Mateo, J.
Porta, N.
Bianchini, D.
McGovern, U.
Elliott, T.
Jones, R.
Syndikus, I.
Ralph, C.
Jain, S.
Varughese, M.
Parikh, O.
Crabb, S.
Robinson, A.
McLaren, D.
Birtle, A.
Tanguay, J.
Miranda, S.
Figueiredo, I.
Seed, G.
Bertan, C.
Flohr, P.
Ebbs, B.
Rescigno, P.
Fowler, G.
Ferreira, A.
Riisnaes, R.
Pereira, R.
Curcean, A.
Chandler, R.
Clarke, M.
Gurel, B.
Crespo, M.
Nava Rodrigues, D.
Sandhu, S.
Espinasse, A.
Chatfield, P.
Tunariu, N.
Yuan, W.
Hall, E.
Carreira, S.
de Bono, J.S.
(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. The lancet. oncology,
Vol.21
(1),
pp. 162-174.
show abstract
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..
de Mol van Otterloo, S.R.
Christodouleas, J.P.
Blezer, E.L.
Akhiat, H.
Brown, K.
Choudhury, A.
Eggert, D.
Erickson, B.A.
Faivre-Finn, C.
Fuller, C.D.
Goldwein, J.
Hafeez, S.
Hall, E.
Harrington, K.J.
van der Heide, U.A.
Huddart, R.A.
Intven, M.P.
Kirby, A.M.
Lalondrelle, S.
McCann, C.
Minsky, B.D.
Mook, S.
Nowee, M.E.
Oelfke, U.
Orrling, K.
Sahgal, A.
Sarmiento, J.G.
Schultz, C.J.
Tersteeg, R.J.
Tijssen, R.H.
Tree, A.C.
van Triest, B.
Hall, W.A.
Verkooijen, H.M.
(2020). The MOMENTUM Study: An International Registry for the Evidence-Based Introduction of MR-Guided Adaptive Therapy. Frontiers in oncology,
Vol.10,
pp. 1328-?.
show abstract
Purpose: MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. Methods and Results: In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). Conclusion: The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer..
Huddart, R.A.
Hall, E.
Lewis, R.
Porta, N.
Crundwell, M.
Jenkins, P.J.
Rawlings, C.
Tremlett, J.
Campani, L.
Hendron, C.
Hussain, S.A.
James, N.D.
BC2001 Investigators,
(2020). Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial. European urology,
Vol.77
(2),
pp. 260-268.
show abstract
Background BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer-specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy.Objective To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants.Design, setting, and participants 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder.Intervention Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111).Outcome measurements and statistical analysis Patients completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months.Results and limitations Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS -5.06 [99% confidence interval: -6.12 to -4.00, p< 0.001]; overall FACT-B TOTAL score -8.22 [-10.76 to -5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point.Conclusions Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy.Patient summary Quality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life..
Birtle, A.
Johnson, M.
Chester, J.
Jones, R.
Dolling, D.
Bryan, R.T.
Harris, C.
Winterbottom, A.
Blacker, A.
Catto, J.W.
Chakraborti, P.
Donovan, J.L.
Elliott, P.A.
French, A.
Jagdev, S.
Jenkins, B.
Keeley, F.X.
Kockelbergh, R.
Powles, T.
Wagstaff, J.
Wilson, C.
Todd, R.
Lewis, R.
Hall, E.
(2020). Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. The lancet,
Vol.395
(10232),
pp. 1268-1277.
Mostafid, A.H.
Porta, N.
Cresswell, J.
Griffiths, T.R.
Kelly, J.D.
Penegar, S.R.
Davenport, K.
McGrath, J.S.
Campain, N.
Cooke, P.
Masood, S.
Knowles, M.A.
Feber, A.
Knight, A.
Catto, J.W.
Lewis, R.
Hall, E.
(2020). CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin-C vs surgical management in low-risk non-muscle-invasive bladder cancer. Bju international,
Vol.125
(6),
pp. 817-826.
show abstract
Objectives To evaluate the activity of intravesical mitomycin-C (MMC) to ablate recurrent low-risk non-muscle-invasive bladder cancer (NMIBC) and assess whether it may enable patients to avoid surgical intervention for treatment of recurrence.Patients and methods CALIBER is a phase II feasibility study. Participants were randomized (2:1) to treatment with four once-weekly MMC 40-mg intravesical instillations (chemoablation arm) or to surgical management. The surgical group was included to assess the feasibility of randomization. The primary endpoint was complete response to intravesical MMC in the chemoablation arm at 3 months, reported with exact 95% confidence intervals (CIs). Secondary endpoints included time to subsequent recurrence, summarized by Kaplan-Meier methods.Results Between February 2015 and August 2017, 82 patients with visual diagnosis of recurrent low-risk NMIBC were enrolled from 24 UK hospitals (chemoablation, n = 54; surgical management, n =28). The median follow-up was 24 months. Complete response at 3 months was 37.0% (20/54; 95% CI 24.3-51.3) with chemoablation and 80.8% (21/26; 95% CI 60.6-93.4) with surgical management. Amongst patients with complete response at 3 months, a similar proportion was recurrence-free by 12 months in both groups (84%). Amongst those with residual disease at 3 months, the 12-month recurrence-free proportion was lower in the surgical management group (40.0%) than in the chemoablation group (84%). Recruitment stopped early as chemoablation did not meet the prespecified threshold of 45% complete responses at 3 months.Conclusion Intravesical chemoablation in low-risk NMIBC is feasible and safe, but did not demonstrate sufficient response in the present trial. After chemoablation there may be a reduction in recurrence rate, even in non-responders, that is greater than with surgery alone. Further research is required to investigate the role and optimal schedule of neoadjuvant intravesical chemotherapy prior to surgery for NMIBC..
Dearnaley, D.
Griffin, C.L.
Lewis, R.
Mayles, P.
Mayles, H.
Naismith, O.F.
Harris, V.
Scrase, C.D.
Staffurth, J.
Syndikus, I.
Zarkar, A.
Ford, D.R.
Rimmer, Y.L.
Horan, G.
Khoo, V.
Frew, J.
Venkitaraman, R.
Hall, E.
(2019). Toxicity and Patient-Reported Outcomes of a Phase 2 Randomized Trial of Prostate and Pelvic Lymph Node Versus Prostate only Radiotherapy in Advanced Localised Prostate Cancer (PIVOTAL). International journal of radiation oncology, biology, physics,
Vol.103
(3),
pp. 605-617.
show abstract
Purpose To establish the toxicity profile of high-dose pelvic lymph node intensity-modulated radiation therapy (IMRT) and to assess whether it is safely deliverable at multiple centers.Methods and materials In this phase 2 noncomparative multicenter trial, 124 patients with locally advanced, high-risk prostate cancer were randomized between prostate-only IMRT (PO) (74 Gy/37 fractions) and prostate and pelvic lymph node IMRT (P&P; 74 Gy/37 fractions to prostate, 60 Gy/37 fractions to pelvis). The primary endpoint was acute lower gastrointestinal (GI) Radiation Therapy Oncology Group (RTOG) toxicity at week 18, aiming to exclude a grade 2 or greater (G2+) toxicity-free rate of 80% in the P&P group. Key secondary endpoints included patient-reported outcomes and late toxicity.Results One hundred twenty-four participants were randomized (62 PO, 62 P&P) from May 2011 to March 2013. Median follow-up was 37.6 months (interquartile range [IQR], 35.4-38.9 months). Participants had a median age of 69 years (IQR, 64-74 years) and median diagnostic prostate-specific androgen level of 21.6 ng/mL (IQR, 11.8-35.1 ng/mL). At week 18, G2+ lower GI toxicity-free rates were 59 of 61 (96.7%; 90% confidence interval [CI], 90.0-99.4) for the PO group and 59 of 62 (95.2%; 90% CI, 88.0-98.7) for the P&P group. Patients in both groups reported similarly low Inflammatory Bowel Disease Questionnaire symptoms and Vaizey incontinence scores. The largest difference occurred at week 6 with 4 of 61 (7%) and 16 of 61 (26%) PO and P&P patients, respectively, experiencing G2+ toxicity. At 2 years, the cumulative proportion of RTOG G2+ GI toxicity was 16.9% (95% CI, 8.9%-30.9%) for the PO group and 24.0% (95% CI, 8.4%-57.9%) for the P&P group; in addition, RTOG G2+ bladder toxicity was 5.1% (95% CI, 1.7%-14.9%) for the PO group and 5.6% (95% CI, 1.8%-16.7%) for the P&P group.Conclusions PIVOTAL demonstrated that high-dose pelvic lymph node IMRT can be delivered at multiple centers with a modest side effect profile. Although safety data from the present study are encouraging, the impact of P&P IMRT on disease control remains to be established..
Walker, A.K.
Karaszi, K.
Valentine, H.
Strauss, V.Y.
Choudhury, A.
McGill, S.
Wen, K.
Brown, M.D.
Ramani, V.
Bhattarai, S.
Teo, M.T.
Yang, L.
Myers, K.A.
Deshmukh, N.
Denley, H.
Browning, L.
Love, S.B.
Iyer, G.
Clarke, N.W.
Hall, E.
Huddart, R.
James, N.D.
Hoskin, P.J.
West, C.M.
Kiltie, A.E.
(2019). MRE11 as a Predictive Biomarker of Outcome After Radiation Therapy in Bladder Cancer. International journal of radiation oncology, biology, physics,
Vol.104
(4),
pp. 809-818.
show abstract
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..
Brand, D.H.
Tree, A.C.
Ostler, P.
van der Voet, H.
Loblaw, A.
Chu, W.
Ford, D.
Tolan, S.
Jain, S.
Martin, A.
Staffurth, J.
Camilleri, P.
Kancherla, K.
Frew, J.
Chan, A.
Dayes, I.S.
Henderson, D.
Brown, S.
Cruickshank, C.
Burnett, S.
Duffton, A.
Griffin, C.
Hinder, V.
Morrison, K.
Naismith, O.
Hall, E.
van As, N.
PACE Trial Investigators,
(2019). Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. The lancet. oncology,
Vol.20
(11),
pp. 1531-1543.
show abstract
Background Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.Methods PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.Findings Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred.Interpretation Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.Funding Accuray and National Institute of Health Research..
Wilkins, A.
Stuttle, C.
Hassan, S.
Blanchard, C.
Cruickshank, C.
Griffin, C.
Probert, J.
Corbishley, C.M.
Parker, C.
Dearnaley, D.
Hall, E.
(2018). Methodology for tissue sample collection within a translational sub-study of the CHHiP trial (CRUK/06/016), a large randomised phase III trial in localised prostate cancer. Clinical and translational radiation oncology,
Vol.10,
pp. 1-6.
show abstract
Background This article presents the methodology for tissue sample collection in Trans-CHHiP, the main translational study within the CHHiP (Conventional or Hypofractionated High dose intensity modulated radiotherapy in Prostate cancer, ISRCTN 97182923) trial. The CHHiP trial randomised 3216 men with localised prostate cancer to 3 different radiotherapy fractionation schedules. Trans-CHHiP aims to identify biomarkers of fraction sensitivity.Methods We outline the process of tissue collection, including central review by a study-specific specialist uropathologist and comparison of the centrally-assigned Gleason grade group with that assigned by the recruiting-centre pathologist.Results 2047 patients provided tissue from 107 pathology departments between August 2012 and April 2014. A highly motivated Clinical Trials Unit chasing samples and a central Trans-CHHiP group that regularly reviewed progress were important for successful sample collection. Agreement in Gleason grade group assigned by the recruiting centre pathologist and the central study-specific uropathologist occurred in 886 out of 1854 (47.8%) cases. Key lessons learned were the need for prospective consent for tissue collection when recruiting patients to the main trial, and the importance of Material Transfer Agreement (MTA) integration into the initial trial site agreement.Conclusions This methodology enabled collection of 2047 patient samples from a large randomised radiotherapy trial. Central pathological review is important to minimise subjectivity in Gleason grade grouping and the impact of grade shift..
Wilson, J.M.
Dearnaley, D.P.
Syndikus, I.
Khoo, V.
Birtle, A.
Bloomfield, D.
Choudhury, A.
Graham, J.
Ferguson, C.
Malik, Z.
Money-Kyrle, J.
O'Sullivan, J.M.
Panades, M.
Parker, C.
Rimmer, Y.
Scrase, C.
Staffurth, J.
Stockdale, A.
Cruickshank, C.
Griffin, C.
Hall, E.
CHHiP Investigators,
(2018). The Efficacy and Safety of Conventional and Hypofractionated High-Dose Radiation Therapy for Prostate Cancer in an Elderly Population: A Subgroup Analysis of the CHHiP Trial. International journal of radiation oncology, biology, physics,
Vol.100
(5),
pp. 1179-1189.
show abstract
Purpose Outcome data on radiation therapy for prostate cancer in an elderly population are sparse. The CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer) trial provides a large, prospectively collected, contemporary dataset in which to explore outcomes by age.Methods and materials CHHiP participants received 3 to 6 months of androgen deprivation therapy and were randomly assigned (1:1:1) to receive 74 Gy in 37 fractions (conventional fractionation), 60 Gy in 20 fractions, or 57 Gy in 19 fractions. Toxicity was assessed using clinician-reported outcome (CRO) and patient-reported outcome questionnaires. Participants were categorized as aged < 75 years or ≥ 75 years. Outcomes were compared by age group.Results Of 3216 patients, 491 (15%) were aged ≥ 75 years. There was no difference in biochemical or clinical failure rates between the groups aged < 75 years and ≥ 75 years for any of the fractionation schedules. In the group aged ≥ 75 years, biochemical or clinical failure-free rates favored hypofractionation, and at 5 years, they were 84.7% for 74 Gy, 91% for 60 Gy, and 87.7% for 57 Gy. The incidence of CRO (grade 3) acute bowel toxicity was 2% in both age groups. The incidence of grade 3 acute bladder toxicity was 8% in patients aged < 75 years and 7% in those aged ≥ 75 years. The 5-year cumulative incidence of CRO grade ≥ 2 late bowel side effects was similar in both age groups. However, in the group aged ≥ 75 years, there was a suggestion of a higher cumulative incidence of bowel bother (small or greater) with 60 Gy compared with 74 Gy and 57 Gy. Patient-reported bladder bother was slightly higher in the group aged ≥ 75 years than the group aged < 75 years, and there was a suggestion of a lower cumulative incidence of bladder bother with 57 Gy compared with 74 Gy and 60 Gy in patients aged ≥ 75 years, which was not evident in those aged < 75 years.Conclusions Hypofractionated radiation therapy appears to be well tolerated and effective in men aged ≥ 75 years. The 57-Gy schedule has potential advantages in that it may moderate long-term side effects without compromising treatment efficacy in this group..
Hague, C.
Foran, B.
Hall, E.
Guild, S.
Joseph, O.
Moule, R.
Nutting, C.
Parsons, S.
Prestwich, R.
Slevin, N.
West, C.
Thomson, D.
(2018). Patient Involvement in the Design of a Phase III Trial Comparing Intensity-modulated Proton Therapy and Intensity-modulated Radiotherapy for Oropharyngeal Cancer. Clinical oncology (royal college of radiologists (great britain)),
Vol.30
(5),
pp. 274-276.
Wilkins, A.C.
Gusterson, B.
Szijgyarto, Z.
Haviland, J.
Griffin, C.
Stuttle, C.
Daley, F.
Corbishley, C.M.
Dearnaley, D.P.
Hall, E.
Somaiah, N.
CHHiP Trial Investigators,
(2018). Ki67 Is an Independent Predictor of Recurrence in the Largest Randomized Trial of 3 Radiation Fractionation Schedules in Localized Prostate Cancer. International journal of radiation oncology, biology, physics,
Vol.101
(2),
pp. 309-315.
show abstract
PURPOSE:To assess whether the cellular proliferation marker Ki67 provides prognostic information and predicts response to radiation therapy fractionation in patients with localized prostate tumors participating in a randomized trial of 3 radiation therapy fractionation schedules (74 Gy/37 fractions vs 60 Gy/20 fractions vs 57 Gy/19 fractions). METHODS AND MATERIALS:A matched case-control study design was used; patients with biochemical/clinical failure >2 years after radiation therapy (BCR) were matched 1:1 to patients without recurrence using established prognostic factors (Gleason score, prostate-specific antigen, tumor stage) and fractionation schedule. Immunohistochemistry was used to stain diagnostic biopsy specimens for Ki67, which were scored using the unweighted global method. Conditional logistic regression models estimated the prognostic value of mean and maximum Ki67 scores on BCR risk. Biomarker-fractionation interaction terms determined whether Ki67 was predictive of BCR by fractionation. RESULTS:Using 173 matched pairs, the median for mean and maximum Ki67 scores were 6.6% (interquartile range, 3.9%-9.8%) and 11.0% (interquartile range, 7.0%-15.0%) respectively. Both scores were significant predictors of BCR in models adjusted for established prognostic factors. Conditioning on matching variables and age, the odds of BCR were estimated to increase by 9% per 1% increase in mean Ki67 score (odds ratio 1.09; 95% confidence interval 1.04-1.15, P = .001). Interaction terms between Ki67 and fractionation schedules were not statistically significant. CONCLUSIONS:Diagnostic Ki67 did not predict BCR according to fractionation schedule in CHHiP; however, it was a strong independent prognostic factor for BCR..
Nutting, C.M.
Morden, J.P.
Beasley, M.
Bhide, S.
Cook, A.
De Winton, E.
Emson, M.
Evans, M.
Fresco, L.
Gollins, S.
Gujral, D.
Harrington, K.
Joseph, M.
Lemon, C.
Luxon, L.
van den Blink, Q.
Mendes, R.
Miah, A.
Newbold, K.
Prestwich, R.
Robinson, M.
Sanghera, P.
Simpson, J.
Sivaramalingam, M.
Srihari, N.N.
Sydenham, M.
Wells, E.
Witts, S.
Hall, E.
COSTAR Investigators,
(2018). Results of a multicentre randomised controlled trial of cochlear-sparing intensity-modulated radiotherapy versus conventional radiotherapy in patients with parotid cancer (COSTAR; CRUK/08/004). European journal of cancer (oxford, england : 1990),
Vol.103,
pp. 249-258.
show abstract
Purpose About 40-60% of patients treated with post-operative radiotherapy for parotid cancer experience ipsilateral sensorineural hearing loss. Intensity-modulated radiotherapy (IMRT) can reduce radiation dose to the cochlea. COSTAR, a phase III trial, investigated the role of cochlear-sparing IMRT (CS-IMRT) in reducing hearing loss.Methods Patients (pT1-4 N0-3 M0) were randomly assigned (1:1) to 3-dimensional conformal radiotherapy (3DCRT) or CS-IMRT by minimisation, balancing for centre and radiation dose of 60Gy or 65Gy in 30 daily fractions. The primary end-point was proportion of patients with sensorineural hearing loss in the ipsilateral cochlea of ≥10 dB bone conduction at 4000 Hz 12 months after radiotherapy compared using Fisher's exact test. Secondary end-points included hearing loss at 6 and 24 months, balance assessment, acute and late toxicity, patient-reported quality of life, time to recurrence and survival.Results From Aug 2008 to Feb 2013, 110 patients (54 3DCRT; 56 CS-IMRT) were enrolled from 22 UK centres. Median doses to the ipsilateral cochlea were 3DCRT: 56.2Gy and CS-IMRT: 35.7Gy (p < 0.0001). 67/110 (61%) patients were evaluable for the primary end-point; main reasons for non-evaluability were non-attendance at follow-up or incomplete audiology assessment. At 12 months, 14/36 (39%) 3DCRT and 11/31 (36%) CS-IMRT patients had ≥10 dB loss (p = 0.81). No statistically significant differences were observed in hearing loss at 6 or 24 months or in other secondary end-points including patient-reported hearing outcomes.Conclusion CS-IMRT reduced the radiation dose below the accepted tolerance of the cochlea, but this did not lead to a reduction in the proportion of patients with clinically relevant hearing loss..
Choudhury, A.
West, C.M.
Porta, N.
Hall, E.
Denley, H.
Hendron, C.
Lewis, R.
Hussain, S.A.
Huddart, R.
James, N.
(2017). The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004). British journal of cancer,
Vol.116
(5),
pp. 649-657.
show abstract
Background Severe chronic hypoxia is associated with tumour necrosis. In patients with muscle invasive bladder cancer (MIBC), necrosis is prognostic for survival following surgery or radiotherapy and predicts benefit from hypoxia modification of radiotherapy. Adding mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy to radiotherapy improved locoregional control (LRC) compared to radiotherapy alone in the BC2001 trial. We hypothesised that tumour necrosis would not predict benefit for the addition of MMC and 5-FU to radiotherapy, but would be prognostic.Methods Diagnostic tumour samples were available from 230 BC2001 patients. Tumour necrosis was scored on whole-tissue sections as absent or present, and its predictive and prognostic significance explored using Cox proportional hazards models. Survival estimates were obtained by Kaplan-Meier methods.Results Tumour necrosis was present in 88/230 (38%) samples. Two-year LRC estimates were 71% (95% CI 61-79%) for the MMC/5-FU chemoradiotherapy group and 49% (95% CI 38-59%) for the radiotherapy alone group. When analysed by tumour necrosis status, the adjusted hazard ratios (HR) for MMC/5-FU vs. no chemotherapy were 0.46 (95% CI: 0.12-0.99; P=0.05, necrosis present) and 0.55 (95% CI: 0.31-0.98; P=0.04, necrosis absent). Multivariable analysis of prognosis for LRC by the presence vs. absence of necrosis yielded a HR=0.89 (95% CI 0.55-1.44, P=0.65). There was no significant association for necrosis as a predictive or prognostic factor with respect to overall survival.Conclusions Tumour necrosis was neither predictive nor prognostic, and therefore MMC/5-FU is an appropriate radiotherapy-sensitising treatment in MIBC independent of necrosis status..
Dearnaley, D.
Syndikus, I.
Mossop, H.
Khoo, V.
Birtle, A.
Bloomfield, D.
Graham, J.
Kirkbride, P.
Logue, J.
Malik, Z.
Money-Kyrle, J.
O'Sullivan, J.M.
Panades, M.
Parker, C.
Patterson, H.
Scrase, C.
Staffurth, J.
Stockdale, A.
Tremlett, J.
Bidmead, M.
Mayles, H.
Naismith, O.
South, C.
Gao, A.
Cruickshank, C.
Hassan, S.
Pugh, J.
Griffin, C.
Hall, E.
CHHiP Investigators,
(2016). Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. The lancet. oncology,
Vol.17
(8),
pp. 1047-1060.
show abstract
Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.Methods CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.Findings Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network..
Harris, V.A.
Staffurth, J.
Naismith, O.
Esmail, A.
Gulliford, S.
Khoo, V.
Lewis, R.
Littler, J.
McNair, H.
Sadoyze, A.
Scrase, C.
Sohaib, A.
Syndikus, I.
Zarkar, A.
Hall, E.
Dearnaley, D.
(2015). Consensus Guidelines and Contouring Atlas for Pelvic Node Delineation in Prostate and Pelvic Node Intensity Modulated Radiation Therapy. International journal of radiation oncology*biology*physics,
Vol.92
(4),
pp. 874-883.
Wilkins, A.
Mossop, H.
Syndikus, I.
Khoo, V.
Bloomfield, D.
Parker, C.
Logue, J.
Scrase, C.
Patterson, H.
Birtle, A.
Staffurth, J.
Malik, Z.
Panades, M.
Eswar, C.
Graham, J.
Russell, M.
Kirkbride, P.
O'Sullivan, J.M.
Gao, A.
Cruickshank, C.
Griffin, C.
Dearnaley, D.
Hall, E.
(2015). Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. The lancet. oncology,
Vol.16
(16),
pp. 1605-1616.
show abstract
Background Patient-reported outcomes (PROs) might detect more toxic effects of radiotherapy than do clinician-reported outcomes. We did a quality of life (QoL) substudy to assess PROs up to 24 months after conventionally fractionated or hypofractionated radiotherapy in the Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial.Methods The CHHiP trial is a randomised, non-inferiority phase 3 trial done in 71 centres, of which 57 UK hospitals took part in the QoL substudy. Men with localised prostate cancer who were undergoing radiotherapy were eligible for trial entry if they had histologically confirmed T1b-T3aN0M0 prostate cancer, an estimated risk of seminal vesicle involvement less than 30%, prostate-specific antigen concentration less than 30 ng/mL, and a WHO performance status of 0 or 1. Participants were randomly assigned (1:1:1) to receive a standard fractionation schedule of 74 Gy in 37 fractions or one of two hypofractionated schedules: 60 Gy in 20 fractions or 57 Gy in 19 fractions. Randomisation was done with computer-generated permuted block sizes of six and nine, stratified by centre and National Comprehensive Cancer Network (NCCN) risk group. Treatment allocation was not masked. UCLA Prostate Cancer Index (UCLA-PCI), including Short Form (SF)-36 and Functional Assessment of Cancer Therapy-Prostate (FACT-P), or Expanded Prostate Cancer Index Composite (EPIC) and SF-12 quality-of-life questionnaires were completed at baseline, pre-radiotherapy, 10 weeks post-radiotherapy, and 6, 12, 18, and 24 months post-radiotherapy. The CHHiP trial completed accrual on June 16, 2011, and the QoL substudy was closed to further recruitment on Nov 1, 2009. Analysis was on an intention-to-treat basis. The primary endpoint of the QoL substudy was overall bowel bother and comparisons between fractionation groups were done at 24 months post-radiotherapy. The CHHiP trial is registered with ISRCTN registry, number ISRCTN97182923.Findings 2100 participants in the CHHiP trial consented to be included in the QoL substudy: 696 assigned to the 74 Gy schedule, 698 assigned to the 60 Gy schedule, and 706 assigned to the 57 Gy schedule. Of these individuals, 1659 (79%) provided data pre-radiotherapy and 1444 (69%) provided data at 24 months after radiotherapy. Median follow-up was 50·0 months (IQR 38·4-64·2) on April 9, 2014, which was the most recent follow-up measurement of all data collected before the QoL data were analysed in September, 2014. Comparison of 74 Gy in 37 fractions, 60 Gy in 20 fractions, and 57 Gy in 19 fractions groups at 2 years showed no overall bowel bother in 269 (66%), 266 (65%), and 282 (65%) men; very small bother in 92 (22%), 91 (22%), and 93 (21%) men; small bother in 26 (6%), 28 (7%), and 38 (9%) men; moderate bother in 19 (5%), 23 (6%), and 21 (5%) men, and severe bother in four (<1%), three (<1%) and three (<1%) men respectively (74 Gy vs 60 Gy, ptrend=0.64, 74 Gy vs 57 Gy, ptrend=0·59). We saw no differences between treatment groups in change of bowel bother score from baseline or pre-radiotherapy to 24 months.Interpretation The incidence of patient-reported bowel symptoms was low and similar between patients in the 74 Gy control group and the hypofractionated groups up to 24 months after radiotherapy. If efficacy outcomes from CHHiP show non-inferiority for hypofractionated treatments, these findings will add to the growing evidence for moderately hypofractionated radiotherapy schedules becoming the standard treatment for localised prostate cancer.Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network..
James, N.D.
Hussain, S.A.
Hall, E.
Jenkins, P.
Tremlett, J.
Rawlings, C.
Crundwell, M.
Sizer, B.
Sreenivasan, T.
Hendron, C.
Lewis, R.
Waters, R.
Huddart, R.A.
BC2001 Investigators,
(2012). Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N engl j med,
Vol.366
(16),
pp. 1477-1488.
show abstract
BACKGROUND: Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone. METHODS: In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects. RESULTS: At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07). CONCLUSIONS: Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.)..
Sharma, R.A.
Plummer, R.
Stock, J.K.
Greenhalgh, T.A.
Ataman, O.
Kelly, S.
Clay, R.
Adams, R.A.
Baird, R.D.
Billingham, L.
Brown, S.R.
Buckland, S.
Bulbeck, H.
Chalmers, A.J.
Clack, G.
Cranston, A.N.
Damstrup, L.
Ferraldeschi, R.
Forster, M.D.
Golec, J.
Hagan, R.M.
Hall, E.
Hanauske, A.-.
Harrington, K.J.
Haswell, T.
Hawkins, M.A.
Illidge, T.
Jones, H.
Kennedy, A.S.
McDonald, F.
Melcher, T.
O'Connor, J.P.
Pollard, J.R.
Saunders, M.P.
Sebag-Montefiore, D.
Smitt, M.
Staffurth, J.
Stratford, I.J.
Wedge, S.R.
NCRI CTRad Academia-Pharma Joint Working Group,
Clinical development of new drug-radiotherapy combinations. Nat rev clin oncol,
Vol.13
(10),
pp. 627-642.
show abstract
In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer..
Hall, E.
Hague, C.
Foran, B.
Guild, S.
Joseph, O.
Moule, R.
Nutting, C.
Parsons, S.
Prestwich, R.
Slevin, N.
West, C.
Thomson, D.
Patient involvement in the design of a phase III trial comparing IMPT and IMRT for oropharyngeal cancer. Clinical oncology,
.