Satellite-based time-series of sea-surface temperature since 1980 for climate applications.

A 42-year climate data record of global sea surface temperature (SST) covering 1980 to 2021 has been produced from satellite observations, with a high degree of independence from in situ measurements. Observations from twenty infrared and two microwave radiometers are used, and are adjusted for their differing times of day of measurement to avoid aliasing and ensure observational stability. A total of 1.5 × 1013 locations are processed, yielding 1.4 × 1012 SST observations deemed to be suitable for climate applications. The corresponding observation density varies from less than 1 km-2 yr-1 in 1980 to over 100 km-2 yr-1 after 2007. Data are provided at their native resolution, averaged on a global 0.05° latitude-longitude grid (single-sensor with gaps), and as a daily, merged, gap-free, SST analysis at 0.05°. The data include the satellite-based SSTs, the corresponding time-and-depth standardised estimates, their standard uncertainty and quality flags. Accuracy, spatial coverage and length of record are all improved relative to a previous version, and the timeseries is routinely extended in time using consistent methods.

Implementing music therapy interventions in a dementia inpatient unit: reflections and practicalities.

There is a growing evidence base to suggest that music therapy is an effective clinical intervention for people with dementia, having positive effects on mood, emotion, communication and memory, and reducing agitation, anxiety and apathy. However, the evidence to support this is predominantly from community settings such as residential care homes or people's own homes. This article captures the authors' experiences and reflections regarding their implementation of a music therapy intervention in a dementia inpatient unit. It explores some of the considerations and learning points gained from their experience, including the practicalities around engaging individuals and staff, the use of space, the timing of sessions, available resources and the potential benefits for patients, family members and the unit as a whole. The authors' experiences suggest that the benefits of music therapy appear to be transferable to the dementia inpatient setting.

Providing music therapy for people with dementia in an acute mental health setting.

As global figures for dementia are set to rise significantly, there has been a shift towards using non-pharmacological interventions such as music therapy to enhance the quality of life for people with the condition. Research into music therapy interventions for this patient group in acute mental health inpatient settings, however, is limited. This article describes a service evaluation that explored whether group music therapy was effective for people with dementia in such settings. Open group music therapy sessions were hosted weekly in two acute wards and the researchers examined the social and behavioural outcomes of participants pre and post-intervention. The results indicated that music therapy significantly improved patient outcomes following participation. The outcome measure developed for this service evaluation was found to be a reliable tool for measuring the effectiveness of music therapy on patient outcomes.

Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial.

AIMS: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial. METHODS: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. RESULTS: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow-up interval of the study (log-rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05-1.92, P = 0.021). CONCLUSIONS: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

Radiation Dose Escalation or Longer Androgen Suppression to Prevent Distant Progression in Men With Locally Advanced Prostate Cancer: 10-Year Data From the TROG 03.04 RADAR Trial.

PURPOSE: To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer. METHODS AND MATERIALS: Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS ± 18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group. RESULTS: A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P = .002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P = .76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P < .0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups. CONCLUSIONS: Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial.

BACKGROUND: The optimal duration of androgen suppression for men with locally advanced prostate cancer receiving radiotherapy with curative intent is yet to be defined. Zoledronic acid is effective in preventing androgen suppression-induced bone loss, but its role in preventing castration-sensitive bone metastases in locally advanced prostate cancer is unclear. The RADAR trial assessed whether the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive 6 months of androgen suppression and prostatic radiotherapy. This report presents 10-year outcomes from this trial. METHODS: For this randomised, phase 3, 2 × 2 factorial trial, eligible men were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 µg/L). We randomly allocated participants in a 2 × 2 factorial design by computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost) in a 1:1:1:1 ratio to four treatment groups. Patients in the control group received 6 months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid). All patients received radiotherapy to the prostate and seminal vesicles, starting from the end of the fifth month of androgen suppression; dosing options were 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions. Treatment allocation was open label. The primary endpoint was prostate cancer-specific mortality and was analysed according to intention-to-treat using competing-risks methods. The trial is closed to follow-up and this is the final report of the main endpoints. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 10·4 years (IQR 7·9-11·7). At this 10-year follow-up, no interactions were observed between androgen suppression and zoledronic acid so the treatment groups were collapsed to compare treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) versus 18 months of androgen suppression plus radiotherapy (18AS+RT) and to compare treatments according to whether or not patients received zoledronic acid. The total number of deaths was 375 (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were attributable to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT). When analysed by duration of androgen suppression, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3-16·0) for 6AS+RT versus 9·7% (7·3-12·0) for 18AS+RT, representing an absolute difference of 3·7% (95% CI 0·3-7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50-0·98], adjusted p=0·035). The addition of zoledronic acid did not affect prostate cancer-specific mortality; the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7-13·7) with zoledronic acid vs 11·7% (9·2-14·1) without, representing an absolute difference of -0·5% (95% CI -3·8 to 2·9; sHR 0·95 [95% CI 0·69-1·32], adjusted p=0·78). Although safety analysis was not prespecified for this 10-year analysis, one new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) occurred since our previous report, bringing the total number of cases of this serious adverse event to three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events to 12 (1% out of all 1065 patients evaluable for safety). No treatment-related deaths occurred during the study. INTERPRETATION: 18 months of androgen suppression plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than 6 months of androgen suppression plus radiotherapy, but the addition of zoledronic acid to this treatment regimen is not beneficial. Evidence from the RADAR and French Canadian Prostate Cancer Study IV trials suggests that 18 months of androgen suppression with moderate radiation dose escalation is an effective but more tolerable option than longer durations of androgen suppression for men with locally advanced prostate cancer including intermediate and high risk elements. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, AbbVie Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, Cancer Standards Institute New Zealand, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Newcastle Radiation Oncology Fund, and Maitland Cancer Appeal.

Oligometastatic bone disease in prostate cancer patients treated on the TROG 03.04 RADAR trial.

BACKGROUND: It remains unclear whether eradication of oligometastases by stereotactic body radiation therapy or other means will result in cure or prolongation of survival in some cases, or merely provide palliation. We address this issue with prospectively collected progression and treatment data from the TROG 03.04 RADAR randomised controlled trial for men with locally advanced prostate cancer (PC). METHODS: Three Fine and Gray competing risk survival models with time-dependent covariates were used to determine whether metastatic progression status at first diagnosis of bony metastases, i.e. number of bony sites involved and presence of prior or simultaneous other sites of progression, impacts on prostate cancer-specific mortality (PCSM) when adjusted for baseline prognostic factors and allocated primary treatment. RESULTS: Between 2003 and 2014, 176 of the 1071 subjects developed bone metastases, 152 developed other sites of progression and 91 died of PC. All subjects received secondary treatment using androgen suppression but none received extirpative treatments. The three models found evidence: 1 - of a clear prognostic gradient according to number of bony metastatic sites; 2 - that other sites of progression contributed to PCSM to a lesser extent than bone progression; and 3 - that further bony metastatic progression in men with up to 3 bony metastases had a major impact on PCSM. CONCLUSION: Randomised trials are essential to determine the value of extirpative treatment for oligometastatic bony metastases due to PC.

Imaging Idiopathic Chylopericardium With 99mTc-SC Lymphoscintigraphy and SPECT/CT.

A 27-year-old asymptomatic active duty military man underwent a screening chest x-ray secondary to a history of tuberculosis exposure. His chest x-ray showed no features of tuberculosis infection but unexpectedly revealed a markedly enlarged cardiac silhouette. Echocardiography demonstrated a large pericardial effusion without tamponade physiology. Pericardiocentesis revealed chylous fluid. The effusion was initially refractory to drainage requiring VATS for therapy. Lymphoscintigraphy was performed using Tc-SC to evaluate lymphatic anatomy and confirm communication with the pericardial space. Novel use was made of SPECT/CT with the hope of better assessing the nature of the abnormal communication and potentially helping guide management.

Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

BACKGROUND: The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. METHODS: We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. RESULTS: Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p<0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. CONCLUSION: RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration.

Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): an open-label, randomised, phase 3 factorial trial.

BACKGROUND: We investigated whether 18 months of androgen suppression plus radiotherapy, with or without 18 months of zoledronic acid, is more effective than 6 months of neoadjuvant androgen suppression plus radiotherapy with or without zoledronic acid. METHODS: We did an open-label, randomised, 2 × 2 factorial trial in men with locally advanced prostate cancer (either T2a N0 M0 prostatic adenocarcinomas with prostate-specific antigen [PSA] ≥10 µg/L and a Gleason score of ≥7, or T2b-4 N0 M0 tumours regardless of PSA and Gleason score). We randomly allocated patients by computer-generated minimisation--stratified by centre, baseline PSA, tumour stage, Gleason score, and use of a brachytherapy boost--to one of four groups in a 1:1:1:1 ratio. Patients in the control group were treated with neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) for 6 months (short-term) and radiotherapy alone (designated STAS); this procedure was either followed by another 12 months of androgen suppression with leuprorelin (intermediate-term; ITAS) or accompanied by 18 months of zoledronic acid (4 mg every 3 months for 18 months, intravenously; STAS plus zoledronic acid) or by both (ITAS plus zoledronic acid). The primary endpoint was prostate cancer-specific mortality. This analysis represents the first, preplanned assessment of oncological endpoints, 5 years after treatment. Analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: Between Oct 20, 2003, and Aug 15, 2007, 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). Median follow-up was 7·4 years (IQR 6·5-8·4). Cumulative incidences of prostate cancer-specific mortality were 4·1% (95% CI 2·2-7·0) in the STAS group, 7·8% (4·9-11·5) in the STAS plus zoledronic acid group, 7·4% (4·6-11·0) in the ITAS group, and 4·3% (2·3-7·3) in the ITAS plus zoledronic acid group. Cumulative incidence of all-cause mortality was 17·0% (13·0-22·1), 18·9% (14·6-24·2), 19·4% (15·0-24·7), and 13·9% (10·3-18·8), respectively. Neither prostate cancer-specific mortality nor all-cause mortality differed between control and experimental groups. Cumulative incidence of PSA progression was 34·2% (28·6-39·9) in the STAS group, 39·6% (33·6-45·5) in the STAS plus zoledronic acid group, 29·2% (23·8-34·8) in the ITAS group, and 26·0% (20·8-31·4) in the ITAS plus zoledronic acid group. Compared with STAS, no difference was noted in PSA progression with ITAS or STAS plus zoledronic acid; however, ITAS plus zoledronic acid reduced PSA progression (sub-hazard ratio [SHR] 0·71, 95% CI 0·53-0·95; p=0·021). Cumulative incidence of local progression was 4·1% (2·2-7·0) in the STAS group, 6·1% (3·7-9·5) in the STAS plus zoledronic acid group, 1·5% (0·5-3·7) in the ITAS group, and 3·4% (1·7-6·1) in the ITAS plus zoledronic acid group; no differences were noted between groups. Cumulative incidences of bone progression were 7·5% (4·8-11·1), 14·6% (10·6-19·2), 8·4% (5·5-12·2), and 7·6% (4·8-11·2), respectively. Compared with STAS, STAS plus zoledronic acid increased the risk of bone progression (SHR 1·90, 95% CI 1·14-3·17; p=0·012), but no differences were noted with the other two groups. Cumulative incidence of distant progression was 14·7% (10·7-19·2) in the STAS group, 17·3% (13·0-22·1) in the STAS plus zoledronic acid group, 14·2% (10·3-18·7) in the ITAS group, and 11·1% (7·6-15·2) in the ITAS plus zoledronic acid group; no differences were recorded between groups. Cumulative incidence of secondary therapeutic intervention was 25·6% (20·5-30·9), 28·9% (23·5-34·5), 20·7% (16·1-25·9), and 15·3% (11·3-20·0), respectively. Compared with STAS, ITAS plus zoledronic acid reduced the need for secondary therapeutic intervention (SHR 0·67, 95% CI 0·48-0·95; p=0·024); no differences were noted with the other two groups. An interaction between trial factors was recorded for Gleason score; therefore, we did pairwise comparisons between all groups. Post-hoc analyses suggested that the reductions in PSA progression and decreased need for secondary therapeutic intervention with ITAS plus zoledronic acid were restricted to tumours with a Gleason score of 8-10, and that ITAS was better than STAS in tumours with a Gleason score of 7 or lower. Long-term morbidity and quality-of-life scores were not affected adversely by 18 months of androgen suppression or zoledronic acid. INTERPRETATION: Compared with STAS, ITAS plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and ITAS alone was effective for tumours with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long- term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score. STAS plus zoledronic acid can be ruled out as a potential therapeutic option. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care (Calvary Mater Newcastle Radiation Oncology Fund), Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand.

Impact of androgen suppression and zoledronic acid on bone mineral density and fractures in the Trans-Tasman Radiation Oncology Group (TROG) 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) randomized controlled trial for locally advanced prostate cancer.

OBJECTIVE: To study the influence of adjuvant androgen suppression and bisphosphonates on incident vertebral and non-spinal fracture rates and bone mineral density (BMD) in men with locally advanced prostate cancer. PATIENTS AND METHODS: Between 2003 and 2007, 1071 men with locally advanced prostate cancer were randomly allocated, using a 2 × 2 trial design, to 6 months i.m. leuprorelin (androgen suppression [AS]) before radiotherapy alone ± 12 months additional leuprorelin ± 18 months zoledronic acid (ZdA), commencing at randomization. The main endpoint was incident thoraco-lumbar vertebral fractures, which were assessed radiographically at randomization and at 3 years, then reassessed by centralized review. Subsidiary endpoints included incident non-spinal fractures, which were documented throughout follow-up, and BMD, which was measured in 222 subjects at baseline, 2 years and 4 years. RESULTS: Incident vertebral fractures at 3 years were observed in 132 subjects. Their occurrence was not increased by 18 months' AS, nor reduced by ZdA. Incident non-spinal fractures occurred in 72 subjects and were significantly related to AS duration but not to ZdA. Osteopenia and osteoporosis prevalence rates at baseline were 23.4 and 1.4%, respectively, at the hip. Treatment for 6 and 18 months with AS caused significant reductions in hip BMD at 2 and 4 years (P < 0.01) and ZdA prevented these losses at both time points. CONCLUSION: In an AS-naïve population, 18 months of ZdA treatment prevented the sustained BMD losses caused by 18 months of AS treatment; however, the study power was insufficient to show that AS duration or ZdA influenced vertebral fracture rates.

Paradoxical metastatic progression following 3 months of neo-adjuvant androgen suppression in the TROG 96.01 trial for men with locally advanced prostate cancer.

PURPOSE: In the TROG 96.01 trial 6 month neo-adjuvant androgen suppression (NAS) and radiotherapy (RT) for locally advanced prostate cancer prevented distant progressions (DPs) when compared to RT alone, but 3 months did not. We ask why? METHODS: Between 1996 and 2000, 802 men with T2-4 N0 M0 prostate cancers received RT alone (0 month NAS) to 66 Gy, 3 months or 6 months NAS before RT. Interval hazards and cumulative incidences of DP were compared using competing risks methodology. RESULTS: In the first 4 follow-up years 39, 40 and 26 DPs were diagnosed in subjects treated with 0, 3 and 6 month NAS, respectively. Compared with 0 month, significant reductions in PSA doubling time in subjects with DP occurred following 3 month NAS (p=0.01), but a significant reduction (p=0.01) and a near significant delay in DPs (p=0.06) occurred after 6 month NAS. Subsequently 25, 20 and 11 DPs occurred in the three trial arms. After early secondary therapy for PSA or local progression 34, 19 and 12 DPs were diagnosed after median delays of almost 4 years. CONCLUSIONS: The data are consistent with the failure of 3 month NAS to prevent the progression of sub-clinical metastatic deposits already present before treatment.

Quality of life in men with locally advanced prostate cancer treated with leuprorelin and radiotherapy with or without zoledronic acid (TROG 03.04 RADAR): secondary endpoints from a randomised phase 3 factorial trial.

BACKGROUND: Adjuvant androgen suppression and bisphosphonates with escalating doses of radiotherapy might improve efficacy outcomes in men with locally advanced prostate cancer. In this study, we investigated whether these treatments had a detrimental effect on patient-reported-outcome (PRO) scores. METHODS: We undertook a phase 3 trial with a 2×2 factorial design in 23 centres in Australia and New Zealand in men with non-metastatic adenocarcinoma of the prostate (stage T2b-4 or T2a, Gleason score ≥7, and baseline prostate-specific antigen concentration [PSA] ≥10 µg/L), and without previous lymph node or systemic metastases or comorbidities that could reduce life expectancy to less than 5 years. The men were randomly assigned in a 1:1:1:1 ratio to 6 months of neoadjuvant (short-term) androgen suppression (STAS) with leuprorelin (22·5 mg every 3 months, intramuscularly) or an additional 12 months (intermediate-term androgen suppression [ITAS]) of leuprorelin with or without 18 months of zoledronic acid (4 mg every 3 months, intravenously). Study drug administration commenced at randomisation after which radiotherapy started within the fifth month in all groups. Treatment allocation was open-label, and computer-generated randomisation, stratified by centre, baseline concentrations of PSA, clinical stage of the tumour, Gleason score, and use of a brachytherapy boost, was done by use of the minimisation technique. PRO scores were calculated from European Organization for Research and Treatment of Cancer quality-of-life and prostate-specific quality-of-life module questionnaires and compared with multiple regression models at baseline, and end of radiotherapy, and 18 months and 36 months according to group and radiation dose. The trial is ongoing and the primary endpoint, prostate-cancer-specific mortality, will be reported in 2014. This study is the final report of PRO scores (a secondary endpoint). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00193856. FINDINGS: 1071 men were randomly assigned to STAS (n=268), STAS plus zoledronic acid (n=268), ITAS (n=268), and ITAS plus zoledronic acid (n=267). At the end of radiotherapy, significant detrimental changes in PRO scores (p<0·01) occurred in all groups. There were no significant differences in global health status between groups at any timepoint. At 18 months, PROs that were significantly worse in the ITAS groups when compared with STAS were hormone-treatment-related symptoms (HTRS; STAS, 10·20 [95% CI 8·66-11·75]; ITAS, 17·36 [13·63-21·08], p<0·01; and ITAS plus zoledronic acid, 19·14 [15·43-22·85], p<0·01), sexual activity (STAS, 26·38 [23·50-29·27]; ITAS, 14·40 [7·44-21·36], p<0·01; and ITAS plus zoledronic acid, 16·34 [9·39-23·28], p<0·01), social function (STAS, 90·31 [87·89-92·73]; ITAS, 87·35 [81·52-93·18], p=0·09; and ITAS plus zoledronic acid, 83·66 [77·85-89·48], p<0·01), fatigue (STAS, 17·05 [14·58-19·51]; ITAS 24·52 [18·58-30·46], p<0·01; and ITAS plus zoledronic acid, 24·26 [18·33-30·18], p<0·01), and financial problems (STAS, 3·39 [1·29-5·48]; ITAS, 8·97 [3·92-14·02], p<0·01; and ITAS plus zoledronic acid, 8·92 [3·89-13·96], p<0·01). With the exception of HTRS, in which marginal differences remained, persisting significant differences disappeared by 36 months. Other factors associated with significant detrimental changes in PRO scores were a brachytherapy boost, incomplete testosterone and haemoglobin recoveries, age, and smoking. INTERPRETATION: Compared with 6 months of androgen suppression, 18 months of androgen suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. FUNDING: National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

Rectal and urinary dysfunction in the TROG 03.04 RADAR trial for locally advanced prostate cancer.

BACKGROUND: The RADAR trial determines whether adjuvant androgen suppression, bisphosphonates and radiation dose escalation for localised prostate cancer (PC) may improve oncologic outcomes. This study examines whether these measures increase rectal and urinary dysfunction and are secondary trial endpoints. METHODS: Using a 2×2 factorial trial design men with locally advanced PC were randomly allocated 6 months i.m. leuprorelin prior to radiotherapy either alone or followed by 12 months i.m. leuprorelin. These two groups received 18 months i.v. zoledronic acid (Z) commencing at randomisation or no further treatment. Radiotherapy dose was escalated in a regulated way using external beam techniques (EBRT) or by a high dose rate brachytherapy (HDRB) boost. Prevalence rates of rectal and urinary dysfunctional symptoms were compared at baseline, the end of RT, 18 and 36 months according to treatment arm, dose and technique using multiple regression models. RESULTS: Between 2003 and 2007, 1071 men were randomly allocated and eligible for inclusion in this study. No persistent differences in rectal or urinary dysfunction were attributable to treatment arm or to increasing EBRT dose. However following HDRB statistical increases (p<0.001) in urinary dysfunction were measured using the EORTC PR25 instrument at 18 and 36 months. CONCLUSION: Adjuvant androgen suppression, bisphosphonates and increasing EBRT dose did not increase rectal or urinary dysfunction in this trial. However dose escalation using HDRB increased urinary dysfunction.

Risk Stratification after Biochemical Failure following Curative Treatment of Locally Advanced Prostate Cancer: Data from the TROG 96.01 Trial.

Purpose. Survival following biochemical failure is highly variable. Using a randomized trial dataset, we sought to define a risk stratification scheme in men with locally advanced prostate cancer (LAPC). Methods. The TROG 96.01 trial randomized 802 men with LAPC to radiation ± neoadjuvant androgen suppression therapy (AST) between 1996 and 2000. Ten-year follow-up data was used to develop three-tier post-biochemical failure risk stratification schemes based on cutpoints of time to biochemical failure (TTBF) and PSA doubling time (PSADT). Schemes were evaluated in univariable, competing risk models for prostate cancer-specific mortality. The performance was assessed by c-indices and internally validated by the simple bootstrap method. Performance rankings were compared in sensitivity analyses using multivariable models and variations in PSADT calculation. Results. 485 men developed biochemical failure. c-indices ranged between 0.630 and 0.730. The most discriminatory scheme had a high risk category defined by PSADT < 4 months or TTBF < 1 year and low risk category by PSADT > 9 months or TTBF > 3 years. Conclusion. TTBF and PSADT can be combined to define risk stratification schemes after biochemical failure in men with LAPC treated with short-term AST and radiotherapy. External validation, particularly in long-term AST and radiotherapy datasets, is necessary.

Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial.

BACKGROUND: The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. METHODS: Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5-7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS: 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9-11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57-0·90; p=0·003) and local progression (0·49, 0·33-0·73; p=0·0005), and improved event-free survival (0·63, 0·52-0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46-0·72; p<0·0001) and local progression (0·45, 0·30-0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42-0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60-1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60-1·23; p=0·398), or all-cause mortality (0·84, 0·65-1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31-0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32-0·74; p=0·0008), and all-cause mortality (0·63, 0·48-0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. INTERPRETATION: 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. FUNDING: Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

A comparison of the prognostic value of early PSA test-based variables following external beam radiotherapy, with or without preceding androgen deprivation: analysis of data from the TROG 96.01 randomized trial.

PURPOSE: We sought to compare the prognostic value of early prostate-specific antigen (PSA) test-based variables for the 802 eligible patients treated in the Trans-Tasman Radiation Oncology Group 96.01 randomized trial. METHODS AND MATERIALS: Patients in this trial had T2b, T2c, T3, and T4 N0 prostate cancer and were randomized to 0, 3, or 6 months of neoadjuvant androgen deprivation therapy (NADT) prior to and during radiation treatment at 66 Gy to the prostate and seminal vesicles. The early PSA test-based variables evaluated were the pretreatment initial PSA (iPSA) value, PSA values at 2 and 4 months into NADT, the PSA nadir (nPSA) value after radiation in all patients, and PSA response signatures in men receiving radiation. Comparisons of endpoints were made using Cox models of local progression-free survival, distant failure-free survival, biochemical failure-free survival, and prostate cancer-specific survival. RESULTS: The nPSA value was a powerful predictor of all endpoints regardless of whether NADT was given before radiation. PSA response signatures also predicted all endpoints in men treated by radiation alone. iPSA and PSA results at 2 and 4 months into NADT predicted biochemical failure-free survival but not any of the clinical endpoints. nPSA values correlated with those of iPSA, Gleason grade, and T stage and were significantly higher in men receiving radiation alone than in those receiving NADT. CONCLUSIONS: The postradiation nPSA value is the strongest prognostic indicator of all early PSA-based variables. However, its use as a surrogate endpoint needs to take into account its dependence on pretreatment variables and treatment method.

The voice of experience: results from Cancer Control New Zealand's first national cancer care survey.

AIMS: The 2009 Cancer Care Survey aimed to gather information from patients about their experiences receiving outpatient cancer care. METHODS: In mid-2009, Cancer Control New Zealand sent an NRC+Picker postal survey to a stratified sample of 3251 eligible adults, who had received outpatient cancer care between October 2008 and March 2009. Eight cancer treatment facilities across New Zealand provided patient lists from which potential respondents were selected. RESULTS: The final response rate to the survey was 68%. Most of the patients surveyed responded very positively to questions related to specialist care coordination (91% positive response; 95%CI: 90-93), the level of privacy (87% positive response; 95%CI: 85-89), and the dignity and respect provided by healthcare professionals (86% positive response; 95%CI: 85-88). However, patients tended to be much less positive about the level of information they received on the effects of cancer treatment on their day-to-day life (responses ranging between 30% and 40% positive) and the level of emotional support provided (36% positive response; 95%CI: 33-39). Responses from different cancer services tended to follow similar patterns, although for twelve questions there was at least a 20% difference in response between services. CONCLUSIONS: Overall, patients rated their outpatient cancer care experiences as positive, but important gaps exist in the provision of information, emotional support, and treating patients within the context of their living situation. Cancer patient experience surveys can achieve high response rates and generate useful information on patient perceptions of their care. This data can be used to inform quality improvement efforts at both national and cancer treatment service levels.

Why are pretreatment prostate-specific antigen levels and biochemical recurrence poor predictors of prostate cancer survival?

BACKGROUND: The value of pretreatment (initial) prostate-specific antigen (iPSA) and biochemical recurrence (BR) as prognostic factors for survival remains unclear. The authors sought to determine why using randomized trial data with 7-year minimum follow-up. METHODS: In the Trans-Tasman Radiation Oncology Group 96.01 trial, 802 men with T2b, T2c, T3, or T4 N0 prostate cancer (PC) were randomized to radiotherapy alone or with 3 or 6 months neoadjuvant androgen deprivation between 1996 and 2000. Cox modeling was used to identify outcome predictors at follow-up landmark points. RESULTS: Higher iPSA was found to be a potent predictor of BR-free survival (P < .01) but was not prognostic for prostate cancer-specific survival (PCSS) from randomization. Patients experiencing BR had unfavorable initial prognostic factors compared with patients who did not. After BR, these factors were not prognostic for PC death in models adjusted for time to BR (TTBR). In these models, TTBR predicted PCSS more satisfactorily than the occurrence of BR itself. Survival probability 5 years after BR exceeded 90% for men with TTBR >/=4 years; however, it dropped to 44% +/- 6% for men with TTBR <1 year. After BR, rapid PSA doubling time (DT), low iPSA, and short TTBR were identified as the most important predictors of inferior PCSS. CONCLUSIONS: When BR occurs, prognostic factors for survival change. Low iPSA, short TTBR, and rapid PSA DT take over at this point, providing reasons why iPSA and occurrence of BR alone predict PCSS unsatisfactorily.