Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Impact of 18F-fluciclovine PET/CT on salvage radiotherapy plans for men with recurrence of prostate cancer postradical prostatectomy.

OBJECTIVES: Imaging options to localize biochemical recurrence (BCR) of prostate cancer after radical prostatectomy (RP) are limited, especially at low prostate-specific antigen (PSA) levels. The FALCON study evaluated the impact of 18F-fluciclovine PET/CT on management plans for patients with BCR. Here, we evaluate salvage radiotherapy decisions in patients post-RP. METHODS: We conducted a subgroup analysis of post-RP patients enrolled in FALCON who had a prescan plan for salvage radiotherapy (± androgen-deprivation therapy). Patients' treatment plans post-18F-fluciclovine PET/CT were compared with their prescan plans. Fisher exact test was used to determine the impact of PSA and Gleason sum on positivity and anatomical patterns of uptake. RESULTS: Sixty-five (63%) FALCON patients had undergone RP. Of these, 62 (median PSA, 0.32 ng/mL) had a prescan plan for salvage radiotherapy. Twenty-one (34%) had 18F-fluciclovine-avid lesions. Disease was confined to the prostate bed in 11 patients (52%) and to the pelvis in a further 5 (24%), while 5 (24%) had extrapelvic findings. Trends towards more disseminated disease with increasing PSA or Gleason sum were observed but did not reach statistical significance. Postscan, 25 (40%) patients had a management change; 17 (68%) were changed to the treatment modality (8 to systemic therapy, 8 to active surveillance, 1 other) and 8 (32%) were radiotherapy field modifications. CONCLUSIONS: Incorporating 18F-fluciclovine PET/CT into treatment planning may help identify patients suitable for salvage radiotherapy, help augment planned radiotherapy to better target lesions and support the clinician to optimise patient management.

Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Efficacy and toxicity outcomes for patients treated with focal salvage high dose rate brachytherapy for locally recurrent prostate cancer.

INTRODUCTION: Isolated local recurrence of prostate cancer following primary radiotherapy or brachytherapy may be treated with focal salvage high dose rate brachytherapy, although there remains an absence of high quality evidence to support this approach. METHODS: Men with prostate cancer treated consecutively between 2015 and 2018 using 19 Gy in a single fraction high dose rate brachytherapy (HDR) for locally recurrent prostate cancer were identified from an institutional database. Univariable analysis was performed to evaluate the relationship between patient, disease and treatment factors with biochemical progression free survival (bPFS). RESULTS: 43 patients were eligible for evaluation. Median follow up duration was 26 months (range 1-60). Median bPFS was 35 months (95% confidence interval 25.6-44.4). Kaplan-Meier estimates for bPFS at 1, 2 and 3 years post salvage were 95.2%, 70.6% and 41.8% respectively. On univariable Cox regression analysis, only nadir PSA was significantly associated with bPFS although the majority of patients were also treated with androgen deprivation therapy. Only one late grade 3 genitourinary toxicity was observed. CONCLUSION: Focal salvage HDR brachytherapy may provide good biochemical control with a low risk of severe toxicity. Further evaluation within clinical trials are needed to establish its role in the management of locally recurrent prostate cancer.

Effect of 18F-Fluciclovine Positron Emission Tomography on the Management of Patients With Recurrence of Prostate Cancer: Results From the FALCON Trial.

PURPOSE: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. METHODS AND MATERIALS: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. RESULTS: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). CONCLUSIONS: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

Ten-year longitudinal health-related quality of life following iodine-125 brachytherapy monotherapy for localized prostate cancer.

PURPOSE: This prospective longitudinal study quantifies health-related quality of life (HRQoL) up to 10 years following permanent iodine-125 (125I) prostate brachytherapy alone for localized prostate cancer. MATERIAL AND METHODS: In total, 120 patients completed a validated expanded prostate cancer index composite (EPIC) questionnaire pre-treatment and at 8 time points after treatment (6 weeks, 6, 10, 18 months, and 2, 3, 5, 10 years). At each time point, clinically relevant small, moderate, and severe declines in HRQoL were defined as 0.2-0.5 SD, 0.5-0.8 SD, and > 0.8 SD of baseline function for each of urinary, bowel, and sexual domains, respectively. RESULTS: Response rates in the first two years were > 90%, but thereafter dropped to 75% and 48% at 5 and 10 years, respectively. 50 patients (41.6%) responded at all stages. Maximal deterioration in mean urinary and sexual summary scores was noted 6 weeks after implant, with severe urinary symptoms and moderate bowel/sexual symptoms. At 6 months, urinary and bowel quality of life (QoL) had improved to mild impairment, which then fully resolved at 10 months. Sexual QoL remained mildly impaired throughout the 10 years of follow-up. At 10 years, new mild impairment of urinary and bowel QoL was found. CONCLUSIONS: Clinically mild changes in urinary, bowel, and sexual QoL are found 10 years after 125I monotherapy. The impairment in sexual function persists from treatment, but urinary and bowel symptoms are new at 10 years.

A comparison of outcomes for patients with intermediate and high risk prostate cancer treated with low dose rate and high dose rate brachytherapy in combination with external beam radiotherapy.

INTRODUCTION: There is evidence to support use of external beam radiotherapy (EBRT) in combination with both low dose rate brachytherapy (LDR-EBRT) and high dose rate brachytherapy (HDR-EBRT) to treat intermediate and high risk prostate cancer. METHODS: Men with intermediate and high risk prostate cancer treated using LDR-EBRT (treated between 1996 and 2007) and HDR-EBRT (treated between 2007 and 2012) were identified from an institutional database. Multivariable analysis was performed to evaluate the relationship between patient, disease and treatment factors with biochemical progression free survival (bPFS). RESULTS: 116 men were treated with LDR-EBRT and 171 were treated with HDR-EBRT. At 5 years, bPFS was estimated to be 90.5% for the LDR-EBRT cohort and 77.6% for the HDR-EBRT cohort. On multivariable analysis, patients treated with HDR-EBRT were more than twice as likely to experience biochemical progression compared with LDR-EBRT (HR 2.33, 95% CI 1.12-4.07). Patients with Gleason ≥8 disease were more than five times more likely to experience biochemical progression compared with Gleason 6 disease (HR 5.47, 95% CI 1.26-23.64). Cumulative incidence of ≥grade 3 genitourinary and gastrointestinal toxicities for the LDR-EBRT and HDR-EBRT cohorts were 8% versus 4% and 5% versus 1% respectively, although these differences did not reach statistical significance. CONCLUSION: LDR-EBRT may provide more effective PSA control at 5 years compared with HDR-EBRT. Direct comparison of these treatments through randomised trials are recommended to investigate this hypothesis further.

Three-year Safety of Radium-223 Dichloride in Patients with Castration-resistant Prostate Cancer and Symptomatic Bone Metastases from Phase 3 Randomized Alpharadin in Symptomatic Prostate Cancer Trial.

BACKGROUND: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment. OBJECTIVE: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection. DESIGN, SETTING, AND PARTICIPANTS: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics. RESULTS AND LIMITATIONS: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up. CONCLUSIONS: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns. PATIENT SUMMARY: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection.

Corrigendum: Can we deliver randomized trials of focal therapy in prostate cancer?

This corrects the article DOI: 10.1038/nrclinonc.2014.44.

Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial.

BACKGROUND: The phase 3 ALSYMPCA trial enrolled metastatic castration-resistant prostate cancer patients with or without baseline opioid use. OBJECTIVE: To assess the efficacy and safety of radium-223 dichloride (radium-223) versus placebo in ALSYMPCA patients by baseline opioid use. DESIGN, SETTING, AND PARTICIPANTS: Nine hundred and twenty one patients enrolled at 136 centers globally. INTERVENTION: Radium-223 (50 kBq/kg, intravenous injection) every 4 wk for six cycles or matching placebo, each plus best standard of care. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoint (overall survival [OS]), main secondary efficacy endpoints, and safety were evaluated by baseline opioid use. Additional analyses included time to first opioid use, time to first external beam radiation therapy for bone pain, and safety of concomitant external beam radiation therapy. RESULTS AND LIMITATIONS: At baseline, 408 (44%) patients had no pain and no analgesic use or mild pain with nonopioid therapy (World Health Organization ladder pain score 0-1 [nonopioid subgroup]), and 513 (56%) had moderate pain with occasional opioids or severe pain with regular daily opioids (World Health Organization ladder pain score 2-3 [opioid subgroup]). Radium-223 significantly prolonged OS versus placebo in nonopioid (hazard ratio [HR]=0.70; 95% confidence interval [CI]: 0.52-0.93; p=0.013) and opioid (HR=0.68; 95% CI: 0.54-0.86; p=0.001) subgroups, and significantly reduced risk of symptomatic skeletal events versus placebo, regardless of baseline opioid use (nonopioid subgroup: HR=0.56, 95% CI: 0.39-0.82, p=0.002; opioid subgroup: HR=0.72, 95% CI: 0.53-0.98, p=0.038). Time to first opioid use for bone pain was significantly delayed with radium-223 versus placebo (HR=0.62, 95% CI: 0.46-0.85, p=0.002). Adverse event incidences were similar between opioid subgroups. CONCLUSIONS: Radium-223 versus placebo significantly prolonged OS and reduced symptomatic skeletal event risk with a favorable safety profile in castration-resistant prostate cancer patients with symptomatic bone metastases, regardless of baseline opioid use. PATIENT SUMMARY: In this ALSYMPCA opioid subgroup analysis, baseline symptom levels did not appear to impact radium-223 dichloride efficacy or safety.

Final quality of life and safety data for patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in the UK Early Access Programme (EAP) (NCT01254279).

OBJECTIVE: To compile the safety profile and quality of life (QoL) data for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel in the UK Early Access Programme (UK EAP). PATIENTS AND METHODS: A total of 112 patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. Patients received cabazitaxel 25 mg/m(2) every 3 weeks with prednisolone 10 mg daily for up to 10 cycles. Safety assessments were performed before each cycle and QoL was recorded at alternate cycles using the EQ-5D-3L questionnaire and visual analogue scale (VAS). The safety profile was compiled after completion of the UK EAP and QoL measures were analysed to record trends. No formal statistical analysis was carried out. RESULTS: The incidences of neutropenic sepsis (6.3%), grade 3 and 4 diarrhoea (4.5%) and grade 3 and 4 cardiac toxicity (0%) were low. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. There were trends towards improved VAS and EQ-5D-3L pain scores during treatment. CONCLUSIONS: The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

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 5mm 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.

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.

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.

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.

Five-year outcomes after iodine-125 seed brachytherapy for low-risk prostate cancer at three cancer centres in the UK.

OBJECTIVE: To report the outcomes of >1000 men with low-risk prostate cancer treated with low-dose-rate (LDR) brachytherapy at three large UK cancer centres. PATIENTS AND METHODS: A total of 1038 patients with low-risk prostate cancer (prostate-specific antigen [PSA] ≤10 ng/mL, Gleason score 6, ≤T2b disease) were treated with LDR iodine 125 (I-125) brachytherapy between 2002 and 2007. Patients were treated at three UK centres. PSA and clinical follow-up was performed at each centre. Biochemical recurrence-free survival was reported for the cohort. RESULTS: The median (range) PSA follow-up for the whole group was 5 years (4 months to 9 years). A total of 79 patients had biochemical failure, defined by a rise in PSA level: 16 patients fulfilled the ASTRO definition of biochemical failure, 25 patients fulfilled the Phoenix definition and 38 patients fulfilled both definitions. The 5-year biochemical relapse-free survival (bRFS) rate was 94.1% by the ASTRO definition and 94.2% by the Phoenix definition. The absence of neoadjuvant hormone therapy was predictive of inferior biochemical control as defined by the Phoenix definition (P = 0.033). CONCLUSIONS: Our prospective multicentre series showed excellent bRFS with LDR I-125 brachytherapy for patients with low-risk prostate cancer. Further work is necessary to define the role of neoadjuvant androgen deprivation therapy in combination with brachytherapy.

Biochemical outcomes for patients with intermediate risk prostate cancer treated with I-125 interstitial brachytherapy monotherapy.

BACKGROUND AND PURPOSE: Routine use of I-125 interstitial brachytherapy (BT) alone in intermediate risk (IR) prostate cancer is controversial. It is often combined with external beam radiotherapy (EBRT). The biochemical outcome of a large cohort of only IR disease treated with BT monotherapy is reported. MATERIALS AND METHODS: Between 2003 and 2007, 615 patients with Memorial Sloan-Kettering Cancer Centre (MSKCC) defined IR disease (one risk factor only-T2b, or Gleason score (GS) 7, or raised initial PSA (iPSA) 10.1-20ng/ml) were treated with BT monotherapy. ASTRO (3 consecutive rises) and Phoenix (nadir plus 2) criteria defined biochemical failure. Potential prognostic factors (pre- and post-implant dosimetric indices, GS 3+4 versus 4+3, androgen deprivation therapy (ADT)) were analysed. RESULTS: Median follow-up was 5.0years. Forty-three patients had stage T2b, 180 had raised iPSA, 392 had GS 7 disease. ADT was received by 108 patients. The 5-year biochemical no evidence of disease (bNED) rates are 87.3% (by ASTRO), 88.6% (by Phoenix). Stratification by risk factor (T2b, GS7, raised iPSA) demonstrated raised iPSA to have poorer outcome only by Phoenix criteria (p=0.0002). Other potential prognostic variables were non-significant. CONCLUSION: Good rates of biochemical control can be achieved in the medium term with BT monotherapy in IR disease. Raised iPSA correlated with a poorer outcome.

SABRE 1 (Surgery Against Brachytherapy - a Randomised Evaluation): feasibility randomised controlled trial (RCT) of brachytherapy vs radical prostatectomy in low-intermediate risk clinically localised prostate cancer.

OBJECTIVE: To determine the feasibility of a phase III randomised controlled trial of brachytherapy vs radical prostatectomy (RP) in men with low-intermediate risk localised prostate cancer. PATIENTS AND METHODS: This parallel, two-group, multicentre, randomised controlled feasibility trial enrolled men with histologically confirmed localised, low-risk prostate cancer and good performance status from five UK hospitals. Participants were randomly allocated (1:1) by remote computer allocation to receive a decision aid (DA) DVD or standard information (control group), followed by a second randomisation (1:1) to brachytherapy or RP. There was no 'blinding' of staff or patients. Primary outcome was feasibility: a recruitment rate of six patients per centre over the last 6 months of recruitment would deem a phase III trial feasible. RESULTS: Between May 2009 and May 2011, 30 patients were randomised (15 in the DA group and 15 in the control group), and four continued to the second treatment randomisation (one from the DA group and three from the control group). One patient was allocated and received brachytherapy and three RP. SABRE 1 closed early due to poor recruitment. All patients were analysed. Screening logbook analysis showed that the main reasons for declining trial entry were a wish to choose treatment or opting for active monitoring. Results from the DA questionnaire (completed by 10 men) showed that four of the men 'felt surgery and radiotherapy had been proven in a high quality trial' and seven felt 'they should make their treatment decision while knowing their doctors opinion'. CONCLUSION: Recruitment to a RP vs brachytherapy trial in localised prostate cancer was not feasible by the use of this two-step randomisation using a DA and previous trials in early prostate cancer have had similar difficulties in recruitment, with only a few achieving their accrual target. The best treatment method for treating low-risk prostate cancer is still unproven in a head-to-head trial and the increasing number of options will make choices correspondingly more difficulty without good quality comparative research. More sophisticated techniques for recruitment may be more successful in future trials in this patient population.