Building the plane while it's flying: implementation lessons from integrating a co-located exercise clinic into oncology care.

BACKGROUND: Despite its therapeutic role during cancer treatment, exercise is not routinely integrated into care and implementation efforts are largely absent from the literature. The aim of this study was to evaluate a strategy to integrate the workflow of a co-located exercise clinic into routine care within a private oncology setting in two clinics in the metropolitan region of Western Australia. METHODS: This prospective evaluation utilised a mixed methods approach to summarise lessons learned during the implementation of an integrated exercise workflow and supporting implementation plan. Data collection was informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Reports detailing utilisation of the exercise service and its referral pathways, as well as patient surveys and meeting minutes documenting the implementation process informed the evaluation. RESULTS: The co-located exercise service achieved integration into routine care within the clinical oncology setting. Patient utilisation was near capacity (reach) and 100% of clinicians referred to the service during the 13-month evaluation period (adoption). Moreover, ongoing adaptations were made to improve the program (implementation) and workflows were integrated into standard operating practices at the clinic (maintenance). The workflow performed as intended for ~70% of exercise participants (effectiveness); however, gaps were identified in utilisation of the workflow by both patients and clinicians. CONCLUSION: Integration of exercise into standard oncology care is possible, but it requires the ongoing commitment of multiple stakeholders across an organisation. The integrated workflow and supporting implementation plan greatly improved utilisation of the co-located exercise service, demonstrating the importance of targeted implementation planning. However, challenges regarding workflow fidelity within and across sites limited its success highlighting the complexities inherent in integrating exercise into clinical oncology care in a real-world setting.

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.

We have the program, what now? Development of an implementation plan to bridge the research-practice gap prevalent in exercise oncology.

BACKGROUND: Exercise has emerged as a promising therapy for people with cancer. Novel programs have been developed to translate research into practice; however, implementation barriers have limited their success in part because successful translation of exercise oncology research into practice requires context-specific implementation plans. The aim of this study was to employ the implementation mapping protocol to develop an implementation plan to support programming of a co-located exercise clinic and cancer treatment center. METHODS: The Implementation Mapping protocol, which consists of five specific iterative tasks, was used. A stakeholder advisory group advised throughout the process. RESULTS: A comprehensive needs assessment was used to identify the organization's general manager as the program adopter; oncologists, center leaders, and various administrative staff as program implementers; and the operations manager as the program maintainer. Twenty performance objectives were identified. The theoretical domains framework was used to identify likely determinants of change, which informed the selection of eight individual implementation strategies across the individual and organizational levels. Finally, an evaluation plan was developed which will be used to measure the success of the implementation plan in the project's next phase. CONCLUSION: The Implementation Mapping protocol provided a roadmap to guide development of a comprehensive implementation plan that considered all ecological domains, was informed by theory, and demonstrated an extensive understanding of the implementation context. Strong research-practitioner partnerships and effective stakeholder engagement were critical to development of the plan.

If you build it, will they come? Evaluation of a co-located exercise clinic and cancer treatment centre using the RE-AIM framework.

OBJECTIVE: Employ the Reach, Effectiveness, Adoption, Implementation, Maintenance framework to evaluate the effectiveness of a co-located exercise clinic model in increasing access to exercise for people undergoing cancer treatment in a private clinic in Western Australia. METHODS: This retrospective evaluation utilised a mixed-method approach to gather feedback from key stakeholder groups involved with the exercise clinic. Questionnaires and workout summary sheets were gathered from 237 exercise clinic participants over the 50-month evaluation period. These were supplemented by survey results from 119 patients who received cancer treatment at the facility, and semi-structured interviews from seven radiation oncologists, eight nurses, and three accredited exercise physiologists involved with the exercise clinic. RESULTS: The co-located clinic demonstrated positive outcomes related to effectiveness and adoption. Participant feedback indicated satisfaction with the exercise programming (effectiveness), and clinicians were receptive to referring patients to the clinic (adoption). However, no clear implementation or maintenance plan was employed and overall reach (12%) remained suboptimal throughout the evaluation period. CONCLUSION: Co-locating an exercise clinic into a treatment facility does not in itself overcome the logistical challenges of providing integrated exercise services to people during cancer treatment. To enhance its utilisation, an implementation plan needs to accompany the intervention.

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.

The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.

BACKGROUND: The current study examined effects, moderators (for whom), and mediators (working mechanisms) of 12 months of exercise on health-related quality of life (HRQoL) in older long-term survivors of prostate cancer. METHODS: In total, 100 men aged 71.7 years (standard deviation, 6.4 years) were randomly assigned to 6 months of supervised aerobic and resistance exercise followed by 6 months of a home-based exercise maintenance program (EX group) or printed education material regarding physical activity for 12 months (PA group). Assessments took place at baseline and after 6 and 12 months. Generalized estimating equations were used to study the effects of EX versus PA on HRQoL at 6 and 12 months, adjusting for baseline HRQoL. The authors examined potential sociodemographic and clinical moderators by adding interaction terms, and potential physical and psychological mediators using the product-of-coefficients test. RESULTS: At 6 months, significant beneficial effects were found for global QoL, physical function, and social function in the EX group compared with the PA group. For physical function, beneficial effects were sustained at 12 months. Moderation analyses demonstrated larger effects of EX versus PA for patients who were married, started exercising sooner after their diagnosis, and previously used bisphosphonates. Changes in lower body functional performance significantly mediated the effect of EX on global QoL, physical function, and social function. No mediating effects on HRQoL were found for aerobic fitness, physical activity, fatigue, distress, or falls self-efficacy. CONCLUSIONS: Aerobic and resistance exercise appears to have beneficial effects on HRQoL among older, long-term survivors of prostate cancer. Effects were moderated by marital status, time since diagnosis, and use of bisphosphonates, and were mediated by lower body functional performance.

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.

A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy -- Adjuvant Versus Early Salvage (RAVES) trial.

OBJECTIVES: To test the hypothesis that observation with early salvage radiotherapy (SRT) is not inferior to 'standard' treatment with adjuvant RT (ART) with respect to biochemical failure in patients with pT3 disease and/or positive surgical margins (SMs) after radical prostatectomy (RP). To compare the following secondary endpoints between the two arms: patient-reported outcomes, adverse events, biochemical failure-free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, cost utility analysis, quality adjusted life years and time to androgen deprivation. PATIENTS AND METHODS: The Radiotherapy - Adjuvant Versus Early Salvage (RAVES) trial is a phase III multicentre randomised controlled trial led by the Trans Tasman Radiation Oncology Group (TROG), in collaboration with the Urological Society of Australia and New Zealand (USANZ), and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). In all, 470 patients are planned to be randomised 1:1 to either ART commenced at ≤4 months of RP (standard of care) or close observation with early SRT triggered by a PSA level of >0.20 ng/mL (experimental arm). Eligible patients have had a RP for adenocarcinoma of the prostate with at least one of the following risk factors: positive SMs ± extraprostatic extension ± seminal vesicle involvement. The postoperative PSA level must be ≤0.10 ng/mL. Rigorous investigator credentialing and a quality assurance programme are designed to promote consistent RT delivery among patients. RESULTS: Trial is currently underway, with 258 patients randomised as of 31 October 2013. International collaborations have developed, including a planned meta-analysis to be undertaken with the UK Medical Research Council/National Cancer Institute of Canada Clinical Trials Group RADICALS (Radiotherapy and Androgen Deprivation In Combination with Local Surgery) trial and an innovative psycho-oncology sub-study to investigate a patient decision aid resource. CONCLUSION: On the current evidence available, it remains unclear if ART is equivalent or superior to observation with early SRT.

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.

Radiotherapy of abdomen with precise renal assessment with SPECT/CT imaging (RAPRASI): design and methodology of a prospective trial to improve the understanding of kidney radiation dose response.

BACKGROUND: The kidneys are a principal dose-limiting organ in radiotherapy for upper abdominal cancers. The current understanding of kidney radiation dose response is rudimentary. More precise dose-volume response models that allow direct correlation of delivered radiation dose with spatio-temporal changes in kidney function may improve radiotherapy treatment planning for upper-abdominal tumours. METHODS/DESIGN: The Radiotherapy of Abdomen with Precise Renal Assessment with SPECT/CT Imaging (RAPRASI) is an observational clinical research study with participating sites at Sir Charles Gairdner Hospital (SCGH) in Perth, Australia and the Peter MacCallum Cancer Centre (PMCC) in Melbourne, Australia. Eligible patients are those with upper gastrointestinal cancer, without metastatic disease, undergoing conformal radiotherapy that will involve incidental radiation to one or both kidneys. For each patient, total kidney function is being assessed before commencement of radiotherapy treatment and then at 4, 12, 26, 52 and 78 weeks after the first radiotherapy fraction, using two procedures: a Glomerular Filtration Rate (GFR) measurement using the 51Cr-ethylenediamine tetra-acetic acid (EDTA) clearance; and a regional kidney perfusion measurement assessing renal uptake of 99mTc-dimercaptosuccinic acid (DMSA), imaged with a Single Photon Emission Computed Tomography / Computed Tomography (SPECT/CT) system. The CT component of the SPECT/CT provides the anatomical reference of the kidney's position. The data is intended to reveal changes in regional kidney function over the study period after the radiotherapy. These SPECT/CT scans, co-registered with the radiotherapy treatment plan, will provide spatial correlation between the radiation dose and regional renal function as assessed by SPECT/CT. From this correlation, renal response patterns will likely be identified with the purpose of developing a predictive model. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000322235.

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.

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.

Implementation barriers to integrating exercise as medicine in oncology: an ecological scoping review.

PURPOSE: While calls have been made for exercise to become standard practice in oncology, barriers to implementation in real-world settings are not well described. This systematic scoping review aimed to comprehensively describe barriers impeding integration of exercise into routine oncology care within healthcare systems. METHODS: A systematic literature search was conducted across six electronic databases (since 2010) to identify barriers to implementing exercise into real-world settings. An ecological framework was used to classify barriers according to their respective level within the healthcare system. RESULTS: A total of 1,376 results were retrieved; 50 articles describing implementation barriers in real-world exercise oncology settings were reviewed. Two hundred and forty-three barriers were identified across all levels of the healthcare system. Nearly 40% of barriers existed at the organizational level (n = 93). Lack of structures to support exercise integration and absence of staff/resources to facilitate its delivery were the most common issues reported. Despite the frequency of barriers at the organizational level, organizational stakeholders were largely absent from the research. CONCLUSIONS: Implementing exercise into routine cancer care is hindered by a web of interrelated barriers across all levels of the healthcare system. Organizational barriers are central to most issues. Future work should take an interdisciplinary approach to explore best practices for overcoming implementation barriers, with organizations as a central focus. IMPLICATIONS FOR CANCER SURVIVORS: This blueprint of implementation barriers highlights critical issues that need to be overcome to ensure people with cancer have access to the therapeutic benefits of exercise during treatment and beyond.

Safety, Effectiveness, and Uptake of Exercise Medicine Integrated Within a Cancer Care Center.

OBJECTIVES: The aim of this study was to evaluate the safety, effectiveness, and acceptability of an exercise clinic co-located within a cancer treatment center to identify best practices for integrating exercise medicine into cancer care. DATA SOURCES: Two-hundred thirty-seven patients were referred to the exercise clinic and completed self-report health and demographic questionnaires. Further assessments were conducted at baseline on 67 patients and following completion of the exercise program by 46 patients. Endpoints included muscular strength, physical function, cardiorespiratory fitness, body composition, quality of life, and fatigue scores. Adverse events were tracked throughout exercise participation to evaluate program safety. CONCLUSION: Exercise programming co-located and aligned with cancer treatment in a real-world clinical setting appears to be safe with only four minor exercise-related adverse events. Effectiveness was demonstrated by all physical performance (2.9%-9.5%), strength (7.4%-27.6%), and balance (10.1%) improving and some patients reported outcomes exhibiting modest but clinically relevant benefit. Importantly, no outcomes including fatigue worsened even though the patients were undergoing radiation and/or chemotherapy. Assessment of patient physical and self-reported outcomes should be co-located where they receive oncological treatment and/or exercise medicine to increase uptake of this aspect of the service. Future work should incorporate and describe program and implementation design to help identify best practices in exercise oncology programming. IMPLICATIONS FOR NURSING PRACTICE: Nurses are a primary driver of exercise among patients receiving treatment for cancer. Their regular patient interactions offer a practical opportunity to collect and record important exercise-related information from patients. As organizations look to develop plans to implement exercise into standard practice, input from nurses is critical to ensure program feasibility.

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.

PSA response signatures - a powerful new prognostic indicator after radiation for prostate cancer?

BACKGROUND: We sought to determine whether inter-patient variations in pattern of PSA changes after radiation exist and, if so, are they prognostically significant. METHODS: In the Trans-Tasman Radiation Oncology Group (TROG) 96.01 randomized controlled trial, patients with T2b,c,3,4 N0 prostate cancer (PC) were randomised to 0, 3 or 6months maximal androgen deprivation prior to 66Gy to the prostate and seminal vesicles (XRT). Patterns of anatomical site of failure were one of the trial endpoints. Serial serum PSA's were mandated at all follow-up visits. Pattern recognition software was developed to characterize PSA response "signatures" (PRS) after therapy in individual patients. RESULTS: By 2000, 270 eligible patients were randomised to radiation alone. Individual patient PSA values were observed to descend after radiation according to one of two characteristic "signatures": single exponential (PRS Type 1), non-exponential (PRS Type 2). Compared to PRS Type 1, men with PRS Type 2 (50% of the group) had lower PSA nadir (nPSA) levels (p<.0001), longer doubling times on relapse (p=.006) and significantly lower rates of local (hazard ratio [HR]: 0.47, 95% confidence interval [0.30-0.75], p=.0014) and distant failure (HR: 0.25[0.13-0.46], p<.0001), death due to PC (HR: 0.20[0.10-0.42], p<.0001) and death due to any cause (HR: 0.37 [0.23-0.60], p<.0001). PRS retained its powerful prognostic significance in Cox models that incorporated all key pre-treatment covariates and nPSA. CONCLUSIONS: PRS reflect the presence of tumor phenotypes that vary substantially in their clinical behavior and response to XRT. Molecular characterization is now necessary.

Is there more than one proctitis syndrome? A revisitation using data from the TROG 96.01 trial.

PURPOSE: We sought to categorize longitudinal radiation-induced rectal toxicity data obtained from men participating in a randomised controlled trial for locally advanced prostate cancer. MATERIALS AND METHODS: Data from self-assessed questionnaires of rectal symptoms and clinician recorded remedial interventions were collected during the TROG 96.01 trial. In this trial, volunteers were randomised to radiation with or without neoadjuvant androgen deprivation. Characterization of longitudinal variations in symptom intensity was achieved using prevalence data. An integrated visualization and clustering approach based on memetic algorithms was used to define the compositions of symptom clusters occurring before, during and after radiation. The utility of the CTC grading system as a means of identifying specific injury profiles was evaluated using concordance analyses. RESULTS: Seven well-defined clusters of rectal symptoms were present prior to treatment, 25 were seen immediately following radiation and 7 at years 1, 2 and 3 following radiation. CTC grading did not concord with the degree of rectal 'distress' and 'problems' at all time points. Concordance was not improved by adding urgency to the CTC scale. CONCLUSIONS: The CTC scale has serious shortcomings. A powerful new technique for non-hierarchical clustering may contribute to the categorization of rectal toxicity data for genomic profiling studies and detailed patho-physiological studies.

Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study.

OBJECTIVE: To investigate changes in bone mineral density (BMD) and osteoporosis, over 3 years of intermittent androgen-suppression therapy (IAST). PATIENTS AND METHODS: This was a Phase II individual cohort study of 72 patients with prostate cancer without metastatic bone disease, enrolled between 1999 and 2002. Patients had 9 months flutamide (250 mg, three times daily) and leuprolide (22.5 mg, 3-monthly depot) after which, patients ceased therapy providing that their PSA levels were <4 ng/mL. AST re-commenced when the PSA level exceeded the pretreatment level or was >20 ng/mL. BMD for hip and spine was the primary endpoint; assessed at baseline; completion of initial treatment period; and at 1 and 2 years after initial treatment (POST period). RESULTS: Osteoporosis increased from 7% at baseline to 10% at 3 years. The BMD declined after 9 months treatment, at -1.9% and -3.3% at hip and spine, respectively (P < 0.001). Subsequent BMD decline in the POST period was attenuated; at 1 years and 2 years later, hip -0.6% (not significant), and -0.8% (P < 0.014), and spine +1.0% and +0.2% (not significant). The BMD change in those remaining 'off' therapy for 2 years (n = 20) was strongly associated with the level of testosterone recovery; a peak testosterone level of <5 nmol/L associated with a greater then normal physiological loss. Testosterone recovery was less likely in older men. CONCLUSION: The attenuation of spine and hip BMD decline after 3-year IAST compared with those reported for continuous AST appears to be due to testosterone driven BMD recovery in the POST period. Failure of testosterone recovery was associated with worse final BMD. By reducing the potential risk for adverse bone complications, intermittent therapy may become an important consideration when the therapeutic ratio is narrow.

Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trial.

BACKGROUND: Surrogate endpoints for prostate cancer-specific mortality after curative primary treatment are not well established. We sought to assess time to biochemical failure (TTBF) and prostate-specific antigen doubling time (PSADT) after failure of curative treatment as candidates for this endpoint. METHODS: PSA and survival data from the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial were used to assess surrogate candidates. Between June 28, 1996, and Feb 16, 2000, 802 eligible men with locally advanced prostate cancer were randomly allocated to prostatic irradiation alone, or to 3 or 6 months of maximum short-term androgen deprivation (STAD) before and during radiation. Successful surrogates were required to satisfy the Prentice criteria and to predict the trial finding. The TROG 96.01 trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. FINDINGS: 6 months of STAD was shown to significantly decrease prostate cancer-specific mortality compared with radiation alone, but 3 months of STAD did not result in a decrease. Relative to radiation alone, the hazard ratio of prostate cancer-specific mortality from randomisation was 0.95 (95% CI 0.63-1.41; p=0.79) in the 3-month STAD treatment arm and 0.56 (0.36-0.88; p=0.01) in the 6-month arm. PSADT predicted the trial finding and satisfied all four Prentice criteria at the cutpoints of less than 12 months and less than 15 months, with proportion of treatment effect ratios between 0.36 and 0.56. Time to biochemical failure was better than PSADT at predicting the trial finding and satisfying all four Prentice criteria at cutpoints of less than 1.5, less than 2, and less than 2.5 years, with proportion of treatment effect ratios between 0.45 and 0.64. INTERPRETATION: This study provides proof of principle that TTBF and PSADT can be useful as surrogate endpoints for prostate cancer-specific mortality and offer potential to substantially reduce follow up in clinical trials. These endpoints now require assessment in multi-trial meta-analyses before use in clinical trials.

Changes in muscle, fat and bone mass after 36 weeks of maximal androgen blockade for prostate cancer.

OBJECTIVE: To assess the effects of androgen deprivation therapy (ADT) on whole-body and regional muscle, fat and bone mass in men with prostate cancer without metastatic bone disease. PATIENTS AND METHODS: Seventy-two men aged 44-88 years underwent spine, hip and whole-body dual-energy X-ray absorptiometry scans at baseline and after 36 weeks of ADT. The change in whole-body and regional lean mass (LM), fat mass (FM), and bone mineral content and density (BMD) were determined. In addition, the prostate specific antigen (PSA), serum testosterone and haemoglobin levels were measured, and the level of physical activity and fatigue assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30. RESULTS: The upper limb, lower limb, trunk and whole-body LM decreased by a mean (sem) of 5.6 (0.6)%, 3.7 (0.5)%, 1.4 (0.5)% and 2.4 (0.4)% (P < 0.01), respectively, while FM increased by 20.7 (3.3)%, 18.7 (2.7)%, 12.0 (2.5)% and 13.8 (2.3)% (P < 0.001). Hip, spine, whole-body and upper limb BMD decreased by 1.9 [corrected] (0.3)% [corrected], 3.3 [corrected] (0.4)%, 1.6 [corrected] (0.3)% and 1.3 (0.3%) (P < 0.001), but not lower limb BMD. Serum testosterone, PSA and haemoglobin levels decreased by 93.3 (0.4)%, 98.2 (0.5)%, and 8.8 (0.9)% (P < 0.001), respectively. In addition, physical activity levels decreased and levels of fatigue increased. CONCLUSION: After 36 weeks of ADT there was a significant decrease in whole-body and regional LM and bone mass, while whole-body and regional FM increased in older men with prostate cancer. Strategies to counteract changes in soft tissue and bone mass during ADT should be formulated to minimize the risk of sarcopenia, osteoporosis and obesity.