382 results on '"Dearnaley DP"'
Search Results
2. Lymph node staging in clinically localized prostate cancer
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Parker, CC, Husband, J, and Dearnaley, DP
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- 1999
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3. Managing testicular cancer
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Dearnaley, DP, Huddart, RA, and Horwich, A
- Published
- 2001
4. Independent Validation of Rectal Dose-volume Constraints using MRC RT01 (ISRCTN47772397) Trial Data
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Gulliford, S, Foo, K, Morgan, RC, Aird, EG, Bidmead, AM, Critchley, H, Evans, PM, Gianolini, S, Mayles, WP, Moore, AR, Sanchez, B, Partridge, M, Sydes, MR, Webb, S, and Dearnaley, DP
- Abstract
Introduction: Treatment plan evaluation requires knowledge of the effect of the plan, not only on the intended target, but also the surrounding normal tissues that are unavoidably irradiated. Recent literature has provided estimations of tolerance doses and proposed dose-volume constraints for many of the organs at risk. However, very few of these recommendations have been independently validated. This study details how constraints proposed for the rectum were tested using data from the RT01 randomised prostate radiotherapy trial. Method: An independent validation of the rectal dose-volume constraints used in the CHHiP trial and proposed recently by Fiorino et al. was performed. The constraints were applied retrospectively to the treatment plans collected from the RT01 trial. Odds ratios (OR) were calculated to compare the reported incidence of specific late rectal toxicity end points in the group of patients whose treatment plan met a specified dose-volume constraint compared to the group of patients who failed that constraint. Results: Statistically significant ORs were observed for every constraint tested (except 75 Gy) for at least one clinical end point. For the CHHiP constraints between 60 and 70 Gy, the ORs calculated for rectal bleeding (RMH score defined in protocol) exceeded 2.5 (P!0.02). Similarly the ORs for CHHiP constraints between 30 and 65 Gy exceeded 2.4 (P!0.021) for urgency (UCLA PCI). The Fiorino constraints between 40 and 60 Gy resulted in ORs O2 (P!0.02) for loose stools (UCLA PCI) Conclusion: Implementing rectal dose-volume constraints from 30 Gy up to the prescription dose will result in a decrease in the incidence of late rectal toxicity. Constraints for doses as low as 30 Gy were statistically significant, further challenging the concept that the rectum is a serial structure where the maximum dose to the organ is the only consideration.
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- 2009
5. Diagnosis and management of early prostate cancer. Report of a British association of urological surgeons working party
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R.J. Simpson, R.S. Kirby, Wiliams G, D. Kirk, P. Malone, and Dearnaley dP
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Gynecology ,Male ,medicine.medical_specialty ,business.industry ,General surgery ,Association (object-oriented programming) ,Biopsy ,Incidence ,Urology ,Prostatic Neoplasms ,Cancer Care Facilities ,Prostate-Specific Antigen ,medicine.disease ,Global Health ,Prostate cancer ,Patient Education as Topic ,Practice Guidelines as Topic ,medicine ,Humans ,Mass Screening ,business ,Societies, Medical - Published
- 1999
6. Randomized trial af bleomycin, Etoposide, and Cisplatin compared to Bleomycin, Etoposide and Cardoplatin in good prognosis metastatic non-seminomatous germ cell cancer:A multiinstitutional MRC/EORTC trial
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Horwich, A, Sleyfer, DT, Foss?, SD, Kaye, SB, Oliver, RTD, Cullen, MH, Mead, GM, de Wit, Ronald, de Mulder, PHM, Dearnaley, DP, Cook, PA, Sylvester, R, Stenning, SP, and Medical Oncology
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SDG 3 - Good Health and Well-being - Published
- 1997
7. Whole‐body magnetic resonance imaging in the detection of skeletal metastases in patients with prostate cancer
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Venkitaraman, R, primary, Cook, GJR, additional, Dearnaley, DP, additional, Parker, CC, additional, Khoo, V, additional, Eeles, R, additional, Huddart, RA, additional, Horwich, A, additional, and Sohaib, SA, additional
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- 2009
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8. Induction of transforming growth factor beta in hormonally treated human prostate cancer
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Muir, GH, primary, Butta, A, additional, Shearer, RJ, additional, Fisher, C, additional, Dearnaley, DP, additional, Flanders, KC, additional, Sporn, MB, additional, and Colletta, AA, additional
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- 1994
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9. Primary malignant mediastinal germ cell tumours: improved prognosis with platinum-based chemotherapy and surgery
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Childs, WJ, primary, Goldstraw, P, additional, Nicholls, JE, additional, Dearnaley, DP, additional, and Horwich, A, additional
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- 1993
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10. Surveillance following orchidectomy for stage I testicular seminoma
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Horwich, A, primary, Alsanjari, N, additional, A'Hern, R, additional, Nicholls, J, additional, Dearnaley, DP, additional, and Fisher, C, additional
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- 1992
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11. Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer.
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Glendenning JL, Barbachano Y, Norman AR, Dearnaley DP, Horwich A, and Huddart RA
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- 2010
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12. Prospective study of factors predicting adherence to medical advice in men with testicular cancer.
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Moynihan C, Norman AR, Barbachano Y, Burchell L, Huddart R, Dearnaley DP, Horwich A, Moynihan, Clare, Norman, Andy R, Barbachano, Yolanda, Burchell, Louise, Huddart, Robert, Dearnaley, David P, and Horwich, Alan
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- 2009
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13. Radiotherapy and hormonal treatment.
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Dearnaley DP
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- 2007
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14. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial.
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Dearnaley DP, Sydes MR, Graham JD, Aird EG, Bottomley D, Cowan RA, Huddart RA, Jose CC, Matthews JH, Millar J, Moore AR, Morgan RC, Russell JM, Scrase CD, Stephens RJ, Syndikus I, Parmar MK, RT01 Collaborators, Dearnaley, David P, and Sydes, Matthew R
- Abstract
Background: In men with localised prostate cancer, conformal radiotherapy (CFRT) could deliver higher doses of radiation than does standard-dose conventional radical external-beam radiotherapy, and could improve long-term efficacy, potentially at the cost of increased toxicity. We aimed to present the first analyses of effectiveness from the MRC RT01 randomised controlled trial.Methods: The MRC RT01 trial included 843 men with localised prostate cancer who were randomly assigned to standard-dose CFRT or escalated-dose CFRT, both administered with neoadjuvant androgen suppression. Primary endpoints were biochemical-progression-free survival (bPFS), freedom from local progression, metastases-free survival, overall survival, and late toxicity scores. The toxicity scores were measured with questionnaires for physicians and patients that included the Radiation Therapy Oncology Group (RTOG), the Late Effects on Normal Tissue: Subjective/Objective/Management (LENT/SOM) scales, and the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) scales. Analysis was done by intention to treat. This trial is registered at the Current Controlled Trials website http://www.controlled-trials.com/ISRCTN47772397.Findings: Between January, 1998, and December, 2002, 843 men were randomly assigned to escalated-dose CFRT (n=422) or standard-dose CFRT (n=421). In the escalated group, the hazard ratio (HR) for bPFS was 0.67 (95% CI 0.53-0.85, p=0.0007). We noted 71% bPFS (108 cumulative events) and 60% bPFS (149 cumulative events) by 5 years in the escalated and standard groups, respectively. HR for clinical progression-free survival was 0.69 (0.47-1.02; p=0.064); local control was 0.65 (0.36-1.18; p=0.16); freedom from salvage androgen suppression was 0.78 (0.57-1.07; p=0.12); and metastases-free survival was 0.74 (0.47-1.18; p=0.21). HR for late bowel toxicity in the escalated group was 1.47 (1.12-1.92) according to the RTOG (grade >/=2) scale; 1.44 (1.16-1.80) according to the LENT/SOM (grade >/=2) scales; and 1.28 (1.03-1.60) according to the UCLA PCI (score >/=30) scale. 33% of the escalated and 24% of the standard group reported late bowel toxicity within 5 years of starting treatment. HR for late bladder toxicity according to the RTOG (grade >/=2) scale was 1.36 (0.90-2.06), but this finding was not supported by the LENT/SOM (grade >/=2) scales (HR 1.07 [0.90-1.29]), nor the UCLA PCI (score >/=30) scale (HR 1.05 [0.81-1.36]).Interpretation: Escalated-dose CFRT with neoadjuvant androgen suppression seems clinically worthwhile in terms of bPFS, progression-free survival, and decreased use of salvage androgen suppression. This additional efficacy is offset by an increased incidence of longer term adverse events. [ABSTRACT FROM AUTHOR]- Published
- 2007
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15. Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873).
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Mason MD, Sydes MR, Glaholm J, Langley RE, Huddart RA, Sokal M, Stott M, Robinson AC, James ND, Parmar MK, Dearnaley DP, Medical Research Council PR04 Collaborators, Mason, Malcolm D, Sydes, Matthew R, Glaholm, John, Langley, Ruth E, Huddart, Robert A, Sokal, Michael, Stott, Mark, and Robinson, Anne C
- Abstract
Background: The most frequent site of metastases from prostate cancer is bone. Adjuvant bisphosphonate treatment improves outcomes of patients with bone metastasis-negative breast cancer, but the effects of bisphosphonates on bone metastases in prostate cancer are not known.Methods: We performed a randomized double-blind placebo-controlled trial to determine whether a first-generation bisphosphonate could improve symptomatic bone metastasis-free survival (time to symptomatic bone metastases or death from prostate cancer) in men with nonmetastatic prostate cancer who were at high risk of developing bone metastases. Between June 1, 1994, and December 31, 1997, 508 men from 26 UK sites and one New Zealand site who were within 3 years of initial prostate cancer diagnosis with no evidence of metastases from current bone scanning were randomly assigned to daily oral sodium clodronate (2080 mg/day, n = 254) or placebo (n = 254) for a maximum of 5 years. Estimates of outcome risks were compared using Kaplan-Meier analyses.Results: The groups allocated to each treatment were well balanced. After a median follow-up of nearly 10 years, no evidence of benefit to the clodronate group was observed in terms of bone metastases-free survival (clodronate versus placebo, 80 events versus 68 events; hazard ratio [HR] = 1.22; 95% confidence interval [CI] = 0.88 to 1.68) or overall survival (clodronate versus placebo, 130 deaths versus 127 deaths; HR = 1.02; 95% CI = 0.80 to 1.30). Adverse events, notably gastrointestinal problems and increased lactate dehydrogenase levels, were more frequent in the clodronate group than in the placebo group; otherwise, clodronate was well tolerated. Modification of trial drug dose was more frequent in the clodronate group than the placebo group (HR = 1.63, 95% CI = 1.21 to 2.19).Conclusion: Adjuvant sodium clodronate does not modify the natural history of nonmetastatic prostate cancer. [ABSTRACT FROM AUTHOR]- Published
- 2007
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16. Clinical review. Regular review: managing testicular cancer.
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Dearnaley DP, Huddart RA, and Horwich A
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- 2001
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17. Regular review: Managing testicular cancer.
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Dearnaley, DP, Huddart, RA, and Horwich, A
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TESTICULAR cancer , *TESTIS tumors , *CANCER , *DIAGNOSIS - Abstract
Discusses testicular cancer. Responsiveness to chemotherapy; Details of testicular germ cell tumours; Genetic and environmental factors as contributors to the development of the cancer; Symptoms of testicular cancer, including firmness, aching, or discomfort; Diagnosis and treatment.
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- 2001
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18. Allelic imbalance in familial and sporadic prostate cancer at the putative human prostate cancer susceptibility locus, HPC1. CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.
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Dunsmuir, WD, Edwards, SM, Lakhani, SR, Young, M, Corbishley, C, Kirby, RS, Dearnaley, DP, Dowe, A, Ardern-Jones, A, Kelly, J, Eeles, RA, Dunsmuir, W D, Edwards, S M, Lakhani, S R, Kirby, R S, Dearnaley, D P, and Eeles, R A
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- 1998
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19. No germline mutations in the dimerization domain of MXI1 in prostate cancer clusters. The CRC/BPG UK Familial Prostate Cancer Study Collaborators. Cancer Research Campaign/British Prostate Group.
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Edwards, SM, Dearnaley, DP, Ardern-Jones, A, Hamoudi, RA, Easton, DF, Ford, D, Shearer, R, Dowe, A, Eeles, RA, Edwards, S M, Dearnaley, D P, Hamoudi, R A, Easton, D F, and Eeles, R A
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- 1997
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20. High dose BCNU chemotherapy with autologous bone marrow transplantation and full dose radiotherapy for grade IV astrocytoma.
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Mbidde, EK, Selby, PJ, Perren, TJ, Dearnaley, DP, Whitton, A, Ashley, S, Workman, P, Bloom, HJG, and McElwain, TJ
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- 1988
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21. Question of dose, fractionation and technique: ingredients for testing hypofractionation in prostate cancer--the CHHiP trial.
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Khoo VS and Dearnaley DP
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- 2008
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22. Does magnetic resonance imaging of the spine have a role in the staging of prostate cancer?
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Venkitaraman R, Cook GJR, Dearnaley DP, Parker CC, Huddart RA, Khoo V, Eeles R, Horwich A, and Sohaib SA
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Aims: Magnetic resonance imaging (MRI) is an effective method for evaluating the spine in patients with a high risk of metastatic disease. The aim of this study was to compare MRI spine with radionuclide bone scan in detecting spinal metastases for staging prostate cancer patients. Materials and methods: A cohort of 99 patients with locally advanced prostate cancer at high risk of skeletal metastasis (prostate-specific antigen > 10 ng/ml, composite Gleason score > 8) or equivocal findings on bone scan were included in the retrospective study, and their MRI spine and bone scans were analysed. Results: Ten patients were detected to have definite spinal metastasis by bone scan, whereas 12 patients had definite skeletal metastasis by MRI spine. Compared with the 'gold standard', derived from clinical and radiological follow-up, the sensitivities for radionuclide bone scan and that for MRI spine for detecting skeletal metastasis were 71.4 and 85.7%, respectively (P = 0.023), whereas the specificities were 96.5 and 97.7%, respectively (P = 0.95). Of the 34 individual metastatic lesions in the spine, 15 were concordantly positive on both scans, whereas five lesions were positive only by bone scan and 11 positive only by MRI. The addition of MRI spine in the staging for prostate cancer resulted in a change of stage and management plan in seven (7%) patients. Conclusion: MRI spine has comparable specificity and slightly better sensitivity than bone scan to detect spinal metastasis from prostate cancer. [ABSTRACT FROM AUTHOR]
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- 2009
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23. Intensity-modulated radiotherapy allows escalation of the radiation dose to the pelvic lymph nodes in patients with locally advanced prostate cancer: preliminary results of a phase I dose escalation study.
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Guerrero Urbano T, Khoo V, Staffurth J, Norman A, Buffa F, Jackson A, Adams E, Hansen V, Clark C, Miles E, McNair H, Nutting C, Parker C, Eeles R, Huddart R, Horwich A, and Dearnaley DP
- Abstract
AIM: Pelvic irradiation in addition to prostate irradiation may improve outcome in locally advanced prostate cancer, but is associated with dose-limiting bowel toxicity. We report the preliminary results of a dose escalation study using intensity-modulated radiotherapy. MATERIALS AND METHODS: Eligible patients had high-risk (T3, Gleason > or =8 or prostate-specific antigen > or =20 ng/ml) or lymph node-positive disease. Intensity-modulated radiotherapy was inverse planned giving 70 Gy/35 fractions to the prostate and 50 Gy/55 Gy/60 Gy in sequential cohorts to the pelvis with a 5 Gy boost to positive lymph nodes. Acute and late toxicity were recorded with Radiation Therapy Oncology Group (RTOG) and Late Effects Normal Tissue - Subjective Objective Management LENT-SOM scales. Neoadjuvant androgen suppression was given for 3 years. This report concerns the 50 and 55 Gy cohorts. RESULTS: Seventy-nine men were recruited (25 to 50 Gy/54 to 55 Gy) with a median follow-up of 2 years. Patients were divided into two groups according to the total bowel volume outlined (median 450 cm(3)). Acute RTOG (> or =2) bowel toxicity was 40 and 50% for the 50 and 55 Gy groups and 38 and 51% for bowel volume <450 cm(3) and > or =450 cm(3), respectively, suggesting both volume and dose relationships for acute effects. Late RTOG diarrhoea > or =grade 2 was only seen with bowel volume > or =450 cm(3), but no dose effect was apparent (12%/50 Gy and 10%/55 Gy). LENT-SOM bowel > or =grade 2 toxicity occurred in 22%/50 Gy and 15%/55 Gy. Only one patient had grade 3 toxicity. A dose volume histogram analysis showed increased late RTOG diarrhoea > or =grade 2 with larger bowel volume irradiated, significant for BV40 >124 cm(3) (P=0.04), BV45 >71 cm(3) (P=0.03) and BV60 >2 cm(3) (P=0.01). CONCLUSIONS: Acute and late bowel toxicity was acceptably low using a pelvic dose of up to 55 Gy over 7 weeks. Both relate to total pelvic bowel volume and dose volume constraints have been defined. [ABSTRACT FROM AUTHOR]
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- 2010
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24. Dose-volume constraints to reduce rectal side effects from prostate radiotherapy: evidence from MRC RT01 Trial ISRCTN 47772397.
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Gulliford SL, Foo K, Morgan RC, Aird EG, Bidmead AM, Critchley H, Evans PM, Gianolini S, Mayles WP, Moore AR, Sánchez-Nieto B, Partridge M, Sydes MR, Webb S, Dearnaley DP, Gulliford, Sarah L, Foo, Kerwyn, Morgan, Rachel C, Aird, Edwin G, and Bidmead, A Margaret
- Abstract
Purpose: Radical radiotherapy for prostate cancer is effective but dose limited because of the proximity of normal tissues. Comprehensive dose-volume analysis of the incidence of clinically relevant late rectal toxicities could indicate how the dose to the rectum should be constrained. Previous emphasis has been on constraining the mid-to-high dose range (>/=50 Gy). Evidence is emerging that lower doses could also be important.Methods and Materials: Data from a large multicenter randomized trial were used to investigate the correlation between seven clinically relevant rectal toxicity endpoints (including patient- and clinician-reported outcomes) and an absolute 5% increase in the volume of rectum receiving the specified doses. The results were quantified using odds ratios. Rectal dose-volume constraints were applied retrospectively to investigate the association of constraints with the incidence of late rectal toxicity.Results: A statistically significant dose-volume response was observed for six of the seven endpoints for at least one of the dose levels tested in the range of 30-70 Gy. Statistically significant reductions in the incidence of these late rectal toxicities were observed for the group of patients whose treatment plans met specific proposed dose-volume constraints. The incidence of moderate/severe toxicity (any endpoint) decreased incrementally for patients whose treatment plans met increasing numbers of dose-volume constraints from the set of V30Conclusion: Considering the entire dose distribution to the rectum by applying dose-volume constraints such as those tested here in the present will reduce the incidence of late rectal toxicity. [ABSTRACT FROM AUTHOR] - Published
- 2010
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25. STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer - a multi-arm multi-stage randomised controlled trial.
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James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Anderson J, Popert RJ, Sanders K, Morgan RC, Stansfeld J, Dwyer J, Masters J, and Parmar MKB
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- 2008
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26. Accuracy and reproducibility of conformal radiotherapy using data from a randomised controlled trial of conformal radiotherapy in prostate cancer (MRC RT01, ISRCTN47772397)
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Stanley S, Griffiths S, Sydes MR, Moore AR, Syndikus I, Dearnaley DP, and RT01 Radiographer Trial Implementation Group on behalf of all the RT01 Collaborators
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AIMS: The MRC RT01 trial used conformal radiotherapy to the prostate, a method that reduces the volume of normal tissue treated by 40-50%. Because of the risk of geographical miss, the trial used portal imaging to examine whether treatment delivery was within the required accuracy. MATERIAL AND METHODS: In total, 843 patients were randomly assigned to receive 64Gy in 32 fractions over 6.5 weeks or 74Gy in 37 fractions over 7.5 weeks. Field displacements and corrections were recorded for all imaged fractions. Displacement trends and their association with time, disease and treatment set-up characteristics were examined using univariate and multivariate analyses. A Radiographer Trial Implementation Group (RTIG) was set up to inform the quality assurance process and to promote the development of best practice. RESULTS: Treatment isocentre positioning was within 5mm in every direction on 6238 (83%) of the 7535 fractions imaged. In total, 532 (81%) of 695 included patients had at least one >/=3mm displacement and 415 (63%) had at least one >/=5mm displacement. Univariate, multivariate and stepwise models of >/=5mm displacements showed an increased likelihood of displacement in weeks 1 and 2 with low melting point alloy (LMPA) blocks compared with multileaf collimators, film verification compared with electronic portal imaging (EPI) and increased number of fractions imaged. Except for LMPA, this was also seen for >/=5mm displacements in weeks 3-6. CONCLUSIONS: Accurate conformal treatment was delivered. The use of EPI was associated with increased reported accuracy. The RTIG was a crucial part of the quality assurance process. [ABSTRACT FROM AUTHOR]
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- 2008
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27. Reply to J.A. Garcia et al.
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Halabi S, Guo S, Roy A, Rydzewska LE, Godolphin P, Hussain M, Tangen C, Thompson I, Xie W, Carducci MA, Morris MJ, Smith MR, Gravis G, Dearnaley DP, Verhagen PJ, Goto TJ, James ND, Buyse ME, Tierney JF, and Sweeney CJ
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- 2024
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28. Prognostic Impact of Prostate-Specific Antigen at 6 Months After Radiotherapy in Localized Prostate Cancer: An Individual Patient Data Analysis of Randomized Trials.
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Kwak L, Ravi P, Armstrong JG, Beckendorf V, Chin JL, D'Amico AV, Dearnaley DP, Di Stasi SM, Gillessen S, Lukka H, Mottet N, Pommier P, Seiferheld W, Sydes MR, Tombal B, Zapatero A, Regan MM, Xie W, and Sweeney CJ
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- Humans, Male, Aged, Prognosis, Middle Aged, Time Factors, Prostatic Neoplasms blood, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms mortality, Prostatic Neoplasms pathology, Prostatic Neoplasms therapy, Prostatic Neoplasms drug therapy, Prostate-Specific Antigen blood, Randomized Controlled Trials as Topic, Androgen Antagonists therapeutic use
- Abstract
Purpose: We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT)., Patients and Methods: Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment., Results: Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL., Conclusion: PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.
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- 2024
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29. Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.
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Halabi S, Roy A, Rydzewska L, Guo S, Godolphin P, Hussain M, Tangen C, Thompson I, Xie W, Carducci MA, Smith MR, Morris MJ, Gravis G, Dearnaley DP, Verhagen P, Goto T, James N, Buyse ME, Tierney JF, and Sweeney C
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- Male, Humans, Progression-Free Survival, Androgen Antagonists, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hormones therapeutic use, Disease-Free Survival, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms drug therapy
- Abstract
Purpose: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials., Methods: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE)., Results: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively., Conclusion: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.
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- 2024
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30. Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition.
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Brand DH, Brüningk SC, Wilkins A, Naismith O, Gao A, Syndikus I, Dearnaley DP, Hall E, van As N, Tree AC, and Gulliford S
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- Male, Humans, Rectum diagnostic imaging, Radiotherapy Dosage, Radiotherapy, Conformal methods, Radiation Injuries etiology, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms complications
- Abstract
Purpose: Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction., Methods and Materials: Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2
α/β= 3 Gy ) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions., Results: The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P = .21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P = .07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P = .05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P = .27-.98)., Conclusions: We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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31. Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.
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Roy S, Romero T, Michalski JM, Feng FY, Efstathiou JA, Lawton CAF, Bolla M, Maingon P, de Reijke T, Joseph D, Ong WL, Sydes MR, Dearnaley DP, Tree AC, Carrier N, Nabid A, Souhami L, Incrocci L, Heemsbergen WD, Pos FJ, Zapatero A, Guerrero A, Alvarez A, San-Segundo CG, Maldonado X, Reiter RE, Rettig MB, Nickols NG, Steinberg ML, Valle LF, Ma TM, Farrell MJ, Neilsen BK, Juarez JE, Deng J, Vangala S, Avril N, Jia AY, Zaorsky NG, Sun Y, Spratt D, and Kishan AU
- Subjects
- Male, Humans, Prostate pathology, Androgen Antagonists therapeutic use, Prostate-Specific Antigen, Prostatic Neoplasms drug therapy, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms pathology, Adenocarcinoma drug therapy, Adenocarcinoma radiotherapy, Adenocarcinoma pathology
- Abstract
Purpose: The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods., Materials and Methods: Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R
2 ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed., Results: Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively., Conclusion: BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.- Published
- 2023
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32. Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.
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Naderi E, Aguado-Barrera ME, Schack LMH, Dorling L, Rattay T, Fachal L, Summersgill H, Martínez-Calvo L, Welsh C, Dudding T, Odding Y, Varela-Pazos A, Jena R, Thomson DJ, Steenbakkers RJHM, Dennis J, Lobato-Busto R, Alsner J, Ness A, Nutting C, Gómez-Caamaño A, Eriksen JG, Thomas SJ, Bates AM, Webb AJ, Choudhury A, Rosenstein BS, Taboada-Valladares B, Herskind C, Azria D, Dearnaley DP, de Ruysscher D, Sperk E, Hall E, Stobart H, Chang-Claude J, De Ruyck K, Veldeman L, Altabas M, De Santis MC, Farcy-Jacquet MP, Veldwijk MR, Sydes MR, Parliament M, Usmani N, Burnet NG, Seibold P, Symonds RP, Elliott RM, Bultijnck R, Gutiérrez-Enríquez S, Mollà M, Gulliford SL, Green S, Rancati T, Reyes V, Carballo A, Peleteiro P, Sosa-Fajardo P, Parker C, Fonteyne V, Johnson K, Lambrecht M, Vanneste B, Valdagni R, Giraldo A, Ramos M, Diergaarde B, Liu G, Leal SM, Chua MLK, Pring M, Overgaard J, Cascallar-Caneda LM, Duprez F, Talbot CJ, Barnett GC, Dunning AM, Vega A, Andreassen CN, Langendijk JA, West CML, Alizadeh BZ, and Kerns SL
- Subjects
- Male, Humans, Breast, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms genetics, Neoplasms radiotherapy
- Abstract
Background: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung)., Methods: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type., Results: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected)., Conclusions: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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33. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol.
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Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, Hoyle A, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Gilson C, Rush H, Abdel-Aty H, Amos CL, Murphy C, Chowdhury S, Malik Z, Russell JM, Parkar N, Pugh C, Diaz-Montana C, Pezaro C, Grant W, Saxby H, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzouebi M, Parikh O, Robinson A, Montazeri AH, Wylie J, Zarkar A, Cathomas R, Brown MD, Jain Y, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, and James ND
- Subjects
- Male, Humans, Abiraterone Acetate, Androgen Antagonists, Androgens, Prednisolone, Docetaxel therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, Meta-Analysis as Topic, Prostatic Neoplasms pathology, Prostatic Neoplasms, Castration-Resistant drug therapy, Prostatic Neoplasms, Castration-Resistant pathology
- Abstract
Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival., Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m
2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544)., Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; pinteraction =0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial)., Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas., Competing Interests: Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas; personal fees or travel support from Pfizer, Ipsen, Novartis (Advanced Accelerator Applications), Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, BeiGene, Takeda, AstraZeneca, and Sanofi Aventis; grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics; receives a share of the royalty income from The Institute of Cancer Research Rewards to Discoverers Scheme for abiraterone; and holds a patent on plasma methylation signatures as biomarkers for prostate cancer (GB1915469.9). LM, AC, CB, CG, HR, CLA, CM, NP, CP, CD-M, DG, MRS, LCB, REL, and MKBP report research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. NWC reports personal fees from Janssen and Astellas. AS reports grants or contracts with the National Institute for Health Research, John Black Charitable Foundation, and Prostate Cancer Foundation. RJJ reports research grants from Astellas, Clovis, Exelixis, Bayer, and Roche; and advisory board participation and speaker's honoraria from Janssen, Astellas, Bayer, Novartis, Pfizer, Merck Serono, MSD, Roche, Ipsen, and Bristol Myers Squibb. CCP reports consulting fees from Advanced Accelerator Applications, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals; and speaker's honoraria from Janssen and Bayer. SG reports consulting fees from Tolremo; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, educational events, and honoraria from Silvio Grasso Consulting, WebMD (Medscape), European Society of Medical Oncology, Orikata, Swiss Group for Clinical Cancer Research, Beijing United Family Hospital and Clinics, Deutchland European School of Oncology, Swiss Academy of Multidisciplinary Oncology, PeerVoice, and Radiotelevisione Svizzera Italiana; travel support from Proteomedix and AstraZeneca; a patent for biomarker discovery (WO 2009138392 A1); advisory board participation for Janssen, MSD, Bayer, Roche, Astellas, Pfizer, Telixpharma, Bristol Myers Squibb, Advanced Accelerator Applications, Orion, Novartis, Modra Pharmaceuticals, AstraZeneca, Myriad Genetic, and Amgen; and a scientific committee role for Pfizer. CG reports institution funding from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi Genzyme; and charitable funding from Cancer Research UK and Medical Research Council. SC reports consulting fees from Telix, Novartis (Advanced Accelerator Applications), Huma, Remedy Bio, and Curesponse; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, Janssen, Astellas, Amgen, and Advanced Accelerator Applications; participation on a data safety monitoring board or advisory board for Amgen, Janssen, and Bayer; and stocks in Huma and Remedy Bio. JMO reports a grant from Prostate Cancer UK. AB reports speaker's fees from Janssen, Astellas, Bristol Myers Squibb, Roche, MSD, and Bayer; support for attending meetings and travel from Janssen and Bayer; and participation on a data safety monitoring board or advisory board for Janssen, Bristol Myers Squibb, and AstraZeneca. NS reports support for travel expenses from Janssen-Cilag. JT reports support from Janssen and Astellas for conference attendance; and participation in advisory boards for Janssen and Astellas. PD reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, Bristol Myers Squibb, Ipsen, EUSA Pharma, and EISAI; support for attending meetings or travel from Janssen and Ipsen; and participation on a data safety monitoring board or advisory board for Pfizer and EUSA Pharma. OP reports support for educational meetings and conference attendance from Janssen and Astellas. AR reports sponsorships for attending a conference from Janssen. AHM reports sponsorship to attend an educational meeting from Astellas. RC reports consulting fees from Astellas, Bayer, Novartis, Janssen, Sanofi, Pfizer, MSD, Bristol Myers Squibb, Roche, Debiopharm, AstraZeneca, Ipsen, and Merck; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Astellas, Janssen, Roche, and Merck; and participation as a board member for the Swiss Group for Clinical Cancer Research. DPD reports consulting fees and participation on an advisory board for Janssen; and a patent for a localisation and stabilisation device (EP1933709B1). MRS reports speaker fees from Eisai and being a non-paid member of independent data monitoring committees for academic sponsors. NDJ reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, Clovis, and Cancer Research UK; and consulting and lecture fees from Astellas and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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34. Comment on "Exploiting dietary fibre and the gut microbiota in pelvic radiotherapy patients".
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Ferreira MR, Andreyev JN, Wedlake L, and Dearnaley DP
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- Humans, Dietary Fiber, Gastrointestinal Tract, Pelvis, Gastrointestinal Microbiome
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- 2023
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35. The Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial.
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Brand DH, Brüningk SC, Wilkins A, Naismith O, Gao A, Syndikus I, Dearnaley DP, van As N, Hall E, Gulliford S, and Tree AC
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- Humans, Male, Dysuria, Hematuria etiology, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms surgery, Radiotherapy, Intensity-Modulated adverse effects, Transurethral Resection of Prostate
- Abstract
Purpose: Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial., Methods and Materials: The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test., Results: The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/β = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/β = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/β = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but α/β ratio estimates remained stable., Conclusions: Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/β ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/β ratio assumptions of 3 to 5 Gy., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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36. Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled Analysis of 18 Randomized Trials from the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium (LEVIATHAN).
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Ma TM, Chu FI, Sandler H, Feng FY, Efstathiou JA, Jones CU, Roach M 3rd, Rosenthal SA, Pisansky T, Michalski JM, Bolla M, de Reijke TM, Maingon P, Neven A, Denham J, Steigler A, Joseph D, Nabid A, Souhami L, Carrier N, Incrocci L, Heemsbergen W, Pos FJ, Sydes MR, Dearnaley DP, Tree AC, Syndikus I, Hall E, Cruickshank C, Malone S, Roy S, Sun Y, Zaorsky NG, Nickols NG, Reiter RE, Rettig MB, Steinberg ML, Reddy VK, Xiang M, Romero T, Spratt DE, and Kishan AU
- Subjects
- Humans, Male, Proportional Hazards Models, Prostate-Specific Antigen, Randomized Controlled Trials as Topic, Retrospective Studies, Neoplasm Recurrence, Local pathology, Prostatic Neoplasms pathology
- Abstract
Context: The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear., Objective: To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT., Evidence Acquisition: A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states., Evidence Synthesis: The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06-1.30), PCSS (HR 2.02, 95% CI 1.75-2.33), and DMFS (HR 1.94, 95% CI 1.75-2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36-1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21-0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups., Conclusions: Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a "second wave" of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis., Patient Summary: Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2022
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37. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).
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James ND, Clarke NW, Cook A, Ali A, Hoyle AP, Attard G, Brawley CD, Chowdhury S, Cross WR, Dearnaley DP, de Bono JS, Diaz-Montana C, Gilbert D, Gillessen S, Gilson C, Jones RJ, Langley RE, Malik ZI, Matheson DJ, Millman R, Parker CC, Pugh C, Rush H, Russell JM, Berthold DR, Buckner ML, Mason MD, Ritchie AWS, Birtle AJ, Brock SJ, Das P, Ford D, Gale J, Grant W, Gray EK, Hoskin P, Khan MM, Manetta C, McPhail NJ, O'Sullivan JM, Parikh O, Perna C, Pezaro CJ, Protheroe AS, Robinson AJ, Rudman SM, Sheehan DJ, Srihari NN, Syndikus I, Tanguay JS, Thomas CW, Vengalil S, Wagstaff J, Wylie JP, Parmar MKB, and Sydes MR
- Subjects
- Abiraterone Acetate therapeutic use, Aged, Androgen Antagonists therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Follow-Up Studies, Hormones, Humans, Male, Prednisolone therapeutic use, Prednisone therapeutic use, Retrospective Studies, Treatment Outcome, Prostatic Neoplasms pathology, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10
-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)- Published
- 2022
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38. High-dose Radiotherapy or Androgen Deprivation Therapy (HEAT) as Treatment Intensification for Localized Prostate Cancer: An Individual Patient-data Network Meta-analysis from the MARCAP Consortium.
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Kishan AU, Wang X, Sun Y, Romero T, Michalski JM, Ma TM, Feng FY, Sandler HM, Bolla M, Maingon P, De Reijke T, Neven A, Steigler A, Denham JW, Joseph D, Nabid A, Carrier N, Souhami L, Sydes MR, Dearnaley DP, Syndikus I, Tree AC, Incrocci L, Heemsbergen WD, Pos FJ, Zapatero A, Efstathiou JA, Guerrero A, Alvarez A, San-Segundo CG, Maldonado X, Xiang M, Rettig MB, Reiter RE, Zaorsky NG, Ong WL, Dess RT, Steinberg ML, Nickols NG, Roy S, Garcia JA, and Spratt DE
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- Bayes Theorem, Hot Temperature, Humans, Male, Multicenter Studies as Topic, Network Meta-Analysis, Quality of Life, Radiotherapy Dosage, Androgen Antagonists therapeutic use, Prostatic Neoplasms drug therapy, Prostatic Neoplasms radiotherapy, Radiotherapy adverse effects, Radiotherapy methods
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Background: The relative benefits of radiotherapy (RT) dose escalation and the addition of short-term or long-term androgen deprivation therapy (STADT or LTADT) in the treatment of prostate cancer are unknown., Objective: To perform a network meta-analysis (NMA) of relevant randomized trials to compare the relative benefits of RT dose escalation ± STADT or LTADT., Design, Setting, and Participants: An NMA of individual patient data from 13 multicenter randomized trials was carried out for a total of 11862 patients. Patients received one of the six permutations of low-dose RT (64 to <74 Gy) ± STADT or LTADT, high-dose RT (≥74 Gy), or high-dose RT ± STADT or LTADT., Outcome Measurements and Statistical Analyses: Metastasis-free survival (MFS) was the primary endpoint. Frequentist and Bayesian NMAs were performed to rank the various treatment strategies by MFS and biochemical recurrence-free survival (BCRFS)., Results and Limitations: Median follow-up was 8.8 yr (interquartile range 5.7-11.5). The greatest relative improvement in outcomes was seen for addition of LTADT, irrespective of RT dose, followed by addition of STADT, irrespective of RT dose. RT dose escalation did not improve MFS either in the absence of ADT (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.80-1.18) or with STADT (HR 0.99, 95% CI 0.8-1.23) or LTADT (HR 0.94, 95% CI 0.65-1.37). According to P-score ranking and rankogram analysis, high-dose RT + LTADT was the optimal treatment strategy for both BCRFS and longer-term outcomes., Conclusions: Conventionally escalated RT up to 79.2 Gy, alone or in the presence of ADT, does not improve MFS, while addition of STADT or LTADT to RT alone, regardless of RT dose, consistently improves MFS. RT dose escalation does provide a high probability of improving BCRFS and, provided it can be delivered without compromising quality of life, may represent the optimal treatment strategy when used in conjunction with ADT., Patient Summary: Using a higher radiotherapy dose when treating prostate cancer does not reduce the chance of developing metastases or death, but it does reduce the chance of having a rise in prostate-specific antigen (PSA) signifying recurrence of cancer. Androgen deprivation therapy improves all outcomes. A safe increase in radiotherapy dose in conjunction with androgen deprivation therapy may be the optimal treatment., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)
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39. Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.
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James ND, Ingleby FC, Clarke NW, Amos CL, Attard G, Brawley CD, Chowdhury S, Cross W, Dearnaley DP, Gilbert DC, Gillessen S, Jones RJ, Langley RE, Macnair A, Malik ZI, Mason MD, Matheson DJ, Millman R, Parker CC, Rush HL, Russell JM, Au C, Ritchie AWS, Mestre RP, Ahmed I, Birtle AJ, Brock SJ, Das P, Ford VA, Gray EK, Hughes RJ, Manetta CB, McLaren DB, Nikapota AD, O'Sullivan JM, Perna C, Peedell C, Protheroe AS, Sundar S, Tanguay JS, Tolan SP, Wagstaff J, Wallace JB, Wylie JP, Zarkar A, Parmar MKB, and Sydes MR
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- Androgen Antagonists therapeutic use, Androgens, Docetaxel therapeutic use, Humans, Male, Prostate-Specific Antigen, Prostatic Neoplasms drug therapy
- Abstract
Background: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival., Methods: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression)., Results: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity., Conclusions: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases., (© The Author(s) 2022. Published by Oxford University Press.)
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40. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.
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Parker CC, James ND, Brawley CD, Clarke NW, Ali A, Amos CL, Attard G, Chowdhury S, Cook A, Cross W, Dearnaley DP, Douis H, Gilbert DC, Gilson C, Gillessen S, Hoyle A, Jones RJ, Langley RE, Malik ZI, Mason MD, Matheson D, Millman R, Rauchenberger M, Rush H, Russell JM, Sweeney H, Bahl A, Birtle A, Capaldi L, Din O, Ford D, Gale J, Henry A, Hoskin P, Kagzi M, Lydon A, O'Sullivan JM, Paisey SA, Parikh O, Pudney D, Ramani V, Robson P, Srihari NN, Tanguay J, Parmar MKB, and Sydes MR
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- Docetaxel therapeutic use, Humans, Male, Quality of Life, Switzerland epidemiology, Prostate pathology, Prostatic Neoplasms pathology
- Abstract
Background: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL)., Methods and Findings: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively., Conclusions: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC., Trial Registration: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CCP reports personal fees from Bayer, personal fees from Janssen, personal fees from Clarity Pharmaceuticals, personal fees from Myovant, personal fees from ITM Oncologics, outside the submitted work NDJ received research funding to the institution from Astellas, Astra Zeneca &Janssen; receipt of honoraria/fees on the advisory board for Astra Zenenca, Clovis, Janssen, Merck, Novartis & Sanofi; received fees as a speaker for Bayer & Novartis NWC received honoraria from Astellas & Janssen; took a consulting/advisory role for Astellas, Janssen, Ferring, Bayer & Sanofi; was paid speakers fees b Janssen & Astellas; received funding for the institution from Astra Zeneca; received meeting and travel expenses from Janssen, Astellas, Sanofi, Astra Zeneca, Ferring & Ipsen GA reports personal fees from Sanofi Aventis, during the conduct of the study; personal fees and non-financial support from Astellas, personal fees and non-financial support from Medivation, personal fees from Novartis, personal fees from Millennium Pharmaceuticals, personal fees and non-financial support from Abbott Laboratories, personal fees and non-financial support from Essa Pharmaceuticals, personal fees and non-financial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, grants from AstraZeneca, grants from Arno Therapeutics, grants from Innocrin Pharma, grants, personal fees and non-financial support from Janssen, personal fees from Veridex, personal fees and non-financial support from Roche/Ventana, personal fees and non-financial support from Pfizer, personal fees from The Institute of Cancer Research (ICR), outside the submitted work; and The Institute of Cancer Research (ICR) receives royalty income from abiraterone I receive a share of this income through the ICR’s Rewards to Discoverers Scheme SC received consulting fees from Telix, remedy & Huma; received payment for speaker fees and/or manuscript writing and/or educational events from Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas; they were a member of the data safety monitoring/advisory board for Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas DPD received payment to the institution from C33589/A19727 Advances in Physics for Precision Radiotherapy; previous employer, The Institute of Cancer Research receives loyalty income from abiraterone, receives personal share of this income through ICR’s Rewards to Discoverer’s Scheme; honoraria for consultancy from Janssen; EP1933709B1 – Location and Stabilisation Device., European patent issued, Pending in Canada and India SG reports personal fees from Orion, personal fees from Janssen Cilag, personal fees from ProteoMedix, personal fees from Amgen, personal fees from MSD, other from Tolero Pharmaceuticals, other from Astellas Pharma, other from Janssen, other from MSD Merck Sharp&Dome, other from Bayer, other from Roche, other from Pfizer, other from Telixpharma, other from Amgen, other from Bristol-Myers Squibb, other from AAA International SA, other from Orion, other from Silvio Grasso Consulting, from Tolremo, outside the submitted work; In addition, Gillessen has a patent WO2009138392 issued and Menarini Silicon Biosystems (Advisory Board 2019) - not compensated Aranda (Advisory Board 2019) - not compensated RJJ received research funding to the institution from Bayer, Astellas & Pfizer; received honoraria on the advisory board for Janssen, Astellas, Bayer, Pfizer; received speaker fees from Janssen, Astellas, Bayer & Pfizer REL received an institutional grant from the MRC CG received research funding to the institution from Janssen, Clovis Oncology, Sanofi, Astellas, Medical Research Council & Cancer Research UK DF received speaker fees and/or manuscript writing and/or educational events from BMS, IPSEN, EUSA, Pfizer, ESAI; they received travel expenses from Janssen & IPSEN MDM is an advisory board member for Endocyte & Clovis AB received payment for lecture/presentation/speaker bureau/manuscript writing or educational event from Boston Scientific AJB received speaker fees and travel support from Janssen DF received payment for lectures for Janssen, Pfizer & BMS; support for attending conferences/meetings from Genisiscare & BMS AMH received research grants from CRUK and NIHR; support attending meetings from the European Association of Urologists; is a member of the European Association of Urologists & the Prostate Cancer Guidelines Group MK received travel, accommodation and conference fees as expenses from Bayer, travel and accommodation fees for Prostate cancer summits from Janssen AL received expenses for attending meetings and/or travel from Astellas, Bayer, BMS & MSD JMOS received speaker fees from AAA, Astellas, Bayer, Janssen, Novartis, Sanofi and participated as an advisory board member and/or member of the data safety monitoring board for AAA, Astellas, Bayer, Janssen, Novartis & Sanofi NNS received travel/meeting payments from Janssen JT received support for conference attendance from Janssen, Roche & Bayer; participated on the advisory board for Astra Zeneca, Astellas & Bayer MKBP received research funding to the Unit he directs from Acoria Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Astellas, AstraZeneca, Baxter, Bayer, BMS US, Bri-Bio, Cepheid, Cipla, Clovis Inc, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, Janssen Products LP, Janssen-Cilag, Johnson & Johnson, Micronoma, Modus Theraputics, Mylan, Novartis, Pfizer, Sanofi, Serum Institute of India, Shionogi, Synteny Biotechnology, Takeda, Tibotec, Transgene, ViiV Healthcare, Virco and Xenothera MRS received research funding to the institution from Astellas, Clovis, Janssen, Novartis, Pfizer, Sanofi-Aventis; received speaker fees from Lilly Oncology & Janssen; independent member of data monitoring committees. All other authors have nothing to declare.
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41. Cost-utility analysis of adding abiraterone acetate plus prednisone/prednisolone to long-term hormone therapy in newly diagnosed advanced prostate cancer in England: Lifetime decision model based on STAMPEDE trial data.
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Clarke CS, Hunter RM, Gabrio A, Brawley CD, Ingleby FC, Dearnaley DP, Matheson D, Attard G, Rush HL, Jones RJ, Cross W, Parker C, Russell JM, Millman R, Gillessen S, Malik Z, Lester JF, Wylie J, Clarke NW, Parmar MKB, Sydes MR, and James ND
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- Acetates, Androgen Antagonists therapeutic use, Cost-Benefit Analysis, Hormones, Humans, Male, Prednisolone therapeutic use, Prednisone, State Medicine, Abiraterone Acetate therapeutic use, Prostatic Neoplasms pathology
- Abstract
Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup., Competing Interests: Besides the funding declared above, • CDB reports grants from Novartis, Sanofi-Aventis, Pfizer, Janssen Pharma, Cancer Research UK, and Medical Research Council. • DD reports personal fees from The Institute of Cancer Research, grants from Cancer Research UK Program Grant and personal fees from Janssen. In addition, DD has a patent EP1933709B1 issued. • GA reports receiving commercial research grants from Janssen and AstraZeneca; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Pfizer, Ferring, Sanofi-Aventis and Roche/Ventana; and has served as a consultant for/advisory board member of Janssen, Bayer, Astellas, Pfizer, Novartis, AstraZeneca, Orion, and Essa. GA has an ownership interest (including patents) in The Institute of Cancer Research Rewards to Discoverers for abiraterone acetate. • RJJ reports grants and personal fees from Astellas, AstraZeneca, Exelixis, and Roche; grants, personal fees and non-financial support from Bayer; personal fees and non-financial support from Bristol Myers Squibb, Janssen, Ipsen, and MSD; and personal fees from Merck Serono, Novartis, Pfizer, Sanofi Genzyme, and EUSA. • WC reports grants from Myriad Genetics. • CP reports personal fees from Bayer, Clarity, ITM (Isotopen Technologien Muenchen AG), Janssen, and Myovant. • SG reports personal fees from Sanofi, Orion, Roche, Janssen Cilag, and Amgen; other benefits from Menarini Silicon Biosystems, Bayer, AAA International, ProteoMediX, Toledo, and MSD; personal fees and other benefits from Astellas Pharma; and grants from Astellas Pharma. • ZM reports involvement in consultancy and advisory boards at Janssen and Sanofi, in advisory boards at Astellas, and sponsorship to attend medical conferences from Astellas, Bayer and Janssen. • NWC reports receiving research grants AstraZeneca and Janssen; honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Ferring, Sanofi-Aventis and has served as a consultant for/advisory board member of Janssen, Bayer, Astellas, Ferring, and AstraZeneca. • MKBP reports unrestricted grant funding to contribute to STAMPEDE overall from Astellas, Clovis Oncology, Novartis, Pfizer and Sanofi. • MRS reports grants from Clovis, grants and non-financial support from Astellas, Janssen, Novartis, Pfizer, and Sanofi to support the running of STAMPEDE; and personal fees from Lilly Oncology and Janssen for educational events unconnected to the submitted work or the underpinning trial. • NDJ reports grants and personal fees from Janssen, Astellas, and Sanofi, and personal fees from AstraZeneca, during the conduct of the study. • CSC, RMH, AG, FCI, DM, HLR, JMR, RM, JFL and JW have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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42. Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial.
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Rush HL, Murphy L, Morgans AK, Clarke NW, Cook AD, Attard G, Macnair A, Dearnaley DP, Parker CC, Russell JM, Gillessen S, Matheson D, Millman R, Brawley CD, Pugh C, Tanguay JS, Jones RJ, Wagstaff J, Rudman S, O'Sullivan JM, Gale J, Birtle A, Protheroe A, Gray E, Perna C, Tolan S, McPhail N, Malik ZI, Vengalil S, Fackrell D, Hoskin P, Sydes MR, Chowdhury S, Gilbert DC, Parmar MKB, James ND, and Langley RE
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- Abiraterone Acetate therapeutic use, Androgen Antagonists therapeutic use, Androstenes, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Docetaxel therapeutic use, Humans, Male, Prostatic Neoplasms pathology, Quality of Life
- Abstract
Purpose: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices., Methods: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints., Results: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001)., Conclusion: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment., Competing Interests: Alicia K. MorgansHonoraria: Genentech, Janssen, Sanofi, AstraZeneca, Astellas Scientific and Medical Affairs Inc, Astellas Pharma, Janssen Oncology, Bayer, Janssen, Clovis Oncology, Myovant Sciences, Advanced Accelerator Applications, Exelixis, Pfizer, MerckConsulting or Advisory Role: AstraZeneca, Sanofi, Bayer, Astellas Pharma, Janssen, Advanced Accelerator Applications, Myovant Sciences, Blue Earth Diagnostics, Myovant Sciences, Exelixis, Novartis, Myriad Genetics, Lantheus Medical Imaging, MerckResearch Funding: Bayer, Seattle Genetics/Astellas, Genentech, AstraZeneca, Astellas Scientific and Medical Affairs Inc, Dendreon, Sanofi, Myovant SciencesTravel, Accommodations, Expenses: Sanofi Noel W. ClarkeHonoraria: Janssen-Cilag, Astellas Pharma, Sanofi, Bayer, AstraZeneca, Ferring, IpsenConsulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Ferring, Bayer, SanofiSpeakers' Bureau: Janssen-Cilag, Astellas PharmaResearch Funding: AstrazenecaTravel, Accommodations, Expenses: Janssen-Cilag, Astellas Pharma, Sanofi, Bayer, AstraZeneca, Ferring, Ipsen Gerhardt AttardHonoraria: Astellas Pharma, Janssen (I)Consulting or Advisory Role: Janssen-Cilag, Veridex, Ventana Medical Systems, Astellas Pharma, Medivation, Novartis, Millennium, Abbott Laboratories, ESSA, Bayer, Pfizer, AstraZeneca, FerringSpeakers' Bureau: Janssen, Astellas Pharma, Takeda, Sanofi, Ventana Medical Systems, Ipsen, AstraZeneca, FerringResearch Funding: Janssen, Arno Therapeutics, Innocrin PharmaPatents, Royalties, Other Intellectual Property: I am on The ICR rewards to inventors list of abiraterone acetateTravel, Accommodations, Expenses: Astellas Pharma, Medivation, Ventana Medical Systems, Abbott Laboratories, Bayer, ESSA, Janssen (I), Astellas Pharma (I), Pfizer (I), FerringOther Relationship: Institute of Cancer Research David P. DearnaleyPatents, Royalties, Other Intellectual Property: Abiraterone acetate was developed at The Institute of Cancer Research, which therefore has a commercial interest in the development of this agent. Professor Dearnaley is on the Institute’s Rewards to Inventors list for abiraterone acetate, patent issued EP1933709B1 (location and stabilization device)Travel, Accommodations, Expenses: Janssen Oncology Christopher C. ParkerHonoraria: Bayer, JanssenConsulting or Advisory Role: Clarity Pharmaceuticals, Myovant Sciences, ITM Oncologics Silke GillessenConsulting or Advisory Role: Astellas Pharma (Inst), Janssen (Inst), Bayer (Inst), Orion Pharma GmbH, Tolero Pharmaceuticals (Inst), MSD Oncology (Inst), Roche (Inst), Amgen, Pfizer (Inst), BMS (Inst), Telix Pharma (Inst), MSD Oncology, AAA HealthCare (Inst), Orion Corporation (Inst), Amgen (Inst)Patents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMedix, Aranda Pharma (Inst), Menarini Silicon Biosystems (Inst) Christopher D. BrawleyResearch Funding: Astellas Pharma, Clovis Oncology, Janssen, Sanofi/Aventis, Pfizer, Novartis, Jacob S. TanguayConsulting or Advisory Role: AstraZeneca, Astellas Pharma, BayerTravel, Accommodations, Expenses: Janssen, Roche, Bayer Robert J. JonesHonoraria: Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Seattle Genetics, Sanofi, Bayer, Roche/Genentech, EUSA Pharma, Pharmacyclics, Clovis OncologyResearch Funding: Roche, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Exelixis, Clovis Oncology, BayerTravel, Accommodations, Expenses: Ipsen, Bayer, Janssen, Astellas Pharma, MSD John WagstaffHonoraria: Bristol Myers Squibb, Roche, Pierre Fabre, Novartis, GlaxoSmithKline UK Ltd., PfizerConsulting or Advisory Role: Bristol Myers Squibb, Roche, Pfizer, Novartis, Pierre FabreSpeakers' Bureau: Bristol Myers Squibb Sarah RudmanHonoraria: Bristol Myers Squibb Foundation, EUSA Pharma, Ipsen, PfizerConsulting or Advisory Role: Ipsen, Pfizer, EUSA Pharma Joe M. O'SullivanConsulting or Advisory Role: Bayer, Janssen, Astellas Pharma, Sanofi, NovartisSpeakers' Bureau: Bayer, Janssen, NovartisResearch Funding: Bayer Alison BirtleHonoraria: Janssen-CilagConsulting or Advisory Role: Roche, Astellas Medivation, Janssen Oncology, AstraZeneca, Sanofi, Bayer Schering Pharma, Bristol Myers Squib, Merck Serono, PfizerSpeakers' Bureau: Bayer, Janssen Oncology, PfizerResearch Funding: Genzyme Andrew ProtheroeEmployment: Genesis Cancer CareHonoraria: Astellas Pharma, MSD Oncology, Ipsen, Astellas Pharma, Merck Serono, Eisai, MerckTravel, Accommodations, Expenses: Bayer, EUSA Pharma Emma GrayEmployment: Genesis Cancer CareHonoraria: Astellas Pharma, MSD Oncology, Ipsen, Astellas Pharma, Merck Serono, Eisai, MerckTravel, Accommodations, Expenses: Bayer, EUSA Pharma Neil McPhailConsulting or Advisory Role: Eisai, GlaxoSmithKline, IpsenTravel, Accommodations, Expenses: Ipsen Zaf I. MalikConsulting or Advisory Role: Sanofi/Aventis Salil VengalilHonoraria: Bristol Myers Squibb, PfizerConsulting or Advisory Role: Merck/PfizerTravel, Accommodations, Expenses: Ipsen Peter HoskinResearch Funding: Varian Medical Systems, Astellas Pharma, Bayer, Roche, Pfizer, Elekta Matthew R. SydesHonoraria: Lilly, Sanofi, JanssenResearch Funding: Astellas Pharma, Janssen-Cilag, Pfizer, Novartis, Sanofi, Clovis Oncology Simon ChowdhuryHonoraria: Clovis Oncology, NovartisConsulting or Advisory Role: Clovis Oncology, Astellas Pharma, Bayer, Pfizer, Janssen-Cilag, BeiGene, NovartisSpeakers' Bureau: Pfizer, Janssen-CilagResearch Funding: Sanofi/Aventis Mahesh K. B. ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Nicholas D. JamesHonoraria: Sanofi, Bayer, Janssen, Astellas PharmaConsulting or Advisory Role: Sanofi, Bayer, Astellas Pharma, Janssen, Clovis Oncology, EUSA pharma, pfizerSpeakers' Bureau: Pierre Fabre, Ferring, Sanofi, Astellas Pharma, Janssen Oncology, MerckResearch Funding: Janssen, Astellas Pharma, Pfizer, Sanofi, Novartis, AstraZenecaTravel, Accommodations, Expenses: Sanofi, Janssen Ruth E. LangleyConsulting or Advisory Role: Bayer Schering PharmaResearch Funding: Bayer Schering PharmaNo other potential conflicts of interest were reported.
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- 2022
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43. In Regard to Shortall et al.
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Ebert MA, Marcello M, Kennedy A, Haworth A, Holloway LC, Greer P, Dowling JA, Jameson MG, Roach D, Joseph DJ, Gulliford SL, Sydes MR, Hall E, and Dearnaley DP
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- 2022
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44. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.
- Author
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Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, Gillessen S, Cook A, Brawley C, Amos CL, Atako N, Pugh C, Buckner M, Chowdhury S, Malik Z, Russell JM, Gilson C, Rush H, Bowen J, Lydon A, Pedley I, O'Sullivan JM, Birtle A, Gale J, Srihari N, Thomas C, Tanguay J, Wagstaff J, Das P, Gray E, Alzoueb M, Parikh O, Robinson A, Syndikus I, Wylie J, Zarkar A, Thalmann G, de Bono JS, Dearnaley DP, Mason MD, Gilbert D, Langley RE, Millman R, Matheson D, Sydes MR, Brown LC, Parmar MKB, and James ND
- Subjects
- Abiraterone Acetate adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Benzamides administration & dosage, Benzamides adverse effects, Chemotherapy, Adjuvant adverse effects, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant statistics & numerical data, Clinical Trials, Phase III as Topic, Disease-Free Survival, Humans, Male, Multicenter Studies as Topic, Neoplasm Grading, Neoplasm Recurrence, Local prevention & control, Nitriles administration & dosage, Nitriles adverse effects, Phenylthiohydantoin administration & dosage, Phenylthiohydantoin adverse effects, Prednisolone adverse effects, Progression-Free Survival, Prostatectomy, Prostatic Neoplasms diagnosis, Prostatic Neoplasms mortality, Randomized Controlled Trials as Topic, Abiraterone Acetate administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Neoplasm Recurrence, Local epidemiology, Prednisolone administration & dosage, Prostatic Neoplasms therapy
- Abstract
Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population., Methods: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial with no overlapping controls, the combination-therapy group also received enzalutamide (160 mg daily orally). ADT was given for 3 years and combination therapy for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression. In this primary analysis, we used meta-analysis methods to pool events from both trials. The primary endpoint of this meta-analysis was metastasis-free survival. Secondary endpoints were overall survival, prostate cancer-specific survival, biochemical failure-free survival, progression-free survival, and toxicity and adverse events. For 90% power and a one-sided type 1 error rate set to 1·25% to detect a target hazard ratio for improvement in metastasis-free survival of 0·75, approximately 315 metastasis-free survival events in the control groups was required. Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation. STAMPEDE is registered with ClinicalTrials.gov, NCT00268476, and with the ISRCTN registry, ISRCTN78818544., Findings: Between Nov 15, 2011, and March 31, 2016, 1974 patients were randomly assigned to treatment. The first trial allocated 455 to the control group and 459 to combination therapy, and the second trial, which included enzalutamide, allocated 533 to the control group and 527 to combination therapy. Median age across all groups was 68 years (IQR 63-73) and median PSA 34 ng/ml (14·7-47); 774 (39%) of 1974 patients were node positive, and 1684 (85%) were planned to receive radiotherapy. With median follow-up of 72 months (60-84), there were 180 metastasis-free survival events in the combination-therapy groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination-therapy groups (median not reached, IQR not evaluable [NE]-NE) than in the control groups (not reached, 97-NE; hazard ratio [HR] 0·53, 95% CI 0·44-0·64, p<0·0001). 6-year metastasis-free survival was 82% (95% CI 79-85) in the combination-therapy group and 69% (66-72) in the control group. There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1·02, 0·70-1·50, p=0·91) and no evidence of between-trial heterogeneity (I
2 p=0·90). Overall survival (median not reached [IQR NE-NE] in the combination-therapy groups vs not reached [103-NE] in the control groups; HR 0·60, 95% CI 0·48-0·73, p<0·0001), prostate cancer-specific survival (not reached [NE-NE] vs not reached [NE-NE]; 0·49, 0·37-0·65, p<0·0001), biochemical failure-free-survival (not reached [NE-NE] vs 86 months [83-NE]; 0·39, 0·33-0·47, p<0·0001), and progression-free-survival (not reached [NE-NE] vs not reached [103-NE]; 0·44, 0·36-0·54, p<0·0001) were also significantly longer in the combination-therapy groups than in the control groups. Adverse events grade 3 or higher during the first 24 months were, respectively, reported in 169 (37%) of 451 patients and 130 (29%) of 455 patients in the combination-therapy and control groups of the abiraterone trial, respectively, and 298 (58%) of 513 patients and 172 (32%) of 533 patients of the combination-therapy and control groups of the abiraterone and enzalutamide trial, respectively. The two most common events more frequent in the combination-therapy groups were hypertension (abiraterone trial: 23 (5%) in the combination-therapy group and six (1%) in control group; abiraterone and enzalutamide trial: 73 (14%) and eight (2%), respectively) and alanine transaminitis (abiraterone trial: 25 (6%) in the combination-therapy group and one (<1%) in control group; abiraterone and enzalutamide trial: 69 (13%) and four (1%), respectively). Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group (one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder), and four in the abiraterone acetate and prednisolone with enzalutamide group (two events each of septic shock and sudden death)., Interpretation: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Abiraterone acetate with prednisolone should be considered a new standard treatment for this population., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas., Competing Interests: Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas Pharma during the conduct of the study; personal fees or travel support from Pfizer, Ipsen, Novartis/AAA, Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Beigene, Takeda, AstraZeneca, and Sanofi-Aventis; and grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics, outside the submitted work; in addition, GA's former employer, The Institute of Cancer Research, receives royalty income from abiraterone and GA receives a share of this income through the Institute's Rewards to Discoverers Scheme. NWC reports personal fees from Janssen Pharmaceuticals and Astellas Pharma, during the conduct of the study; and personal fees from Bayer outside the submitted work. WC reports personal fees from Janssen and Bayer, outside the submitted work. RJJ reports grants from Sanofi, and grants and non-financial support from Novartis, during the conduct of the study; grants, personal fees, and non-financial support from Sanofi and Novartis, and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. CCP reports personal fees from AAA and Janssen, and research funding and speaker's honoraria from Bayer, outside the submitted work. SG reports personal fees from Bayer, Janssen Cilag, Dendreon Corporation, Millennium Pharmaceuticals, Orion, Sanofi, and MaxiVax; and speaker's fees and travel support from Bayer, CureVac, Janssen Cilag, Astellas, AAA Advanced Accelerator Applications International, Bristol-Myers Squibb (BMS), Ferring, Roche, Orion, lnnocrin Pharmaceuticals, Sanofi, Novartis, Nektar Therapeutics, and ProteoMedix, outside the submitted work. SC reports grants and personal fees from Sanofi-Aventis and personal fees from Janssen Pharmaceutical, outside the submitted work. ZM reports consultancy and advisory board membership for Janssen Consultancy, advisory board membership for Sanofi and Astellas, and sponsorship to attend medical conferences from Astellas, Bayer, and Janssen. JMR reports personal fees from Janssen (lecture fee), outside the submitted work. JB reports payments from Janssen for webinar presentations. AL reports payment or honoraria for lectures, presentation, or events from BMS, and support for attending meetings or travel from Astellas, Bayer, BMS, and Merck Sharpe and Dohme. IP reports sponsorship from Bayer for attending the European Society for Medical Oncology congress virtually in 2021. JMO reports participating on a data safety monitoring board or advisory board for AA, Astellas, Bayer, Janssen, Novartis, and Sanofi. AB reports speaker's fees and travel support from Astellas, and personal fees, speaker's fees, and travel support from Sanofi and Janssen, during the conduct of the study; speaker's fees and travel support from Bayer and AstraZeneca, outside the submitted work; and speaker fee payment from Janssen. NS reports support for attending meetings or travel from Jansen, Astellas, and Eusa Pharma UK. JT reports support for travel and speaker fees from Jansen, Roche, and Bayer, and participating on a data safety monitoring board or advisory board for AstraZeneca, Astellas, and Bayer. JWa reports a paid consultancy for BMS, Eisai, Novartis, and MSD, oustide the submitted work. OP reports participating on a data safety monitoring board and advisory board for Janssen in October, 2021. IS reports support for attending meetings or travel for the 2020 American Society of Clinical Oncology Genitourinary Cancers symposium from Bayer. AZ reports payment or honoraria for lectures, presentations, speaking, bureaus, manuscript writing, or educational events from Pfizer, Janssen, Astellas, and Sanofi, and received support for attending meetings or travel from Bayer and Merck Sharpe and Dohme. JSdB reports employment by the Institute of Cancer Research that has a commercial interest in abiraterone acetate and personal fees from Janssen, during the conduct of the study; and personal fees, speaker's fees, and travel support from AstraZeneca, Pfizer, GlaxoSmithKline, Taiho, Daiichi, Novartis, Genmab, Merck Serono, Merck, and Genentech/Roche, outside the submitted work. DPD reports personal fees and speaker's fees and travel support from Takeda, Amgen, Astellas, Sandoz, and Cadence Research; personal fees and non-financial support from Janssen; travel support from Clovis; and personal fees and non-financial support from International Society for the Study and Exchange of evidence from Clinical research And Medical experience, outside the submitted work; in addition, DPD has a patent (GB9305269–17-substituted steroids useful in cancer treatment) with royalties paid to Janssen Pharmaceutical. MDM reports personal fees from Sanofi, Bayer, Dendreon, BMS, and Janssen, outside the submitted work. REL reports support for the present manuscript with funding from the UK Medical Research Council, part of the UK Research and Innovation. DM reports grants or contracts from Health Education England made to their institution, University of Wolverhampton, payments from Routledge for royalties on a book, payments from Authors' licensing and collecting society for royalties on photocopies of the book and chapters, and unpaid role as chair of a patient advocacy group, Prostate Cancer Research. MRS reports grants and non-financial support from Sanofi-Aventis, Novartis, Pfizer, Janssen, and Astellas, during the conduct of the study; and personal fees from Eli-Lilly, outside the submitted work. MKBP reports grants and non-financial support from Janssen, during the conduct of the study; and grants and non-financial support from Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi, outside the submitted work. NDJ reports grants and personal fees from Sanofi and Novartis, during the conduct of the study; and grants and personal fees from Janssen, Astellas, and Bayer, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
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45. Impact of Pelvic Radiation Therapy for Prostate Cancer on Global Metabolic Profiles and Microbiota-Driven Gastrointestinal Late Side Effects: A Longitudinal Observational Study.
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Ferreira MR, Sands CJ, Li JV, Andreyev JN, Chekmeneva E, Gulliford S, Marchesi J, Lewis MR, and Dearnaley DP
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- Humans, Male, Metabolome, Metabolomics, Pelvis, Microbiota, Prostatic Neoplasms radiotherapy
- Abstract
Purpose: Radiation therapy to the prostate and pelvic lymph nodes (PLNRT) is part of the curative treatment of high-risk prostate cancer. Yet, the broader influence of radiation therapy on patient physiology is poorly understood. We conducted comprehensive global metabolomic profiling of urine, plasma, and stools sampled from patients undergoing PLNRT for high-risk prostate cancer., Methods and Materials: Samples were taken from 32 patients at 6 timepoints: baseline, 2 to 3 and 4 to 5 weeks of PLNRT; and 3, 6, and 12 months after PLNRT. We characterized the global metabolome of urine and plasma using
1 H nuclear magnetic resonance spectroscopy and ultraperformance liquid chromatography-mass spectrometry, and of stools with nuclear magnetic resonance. Linear mixed-effects modeling was used to investigate metabolic changes between timepoints for each biofluid and assay and determine metabolites of interest., Results: Metabolites in urine, plasma and stools changed significantly after PLNRT initiation. Metabolic profiles did not return to baseline up to 1 year post-PLNRT in any biofluid. Molecules associated with cardiovascular risk were increased in plasma. Pre-PLNRT fecal butyrate levels directly associated with increasing gastrointestinal side effects, as did a sharper fall in those levels during and up to 1 year postradiation therapy, mirroring our previous results with metataxonomics., Conclusions: We showed for the first time that an overall metabolic effect is observed in patients undergoing PLNRT up to 1 year posttreatment. These metabolic changes may effect on long-term morbidity after treatment, which warrants further investigation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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46. Relugolix, an oral gonadotropin-releasing hormone antagonist for the treatment of prostate cancer.
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George DJ and Dearnaley DP
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- Cardiovascular Diseases chemically induced, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Humans, Incidence, Leuprolide administration & dosage, Leuprolide adverse effects, Leuprolide pharmacology, Male, Phenylurea Compounds adverse effects, Prostatic Neoplasms blood, Prostatic Neoplasms pathology, Pyrimidinones adverse effects, Randomized Controlled Trials as Topic, Testosterone blood, Treatment Outcome, Cardiovascular Diseases epidemiology, Gonadotropin-Releasing Hormone antagonists & inhibitors, Phenylurea Compounds administration & dosage, Prostatic Neoplasms drug therapy, Pyrimidinones administration & dosage
- Abstract
Androgen deprivation therapy using gonadotropin-releasing hormone (GnRH) analogues is standard treatment for intermediate and advanced prostate cancer. GnRH agonist therapy results in an initial testosterone flare, and increased metabolic and cardiovascular risks. The GnRH antagonist relugolix is able to reduce serum testosterone levels in men with prostate cancer without inducing testosterone flare. In the HERO Phase III trial, relugolix was superior to leuprolide acetate at rapidly reducing testosterone and continuously suppressing testosterone, with faster post-treatment recovery of testosterone levels. Relugolix was associated with a 54% lower incidence of major adverse cardiovascular events than leuprolide acetate. As the first oral GnRH antagonist approved for the treatment of advanced prostate cancer, relugolix offers a new treatment option.
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- 2021
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47. Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial.
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Brand DH, Brüningk SC, Wilkins A, Fernandez K, Naismith O, Gao A, Syndikus I, Dearnaley DP, Tree AC, van As N, Hall E, and Gulliford S
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Anal Canal physiopathology, Anal Canal radiation effects, Diarrhea complications, Dose Fractionation, Radiation, Gastrointestinal Hemorrhage complications, Humans, Linear Models, Male, Middle Aged, Outcome Assessment, Health Care, Probability, Proctitis complications, Radiation Injuries complications, Rectum diagnostic imaging, Urethral Stricture complications, Organs at Risk radiation effects, Prostatic Neoplasms radiotherapy, Radiation Tolerance, Rectum radiation effects
- Abstract
Purpose: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy., Methods and Materials: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the models., Results: Late rectal α/β ratio estimates (without DMF) ranged from bleeding (G1 + α/β = 1.6 Gy; 95% CI, 0.9-2.5 Gy) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 1.4-9.1 Gy). Bowel pain modelled poorly (α/β, 3.6 Gy; 95% CI, 0.0-840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (P = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1 + α/β ratio = 2.4 Gy; G2 + α/β ratio = 2.3 Gy., Conclusions: We estimated α/β ratios for several common late adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2021
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48. The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy.
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Hamilton RJ, Ding K, Crook JM, O'Callaghan CJ, Higano CS, Dearnaley DP, Horwitz EM, Goldenberg SL, Gospodarowicz MK, and Klotz L
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- Androgen Antagonists adverse effects, Androgens, Humans, Male, Prostate-Specific Antigen, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Prostatic Neoplasms drug therapy
- Abstract
Background: Studies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT)., Objective: To perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes., Design, Setting, and Participants: Patients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate., Outcome Measurements and Statistical Analysis: The primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT., Results and Limitations: Of 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53-0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48-0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication., Conclusions: In men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted., Patient Summary: We found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy., (Copyright © 2020. Published by Elsevier B.V.)
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- 2021
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49. Intermediate clinical endpoints in localised prostate cancer.
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Tree AC, Dearnaley DP, and Hall E
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- Humans, Male, Prostatectomy, Prostatic Neoplasms surgery
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- 2021
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50. Reduced Dose Posterior to Prostate Correlates With Increased PSA Progression in Voxel-Based Analysis of 3 Randomized Phase 3 Trials.
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Marcello M, Denham JW, Kennedy A, Haworth A, Steigler A, Greer PB, Holloway LC, Dowling JA, Jameson MG, Roach D, Joseph DJ, Gulliford SL, Dearnaley DP, Sydes MR, Hall E, and Ebert MA
- Subjects
- Datasets as Topic, Humans, Male, Organs at Risk diagnostic imaging, Organs at Risk radiation effects, Proportional Hazards Models, Prostate diagnostic imaging, Prostate pathology, Prostatic Neoplasms diagnostic imaging, Prostatic Neoplasms pathology, Radiotherapy Dosage, Seminal Vesicles diagnostic imaging, Seminal Vesicles radiation effects, Tomography, X-Ray Computed, Disease Progression, Prostate radiation effects, Prostate-Specific Antigen metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms radiotherapy
- Abstract
Purpose: Reducing margins during treatment planning to decrease dose to healthy organs surrounding the prostate can risk inadequate treatment of subclinical disease. This study aimed to investigate whether lack of dose to subclinical disease is associated with increased disease progression by using high-quality prostate radiation therapy clinical trial data to identify anatomically localized regions where dose variation is associated with prostate-specific antigen progression (PSAP)., Methods and Materials: Planned dose distributions for 683 patients of the Trans-Tasman Radiation Oncology Group 03.04 Randomized Androgen Deprivation and Radiotherapy (RADAR) trial were deformably registered onto a single exemplar computed tomography data set. These were divided into high-risk and intermediate-risk subgroups for analysis. Three independent voxel-based statistical tests, using permutation testing, Cox regression modeling, and least absolute shrinkage selection operator feature selection, were applied to identify regions where dose variation was associated with PSAP. Results from the intermediate-risk RADAR subgroup were externally validated by registering dose distributions from the RT01 (n = 388) and Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer Trial (CHHiP) (n = 253) trials onto the same exemplar and repeating the tests on each of these data sets., Results: Voxel-based Cox regression revealed regions where reduced dose was correlated with increased prostate-specific androgen progression. Reduced dose in regions associated with coverage at the posterior prostate, in the immediate periphery of the posterior prostate, and in regions corresponding to the posterior oblique beams or posterior lateral beam boundary, was associated with increased PSAP for RADAR and RT01 patients, but not for CHHiP patients. Reduced dose to the seminal vesicle region was also associated with increased PSAP for RADAR intermediate-risk patients., Conclusions: Ensuring adequate dose coverage at the posterior prostate and immediately surrounding posterior region (including the seminal vesicles), where aggressive cancer spread may be occurring, may improve tumor control. It is recommended that particular care be taken when defining margins at the prostate posterior, acknowledging the trade-off between quality of life due to rectal dose and the preferences of clinicians and patients., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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