be considered for fit elderly patients with MIBC.
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http://dx.doi.org/10.1016/j.radonc.2018.05.022DOI Listing
December 2018

Development and Validation of a 28-gene Hypoxia-related Prognostic Signature for Localized Prostate Cancer.

EBioMedicine 2018 May 23;31:182-189. Epub 2018 Apr 23.

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, UK; NIHR Manchester Biomedical Research Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, UK. Electronic address:

Background: Hypoxia is associated with a poor prognosis in prostate cancer. This work aimed to derive and validate a hypoxia-related mRNA signature for localized prostate cancer.

Method: Hypoxia genes were identified in vitro via RNA-sequencing and combined with in vivo gene co-expression analysis to generate a signature. The signature was independently validated in eleven prostate cancer cohorts and a bladder cancer phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON).

Results: A 28-gene signature was derived. Patients with high signature scores had poorer biochemical recurrence free survivals in six of eight independent cohorts of prostatectomy-treated patients (Log rank test P < .05), with borderline significances achieved in the other two (P < .1). The signature also predicted biochemical recurrence in patients receiving post-prostatectomy radiotherapy (n = 130, P = .007) or definitive radiotherapy alone (n = 248, P = .035). Lastly, the signature predicted metastasis events in a pooled cohort (n = 631, P = .002). Prognostic significance remained after adjusting for clinic-pathological factors and commercially available prognostic signatures. The signature predicted benefit from hypoxia-modifying therapy in bladder cancer patients (intervention-by-signature interaction test P = .0026), where carbogen and nicotinamide was associated with improved survival only in hypoxic tumours.

Conclusion: A 28-gene hypoxia signature has strong and independent prognostic value for prostate cancer patients.
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http://dx.doi.org/10.1016/j.ebiom.2018.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014579PMC
May 2018

Bladder cancer and the National Cancer Data Base: New insight or misinformation?

Cancer 2018 03 16;124(6):1105-1107. Epub 2018 Jan 16.

Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.

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http://dx.doi.org/10.1002/cncr.31210DOI Listing
March 2018

Focal boost to residual gross tumor volume in brachytherapy for cervical cancer-A feasibility study.

Brachytherapy 2018 Jan - Feb;17(1):181-186. Epub 2017 Nov 15.

Cancer Centre, Mount Vernon Hospital, Northwood, Middlesex, UK. Electronic address:

Purpose: Image-guided plan optimization with MRI and CT for interstitial and intracavitary brachytherapy is an established technique in treating cervical cancer. The purpose of this study was to assess the feasibility of boosting the dose to the residual gross tumor volume (GTV-T) to 140% of the high-risk clinical target volume (HR-CTV) prescription.

Methods And Materials: Brachytherapy plans from 50 consecutive patients were analyzed in this study. All received external beam radiotherapy followed by brachytherapy (6 Gy × 4 fraction or 7 Gy × 4 fraction to HR-CTV). The original treatment plans were reoptimized escalating the GTV-T dose 140% of the original HR-CTV prescription dose to 8.4 Gy and 9.8 Gy/ per fraction, respectively, with the aim of achieving GTV-TV ≥ 90% and D ≥ 100 Gy. The HR-CTV coverage and organ at risk (OAR) dose-volume histogram values were kept within the tolerance, which had been accepted for the original clinical plans.

Results: A total of 24 patients (48%) achieved the planning goal after reoptimization. There was no significant difference between the D of the OARs of the clinical plan and the study boost plan. The factors having greatest impact on the delivered dose to the GTV-T are proximity of the OAR, intrauterine positioned outside the GTV-T, and suboptimal interstitial placement for boosting GTV-T.

Conclusions: It is possible to boost the prescription dose to the GTV-T achieving 140% increase, which equates to an EQD > 100 Gy. Plans without both interstitial catheters and/or intrauterine within the GTV-T are most likely to be suboptimal. This planning study demonstrates that dose escalation to the GTV-T is feasible and further work into clinical application should be considered.
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http://dx.doi.org/10.1016/j.brachy.2017.09.012DOI Listing
July 2018

The optimism surrounding stereotactic body radiation therapy and immunomodulation.

Chin Clin Oncol 2017 Sep;6(Suppl 2):S9

Mount Vernon Cancer Centre, Northwood, UK.

In recent years, rapidly evolving radiation techniques have enabled the precise delivery of very high doses of radiation to local targets with stereotactic ablative body radiotherapy (SABR). In addition to its direct cytotoxicity, radiation and in particular SABR has powerful immunomodulatory effects resulting in immunogenic cell death and potentiation of the anti-tumour immune response. However, due to the immunosuppressive nature of non-irradiated sites of metastases, radiotherapy alone is seldom sufficient to induce the systemic response required for distant tumour rejection. Immune checkpoint inhibitors are a novel class of immunomodulatory agents shown to have robust efficacy against a number of malignancies. These drugs can augment the effects of radiotherapy by helping overcome tumour-induced immunosuppression at local and distant sites. Similarly, radiation may complement immunotherapy by priming tumours in preparation for the adaptive immune response, thereby leading to more prolonged clinical effects. This synergistic relationship has been demonstrated in laboratory models and has been extended to a number of early phase clinical studies.
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http://dx.doi.org/10.21037/cco.2017.05.01DOI Listing
September 2017

The evolution of brachytherapy for prostate cancer.

Nat Rev Urol 2017 Jun;14(7):415-439

Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, USA.

Brachytherapy (BT), using low-dose-rate (LDR) permanent seed implantation or high-dose-rate (HDR) temporary source implantation, is an acceptable treatment option for select patients with prostate cancer of any risk group. The benefits of HDR-BT over LDR-BT include the ability to use the same source for other cancers, lower operator dependence, and - typically - fewer acute irritative symptoms. By contrast, the benefits of LDR-BT include more favourable scheduling logistics, lower initial capital equipment costs, no need for a shielded room, completion in a single implant, and more robust data from clinical trials. Prospective reports comparing HDR-BT and LDR-BT to each other or to other treatment options (such as external beam radiotherapy (EBRT) or surgery) suggest similar outcomes. The 5-year freedom from biochemical failure rates for patients with low-risk, intermediate-risk, and high-risk disease are >85%, 69-97%, and 63-80%, respectively. Brachytherapy with EBRT (versus brachytherapy alone) is an appropriate approach in select patients with intermediate-risk and high-risk disease. The 10-year rates of overall survival, distant metastasis, and cancer-specific mortality are >85%, <10%, and <5%, respectively. Grade 3-4 toxicities associated with HDR-BT and LDR-BT are rare, at <4% in most series, and quality of life is improved in patients who receive brachytherapy compared with those who undergo surgery.
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http://dx.doi.org/10.1038/nrurol.2017.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542347PMC
June 2017

Treat All Known Disease.

Authors:
Peter J Hoskin

Int J Radiat Oncol Biol Phys 2017 07;98(3):494

Mount Vernon Cancer Centre, Northwood, UK.

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http://dx.doi.org/10.1016/j.ijrobp.2016.12.006DOI Listing
July 2017

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

N Engl J Med 2017 07 3;377(4):338-351. Epub 2017 Jun 3.

From the Institute of Cancer and Genomic Sciences, University of Birmingham (N.D.J.), and University Hospital Birmingham (A.Z.), Birmingham, the Institute of Cancer Research (J.S.B., D.P.D., G.A.), Medical Research Council Clinical Trials Unit at University College London (M.R. Spears, C.L.A., C.G., C.B., M.K.B.P., M.R. Sydes), King's College London and Guy's and St. Thomas' NHS Foundation Trust (S.C.), and Royal Marsden NHS Foundation Trust (C.C.P.), London, Salford Royal NHS Foundation Trust, Salford (N.W.C.), Cardiff University School of Medicine (M.D.M.) and Velindre Cancer Centre (J.F.L.), Cardiff, Gloucestershire Royal Hospital (A.W.S.R.) and Gloucestershire Hospitals NHS Foundation Trust (J.B.), Gloucester, University of Glasgow, Glasgow (R.J.J., J.M.R.), St. James's University Hospital, Leeds (W.R.C.), University Hospital of North-Midlands, Stoke-on-Trent (F.A.), Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter (S.A.), Rosemere Cancer Centre, Royal Preston Hospital, Preston (A.J.B.), Dorset Cancer Centre, Poole Hospital, Poole (S.B.), Royal Derby Hospital, Derby (P.C.), Weston Park Hospital, Sheffield (C.F.), Portsmouth Oncology Centre, Queen Alexandra Hospital, Portsmouth (J.G.), Musgrove Park Hospital, Taunton (E.G.), Hull and East Yorkshire Hospitals NHS Trust, Hull (M.H.), Mount Vernon Cancer Centre, Northwood (P.J.H.), Clatterbridge Cancer Centre, Wirral (Z.I.M.), Brighton and Sussex University Hospitals NHS Trust (F.M.) and Sussex Cancer Centre, Royal Sussex County Hospital (A.R.), Brighton, NHS Highland, Inverness (N.M.), Royal Surrey County Hospital, Guildford (J.M.-K.), Northern Ireland Cancer and Queens University, Belfast (J.O.), Lancashire Teaching Hospitals NHS Trust, Preston (O.P.), Churchill Hospital, Oxford (A.P.), Shrewsbury and Telford Hospitals NHS Trust, Shrewsbury (N.N.S.), East Kent Hospitals NHS Trust, Canterbury (C.T.), Swansea University College of Medicine, Swansea (J. Wagstaff), and Christie NHS Foundation Trust, Manchester (J. Wylie) - all in the United Kingdom; and the Department of Medical Oncology, Kantonsspital St. Gallen, St. Gallen (S.G.), and University Hospital of Lausanne, Lausanne (D.R.B.) - both in Switzerland. Two of the authors (D.M., R.M.) were unaffiliated lay members of the STAMPEDE investigators.

Background: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design.

Methods: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).

Results: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).

Conclusions: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).
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http://dx.doi.org/10.1056/NEJMoa1702900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533216PMC
July 2017

A Gene Signature for Selecting Benefit from Hypoxia Modification of Radiotherapy for High-Risk Bladder Cancer Patients.

Clin Cancer Res 2017 Aug 11;23(16):4761-4768. Epub 2017 Apr 11.

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, Manchester, United Kingdom.

Hypoxia modification improves overall survival in muscle-invasive bladder cancer patients who undergo radiotherapy. There is evidence that hypoxic tumors benefit most from hypoxia modification. The study aimed to identify or derive a hypoxia gene signature that predicts benefit from hypoxia-modifying treatment in bladder cancer. Published hypoxia signatures were tested and a new one derived by analyzing bladder cancer transcriptomic data from public databases. Tumor samples were available from the BCON phase III randomized trial of radiotherapy alone or with carbogen and nicotinamide (CON). Gene expression data were generated for 151 tumors using Affymetrix Human 1.0 Exon ST arrays and used for independent validation. A 24-gene signature was derived, which was prognostic in four of six independent surgical cohorts ( = 679; meta HR, 2.32; 95% CI, 1.73-3.12; < 0.0001). The signature was also prognostic in BCON patients receiving radiotherapy alone ( = 75; HR for local relapse-free survival, 2.37; 95% CI, 1.26-4.47; = 0.0076). The signature predicted benefit from CON ( = 76; HR, 0.47; 95% CI, 0.26-0.86; = 0.015). Prognostic significance ( = 0.017) and predictive significance ( = 0.058) remained after adjusting for clinicopathologic variables. A test for interaction between hypoxia status and treatment arms was significant ( = 0.0094). A 24-gene hypoxia signature has strong and independent prognostic and predictive value for muscle-invasive bladder cancer patients. The signature can aid identification of patients likely to benefit from the addition of carbogen and nicotinamide to radiotherapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0038DOI Listing
August 2017

The dosimetric impact of air in vaginal vault brachytherapy.

Brachytherapy 2016 Nov - Dec;15(6):832-838. Epub 2016 Sep 29.

Cancer Centre, Mount Vernon Hospital, Middlesex, UK. Electronic address:

Purpose: Vaginal vault brachytherapy is an adjuvant treatment to reduce risk of local recurrence in endometrial cancer. Axial imaging has demonstrated the presence of air gaps between the surface of a cylindrical applicator and mucosal wall. The impact of these on dosimetry and applicability of the TG-43 formalism in the presence of air has been assessed.

Methods And Materials: The planning CT scans for a retrospective sample of 82 patients were examined for the presence of air gaps. These were quantified in terms of the radial and longitudinal aspect with reference to the applicator, frequency per patient, and location along the applicator. Monte Carlo calculations and ionization chamber measurements were made in a phantom to estimate the uncertainty of the TG-43 algorithm.

Results: The overall incidence of air gaps was 91.4%. The most common radial size was between 2 and 3 mm (43.0%) that resulted in an average dose reduction of 14.8%. There is a strong correlation between radial dimension and TG-43 calculated dose reduction. Monte Carlo simulations and phantom measurements indicated that the inhomogeneity resulted in a maximum of 2.4% deviation from doses calculated using TG-43.

Conclusions: Air gaps are common. TG-43 formalism is not significantly compromised by the presence of air. However, the presence of the air does produce a displacement of the mucosal surface away from the applicator and this causes a significant dose reduction.
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http://dx.doi.org/10.1016/j.brachy.2016.08.006DOI Listing
July 2017