David Bottomley

Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer

BACKGROUND Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial

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.

Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: Long-term results from the MRC RT01 randomised controlled trial

BACKGROUND The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. METHODS RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. FINDINGS Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003). INTERPRETATION At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. FUNDING UK Medical Research Council.

Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial

BACKGROUND Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. METHODS In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. FINDINGS Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. INTERPRETATION Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. FUNDING Algeta ASA and Bayer HealthCare Pharmaceuticals.

Focal Therapy: Patients, Interventions, and Outcomes—A Report from a Consensus Meeting

Background Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. Objective To gather expert opinion on patient selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. Design, setting, and participants Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. Outcome measurements and statistical analysis Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. Results and limitations Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging–targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5 mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of ≤3 mm of Gleason 3 + 3 did not need further treatment; and focal retreatment rates of ≤20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. Conclusions The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. Patient summary In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer.

Outcomes Following Iodine-125 Monotherapy for Localized Prostate Cancer: The Results of Leeds 10-Year Single-Center Brachytherapy Experience

PURPOSE This study reports the 10-year experience of permanent brachytherapy monotherapy at a single UK center. METHODS AND MATERIALS Between March 1995 and September 2004, 1,298 patients underwent trans-rectal ultrasound (TRUS) planned transperineal brachytherapy delivering 145 Gy using I-125. No patient received supplemental external beam; 44.2% received neoadjuvant hormones. In 688, CT postimplant dosimetry was available. Outcome data were analyzed in terms of overall survival (OS), disease specific survival (DSS), and PSA relapse-free survival (PSA-RFS). RESULTS The mean age was 62.9 (range, 34-83) years. Median follow-up was 4.9 years (range, 2.03-11.7 years). OS and DSS were 85% and 95%, respectively, at 10 years. Twenty-one patients died from prostate cancer (1.6%) and 34 (2.5%) from unrelated causes. Seventy-four (5.7%) developed evidence of clinical failure. Overall PSA-RFS was 79.9% and 72.1% at 10 years (American Society for Therapeutic Radiology and Oncology [ASTRO] and Nadir+2 definitions, respectively). Higher presenting PSA or Gleason score and use of neoadjuvant hormones were associated with an increased risk of biochemical failure (p <0.01). Biochemical control was achieved in 86.4%, 76.7%, and 60.6% (ASTRO) and 72.3%, 73.5%, and 57.6% (Nadir+2) of patients in low-, intermediate-, and high-risk groups, respectively. Biochemical control was achieved in 88% of patients with D(90) > or =140 Gy and in 78% of patients with D(90) <140 Gy (p <0.01). CONCLUSIONS I-125 brachytherapy alone achieved excellent rates of medium-term biochemical control in both low- and selected intermediate-risk localized prostate cancer patients. Postimplant dosimetry improved with experience and longer follow-up, confirming the relationship of D(90) with biochemical control.

Updated analysis of the phase III, double-blind, randomized, multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with bone metastases (ALSYMPCA)

LBA4512 Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. METHODS Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wks or matching placebo. An updated descriptive analysis of OS, based on 528 events, was performed including data from all randomized pts prior to implementing crossover to Ra-223 for placebo pts. RESULTS 921 pts (Ra-223, n = 614; placebo, n = 307) were randomized from 6/2008-2/2011. Ra‑223 significantly improved OS vs placebo (median 14.9 mo vs 11.3 mo, respectively; HR = .695; 95% CI, .581-.832; p = 0.00007), and time to first SRE was significantly prolonged (median 15.6 mo vs 9.8 mo, respectively; HR = 0.658; 95% CI, 0.522-0.830; p = 0.00037). Safety and tolerability of Ra-223 remained favorable, with low myelosuppression (e.g., gr 3/4 neutropenia in 2.2% and 0.7% and gr 3/4 thrombocytopenia in 6.3% and 2% of the Ra-223 and placebo groups, respectively). CONCLUSIONS On updated analysis, the median OS benefit for Ra-223 increased from 2.8 to 3.6 months, with a hazard ratio of 0.695 (i.e., 30.5% reduction in risk of death). Ra-223 is an effective therapy that improves OS and time to first SRE with a highly favorable safety profile, and may provide a new standard of care for CRPC pts with bone mets.

Can we deliver randomized trials of focal therapy in prostate cancer

Tissue-preserving focal therapies, such as brachytherapy, cryotherapy, high-intensity focused ultrasound and photodynamic therapy, aim to target individual cancer lesions rather than the whole prostate. These treatments have emerged as potential interventions for localized prostate cancer to reduce treatment-related adverse-effects associated with whole-gland treatments, such as radical prostatectomy and radiotherapy. In this article, the Prostate Cancer RCT Consensus Group propose that a novel cohort-embedded randomized controlled trial (RCT) would provide a means to study men with clinically significant localized disease, which we defined on the basis of PSA level (≤15 ng/ml or ≤20 ng/ml), Gleason grade (Gleason pattern ≤4 + 4 or ≤4 + 3) and stage (≤cT2cN0M0). This RCT should recruit men who stand to benefit from treatment, with the control arm being whole-gland surgery or radiotherapy. Composite outcomes measuring rates of local and systemic salvage therapies at 3–5 years might best constitute the basis of the primary outcome on which to change practice.

Outcomes from Gleason 7, intermediate risk, localized prostate cancer treated with Iodine-125 monotherapy over 10 years

BACKGROUND AND PURPOSE The effect of predominating Gleason grade (3+4 versus 4+3) in Gleason sum score (GS) 7 prostate cancer (PCa) on brachytherapy outcomes is unclear. The 10 year experience of permanent brachytherapy monotherapy at a single UK centre for GS 7, intermediate risk (Memorial Sloan-Kettering model), PSA < or = 10 ng/ml, localised PCa is reported. MATERIALS AND METHODS Between 1995 and 2004, the outcomes of 187 patients with GS 7 PCa (PSA < or = 10 ng/ml) were analysed from a cohort of 1298 men treated with permanent Iodine-125 prostate brachytherapy, including PSA relapse-free survival (PSA-RFS). RESULTS Median follow-up was 5.0 years (range 2.0-10.1 years). One patient has died of PCa. At 10 years, PSA-RFS was 82.4%/78% (ASTRO consensus and nadir +2 definitions). For GS 3+4, 5 year PSA-RFS was 86.7%/87.9% and for GS 4+3: 85.2%/96.6% respectively, with no significant difference between groups. Five year PSA-RFS (ASTRO) of 92.6% was seen for D(90) > or = 140 Gy (50% total), compared with 77.0% below 140 Gy (p=0.08). CONCLUSIONS Iodine-125 brachytherapy monotherapy achieved good rates of medium term biochemical control in GS 7, intermediate risk localised PCa patients. There was a trend to improved outcomes in men with a D90 in excess of 140 Gy.

Prostate-specific antigen relapse-free survival in patients with localized prostate cancer treated by brachytherapy

Brachytherapy has become a very popular way of treating prostate cancer worldwide, and increasing attempts are being made by radiation oncologists to find the exact type of patient for whom this treatment is the most suitable. One of the largest series has come from Leeds, and the authors present the PSA relapse‐free survival in 667 patients with localised prostate cancer treated by brachytherapy in their department.