Tumor evolution metrics predict recurrence beyond 10 years in locally advanced prostate cancer.

Cancer evolution lays the groundwork for predictive oncology. Testing evolutionary metrics requires quantitative measurements in controlled clinical trials. We mapped genomic intratumor heterogeneity in locally advanced prostate cancer using 642 samples from 114 individuals enrolled in clinical trials with a 12-year median follow-up.

Weekly ultra-hypofractionated radiotherapy in localised prostate cancer.

Background: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

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.

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types.

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).

International Society of Urological Pathology (ISUP) Gleason Grade Groups stratify outcomes in the CHHiP Phase 3 prostate radiotherapy trial.

Objectives: To compare the results of Gleason Grade Group (GGG) classification following central pathology review with previous local pathology assessment, and to examine the difference between using overall and worst GGG in a large patient cohort treated with radiotherapy and short-course hormone therapy.

Patients And Methods: Patients with low- to high-risk localized prostate cancer were randomized into the multicentre CHHiP fractionation trial between 2002 and 2011. Patients received short-course hormone therapy (≤6 month) and radical intensity-modulated radiotherapy (IMRT).

Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition.

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.

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.

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.

A Personalized Clinical Dynamic Prediction Model to Characterize Prognosis for Patients With Localized Prostate Cancer: Analysis of the CHHiP Phase 3 Trial.

Purpose: The CHHiP trial assessed moderately hypofractionated radiation therapy in localized prostate cancer. We utilized longitudinal prostate-specific antigen (PSA) measurements collected over time to evaluate and characterize patient prognosis.

Methods And Materials: We developed a clinical dynamic prediction joint model to predict the risk of biochemical or clinical recurrence.

Multi-candidate immunohistochemical markers to assess radiation response and prognosis in prostate cancer: results from the CHHiP trial of radiotherapy fractionation.

Background: Protein markers of cellular proliferation, hypoxia, apoptosis, cell cycle checkpoints, growth factor signalling and inflammation in localised prostate tumours have previously shown prognostic ability. A translational substudy within the CHHiP trial of radiotherapy fractionation evaluated whether these could improve prediction of prognosis and assist treatment stratification following either conventional or hypofractionated radiotherapy.

Methods: Using case:control methodology, patients with biochemical or clinical failure after radiotherapy (BCR) were matched to patients without recurrence according to established prognostic factors (Gleason score, presenting PSA, tumour-stage) and fractionation schedule.

Standard and Hypofractionated Dose Escalation to Intraprostatic Tumor Nodules in Localized Prostate Cancer: 5-Year Efficacy and Toxicity in the DELINEATE Trial.

Purpose: Our purpose was to report 5-year efficacy and toxicity of intraprostatic lesion boosting using standard and hypofractionated radiation therapy.

Methods And Materials: DELINEATE (ISRCTN 04483921) is a single center phase 2 multicohort study including standardly fractionated (cohort A: 74 Gy/37F to prostate and seminal vesicles [PSV]; cohort C 74 Gy/37F to PSV plus 60 Gy/37F to pelvic lymph nodes) and moderately hypofractionated (cohort B: 60 Gy/20F to PSV) prostate intensity-modulated radiation therapy patients with National Comprehensive Cancer Network intermediate/high-risk disease. Patients received an integrated boost of 82 Gy (cohorts A and C) or 67 Gy (cohort B) to multiparametric magnetic resonance imaging identified lesion(s).

The Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial.

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.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

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.

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial.

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.

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.

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.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

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.

Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial.

Background: Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis.