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.

Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy. METHODS: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652. FINDINGS: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]). INTERPRETATION: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity. FUNDING: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia.

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.

Immediate versus delayed exercise in men initiating androgen deprivation: effects on bone density and soft tissue composition.

OBJECTIVES: To examine whether it is more efficacious to commence exercise medicine in men with prostate cancer at the onset of androgen-deprivation therapy (ADT) rather than later on during treatment to preserve bone and soft-tissue composition, as ADT results in adverse effects including: reduced bone mineral density (BMD), loss of muscle mass, and increased fat mass (FM). PATIENTS AND METHODS: In all, 104 patients with prostate cancer, aged 48-84 years initiating ADT, were randomised to immediate exercise (IMEX, n = 54) or delayed exercise (DEL, n = 50) conditions. The former consisted of 6 months of supervised resistance/aerobic/impact exercise and the latter comprised 6 months of usual care followed by 6 months of the identical exercise programme. Regional and whole body BMD, lean mass (LM), whole body FM and trunk FM, and appendicular skeletal muscle (ASM) were assessed by dual X-ray absorptiometry, and muscle density by peripheral quantitative computed tomography at baseline, and at 6 and 12 months. RESULTS: There was a significant time effect (P < 0.001) for whole body, spine and hip BMD with a progressive loss in the IMEX and DEL groups, although lumbar spine BMD was largely preserved in the IMEX group at 6 months compared with the DEL group (-0.4% vs -1.6%). LM, ASM, and muscle density were preserved in the IMEX group at 6 months, declined in the DEL group at 6 months (-1.4% to -2.5%) and then recovered at 12 months after training. FM and trunk FM increased (P < 0.001) over the 12-month period in the IMEX (7.8% and 4.5%, respectively) and DEL groups (6.5% and 4.3%, respectively). CONCLUSIONS: Commencing exercise at the onset of ADT preserves lumbar spine BMD, muscle mass, and muscle density. To avoid treatment-related adverse musculoskeletal effects, exercise medicine should be prescribed and commenced at the onset of ADT.

Responsiveness to Resistance-Based Multimodal Exercise Among Men With Prostate Cancer Receiving Androgen Deprivation Therapy.

BACKGROUND: Androgen deprivation therapy (ADT) in the management of prostate cancer (PCa) results in an array of adverse effects, and exercise is one strategy to counter treatment-related musculoskeletal toxicities. This study assessed the prevalence of exercise responsiveness in men with PCa undergoing ADT in terms of body composition, muscle strength, and physical function. METHODS: Prospective analyses were performed in 152 men (aged 43-90 years) with PCa receiving ADT who were engaged in resistance exercise combined with aerobic or impact training for 3 to 6 months. Whole-body lean mass and fat mass (FM), trunk FM, and appendicular skeletal muscle were assessed with dual x-ray absorptiometry; upper and lower body muscle strength were assessed with the one-repetition maximum; and physical function was assessed with a battery of tests (6-m usual, fast, and backward walk; 400-m walk; repeated chair rise; stair climb). RESULTS: Significant improvements were seen (P<.01) in lean mass (0.4±1.4 kg [range, -2.8 to +4.1 kg]), appendicular skeletal muscle (0.2±0.8 kg [range, -1.9 to +1.9 kg]), and all measures of muscle strength (chest press, 2.9±5.8 kg [range, -12.5 to +37.5 kg]; leg press, 29.2±27.6 kg [range, -50.0 to +140.0 kg]) and physical function (from -0.1±0.5 s [range, +1.3 to -2.1 s] for the 6-m walk; to -8.6±15.2 s [range, +25.2 to -69.7 s] for the 400-m walk). An increase in FM was also noted (0.6±1.8 kg [range, -3.6 to +7.3 kg]; P<.01). A total of 21 men did not exhibit a favorable response in at least one body composition component, 10 did not experience improved muscle strength, and 2 did not have improved physical function. However, all patients responded in at least one of the areas, and 120 (79%) favorably responded in all 3 areas. CONCLUSIONS: Despite considerable heterogeneity, most men with PCa receiving ADT responded to resistance-based multimodal exercise, and therefore our findings indicate that this form of exercise can be confidently prescribed to produce beneficial effects during active treatment.

Associations between sex, age and spiritual well-being scores on the EORTC QLQ-SWB32 for patients receiving palliative care for cancer: A further analysis of data from an international validation study.

OBJECTIVE: The EORTC QOL Group has recently completed the cross-cultural development and validation of a standalone measure of spiritual well-being (SWB) for cancer patients receiving palliative care: the EORTC QLQ-SWB32. The measure includes four scales: Relationships with Others, Relationship with Self, Relationship with Someone or Something Greater, and Existential, plus a Global-SWB item. This paper reports on further research investigating relationships between sex, age and SWB for patients receiving palliative care for cancer-adjusting for other socio-demographic, clinical and function variables, including WHO performance status and EORTC QLQ-C15-PAL emotional and physical function scores. METHODS: Cross-sectional data from the validation study were used, and chi-square, independent t tests, Mann-Whitney U tests and multiple regression analyses applied. RESULTS: The study included 451 participants with advanced and incurable cancer, from 14 countries. Adjusted analyses found better scores for female participants than males on three of the four EORTC QLQ-SWB32 subscales; Relationship with others, Relationship with Someone or Something Greater and Existential plus Global-SWB. Older age was positively associated with better Relationship with Self. CONCLUSION: The findings from our participants suggest that it might be beneficial if healthcare providers seeking to address patients' spiritual needs pay particular attention to male patients, younger patients and those with poor emotional functioning.

RT Prepare: a radiation therapist-delivered intervention reduces psychological distress in women with breast cancer referred for radiotherapy.

BACKGROUND: The aims of this study were to determine whether a radiation therapist-led patient education intervention (RT Prepare) reduced breasts cancer patients' psychological distress (primary endpoint); anxiety, depression and concerns about radiotherapy, and increased knowledge of radiotherapy and preparedness (secondary endpoints). Patient health system usage and costs were also assessed. METHODS: A multiple-baseline study across three sites. The RT Prepare intervention comprised two consultations with a radiation therapist: prior to treatment planning and on the first day of treatment. Radiation therapists focused on providing sensory and procedural information and addressing patients' pre-treatment anxiety. Usual care data were collected prior to intervention commencement. Data collection occurred: after meeting their radiation oncologist, prior to treatment planning, first day of treatment and after treatment completion. Multilevel mixed effects regression models were used. RESULTS: In total, 218 usual care and 190 intervention patients participated. Compared with usual care, intervention participants reported lower psychological distress at treatment commencement (p = 0.01); lower concerns about radiotherapy (p < 0.01); higher patient knowledge (p < 0.001); higher preparedness for procedural concerns (p < 0.001) and higher preparedness for sensory-psychological concerns at treatment planning (p < 0.001). Mean within-trial costs per patient were estimated at $AU159 (US$120); mean ongoing costs at $AU35 (US$26). CONCLUSION: The RT Prepare intervention was effective in reducing breast cancer patients' psychological distress and preparing patients for treatment. This intervention provides an opportunity for radiation therapists to extend their role into providing patients with information and support prior to treatment to reduce psychological distress.

Time on androgen deprivation therapy and adaptations to exercise: secondary analysis from a 12-month randomized controlled trial in men with prostate cancer.

OBJECTIVES: To explore if duration of previous exposure to androgen deprivation therapy (ADT) in men with prostate cancer (PCa) undertaking a year-long exercise programme moderates the exercise response with regard to body composition and muscle performance, and also to explore the moderator effects of baseline testosterone, time since ADT, and baseline value of the outcome. PATIENTS AND METHODS: In a multicentre randomized controlled trial, 100 men who had previously undergone either 6 months (short-term) or 18 months (long-term) of ADT in combination with radiotherapy, as part of the TROG 03.04 RADAR trial, were randomized to 6 months supervised exercise, followed by a 6-month home-based maintenance programme, or to printed physical activity educational material for 12 months across 13 university-affiliated exercise clinics in Australia and New Zealand. The participants were long-term survivors of PCa with a mean age of 71.7 ± 6.4 years, and were assessed for lower extremity performance (repeated chair rise), with a subset of men (n = 57) undergoing additional measures for upper and lower body muscle strength and body composition (lean mass, fat mass, appendicular skeletal muscle [ASM]) by dual X-ray absorptiometry. Data were analysed using generalized estimating equations. RESULTS: Time on ADT significantly moderated the exercise effects on chair rise (ßinteraction = -1.3 s, 95% confidence interval [CI] -2.6 to 0.0), whole-body lean mass (ßinteraction = 1194 g, 95% CI 234 to 2153) and ASM mass (ßinteraction = 562 g, 95% CI 49 to 1075), and approached significance for fat mass (ßinteraction = -1107 g, 95% CI -2346 to 132), with greater benefits for men previously on long-term ADT. At 6 months, the intervention effects on chair rise time -1.5 s (95% CI -2.5 to -0.5), whole-body lean mass 824 g (95% CI 8 to 1640), ASM mass 709 g (95% CI 260 to 1158), and fat mass -1377 g (95% CI -2156 to -598) were significant for men previously on long-term ADT, but not for men on short-term ADT. At 12 months, the intervention effects for men on long-term ADT remained significant for the chair rise, with improved performance (-2.0 s, 95% CI -3.0 to -1.0) and increased ASM (537 g, 95% CI 153 to 921). Time on ADT did not moderate the exercise effects on muscle strength, nor did time since ADT cessation moderate any intervention effects. Similarly, testosterone and baseline values of the outcome had negligible moderator effects. CONCLUSIONS: Men with PCa previously treated long-term with ADT respond more favourably to exercise in terms of lower body muscle performance and body composition (lean and fat mass, and ASM) than those with short-term ADT exposure. As a result, men who were formerly on long-term androgen suppression regimens should be especially prescribed exercise medicine interventions to alleviate residual treatment-related adverse effects.

Body composition, fatigue and exercise in patients with prostate cancer undergoing androgen-deprivation therapy.

OBJECTIVES: To investigate the association between lean mass (LM) and fat mass (FM) with fatigue and vitality before and after exercise in patients with prostate cancer already undergoing androgen-deprivation therapy (ADT). SUBJECTS AND METHODS: Cross-sectional associations between LM and FM with fatigue and/or vitality measures were examined in 229 patients (aged 43-90 years). Prospective analysis was undertaken in 129 patients who underwent a supervised 3-6 months exercise programme (predominantly resistance + aerobic). Whole body and appendicular LM, and total and trunk FM were assessed by dual X-ray absorptiometry. Fatigue was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-30) and vitality using the Short Form-36. RESULTS: Based on the EORTC QLQ-30, 19% of patients had clinically relevant fatigue. There was no association between LM and fatigue; however, total (P = 0.013), trunk (P = 0.015) and percentage (P = 0.008) FM were higher in fatigued than not fatigued patients, with total and trunk FM 5.0 and 2.6 kg higher, respectively. For quartiles of vitality, a similar pattern emerged for FM with those in the lowest quartile of vitality having the highest FM values (P = 0.014-0.034). In contrast, following supervised exercise, change in fatigue and vitality were associated with change in total LM (r = -0.182, P = 0.042 and r = 0.309, P = 0.001, respectively) but not FM. Patients fatigued at baseline but not fatigued following the exercise programme gained a median (interquartile range) of 2.1 (0.7-3.2) kg LM. CONCLUSION: In patients with prostate cancer treated with ADT, body composition is associated with fatigue, with higher total and trunk FM in those with clinically relevant fatigue. However, following exercise those no longer fatigued had an accompanying substantial increase in LM. Modifying body composition, both LM and FM, in patients with prostate cancer may favourably alter cancer-related fatigue levels and should be a target of exercise medicine in this population.

Implementing exercise in cancer care: study protocol to evaluate a community-based exercise program for people with cancer.

BACKGROUND: Clinical research has established the efficacy of exercise in reducing treatment-related side-effects and increasing wellbeing in people with cancer. Major oncology organisations have identified the importance of incorporating exercise in comprehensive cancer care but information regarding effective approaches to translating evidence into practice is lacking. This paper describes the implementation of a community-based exercise program for people with cancer and the protocol for program evaluation. METHODS/DESIGN: The Life Now Exercise program is a community-based exercise intervention designed to mitigate and rehabilitate the adverse effects of cancer and its treatment and improve physical and psychosocial wellbeing in people with cancer. Involvement in the program is open to people with any diagnosis of cancer who are currently receiving treatment or within 2 years of completing treatment. The 3-month intervention consists of twice weekly group-based exercise sessions administered in community exercise clinics under the supervision of exercise physiologists trained to deliver the program. Evaluation of the program involves measures of uptake, safety, adherence and effectiveness (including cost effectiveness) as assessed at the completion of the program and 6 months follow-up. DISCUSSION: To bridge the gap between research and practice, the Life Now Exercise program was designed and implemented to provide people with cancer access to evidence-based exercise medicine. The framework for program implementation and evaluation offers insight into the development of feasible, generalizable and sustainable supportive care services involving exercise. Community-based exercise programs specifically designed for people with cancer are necessary to facilitate adherence to international guidelines advising patients to participate in high-quality exercise. TRIAL REGISTRATION: ACTRN12616001669482 (retrospectively registered 5 Dec 2016).

Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

BACKGROUND: Androgen-deprivation therapy is offered to men with prostate cancer who have a rising prostate-specific antigen after curative therapy (PSA relapse) or who are considered not suitable for curative treatment; however, the optimal timing for its introduction is uncertain. We aimed to assess whether immediate androgen-deprivation therapy improves overall survival compared with delayed therapy. METHODS: In this randomised, multicentre, phase 3, non-blinded trial, we recruited men through 29 oncology centres in Australia, New Zealand, and Canada. Men with prostate cancer were eligible if they had a PSA relapse after previous attempted curative therapy (radiotherapy or surgery, with or without postoperative radiotherapy) or if they were not considered suitable for curative treatment (because of age, comorbidity, or locally advanced disease). We used a database-embedded, dynamically balanced, randomisation algorithm, coordinated by the Cancer Council Victoria, to randomly assign participants (1:1) to immediate androgen-deprivation therapy (immediate therapy arm) or to delayed androgen-deprivation therapy (delayed therapy arm) with a recommended interval of at least 2 years unless clinically contraindicated. Randomisation for participants with PSA relapse was stratified by type of previous therapy, relapse-free interval, and PSA doubling time; randomisation for those with non-curative disease was stratified by metastatic status; and randomisation in both groups was stratified by planned treatment schedule (continuous or intermittent) and treatment centre. Clinicians could prescribe any form and schedule of androgen-deprivation therapy and group assignment was not masked. The primary outcome was overall survival in the intention-to-treat population. The trial closed to accrual in 2012 after review by the independent data monitoring committee, but data collection continued for 18 months until Feb 26, 2014. It is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12606000301561) and ClinicalTrials.gov (NCT00110162). FINDINGS: Between Sept 3, 2004, and July 13, 2012, we recruited 293 men (261 with PSA relapse and 32 with non-curable disease). We randomly assigned 142 men to the immediate therapy arm and 151 to the delayed therapy arm. Median follow-up was 5 years (IQR 3·3-6·2) from the date of randomisation. 16 (11%) men died in the immediate therapy arm and 30 (20%) died in the delayed therapy arm. 5-year overall survival was 86·4% (95% CI 78·5-91·5) in the delayed therapy arm versus 91·2% (84·2-95·2) in the immediate therapy arm (log-rank p=0·047). After Cox regression, the unadjusted HR for overall survival for immediate versus delayed arm assignment was 0·55 (95% CI 0·30-1·00; p=0·050). 23 patients had grade 3 treatment-related adverse events. 105 (36%) men had adverse events requiring hospital admission; none of these events were attributable to treatment or differed between treatment-timing groups. The most common serious adverse events were cardiovascular, which occurred in nine (6%) patients in the delayed therapy arm and 13 (9%) in the immediate therapy arm. INTERPRETATION: Immediate receipt of androgen-deprivation therapy significantly improved overall survival compared with delayed intervention in men with PSA-relapsed or non-curable prostate cancer. The results provide benchmark evidence of survival rates and morbidity to discuss with men when considering their treatment options. FUNDING: Australian National Health and Medical Research Council and Cancer Councils, The Royal Australian and New Zealand College of Radiologists, Mayne Pharma Australia.

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.

Can supervised exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: a randomised controlled trial.

OBJECTIVE: To determine if supervised exercise minimises treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy (ADT). This is the first study to date that has investigated the potential role of exercise in preventing ADT toxicity rather than recovering from established toxicities. PATIENTS AND METHODS: Sixty-three men scheduled to receive ADT were randomly assigned to a 3-month supervised exercise programme involving aerobic and resistance exercise sessions commenced within 10 days of their first ADT injection (32 men) or usual care (31 men). The primary outcome was body composition (lean and fat mass). Other study outcomes included bone mineral density, physical function, blood biomarkers of chronic disease risk and bone turnover, general and prostate cancer-specific quality of life, fatigue and psychological distress. Outcomes were compared between groups using analysis of covariance adjusted for baseline values. RESULTS: Compared to usual care, a 3-month exercise programme preserved appendicular lean mass (P = 0.019) and prevented gains in whole body fat mass, trunk fat mass and percentage fat with group differences of -1.4 kg (P = 0.001), -0.9 kg (P = 0.008) and -1.3% (P < 0.001), respectively. Significant between-group differences were also seen favouring the exercise group for cardiovascular fitness (peak oxygen consumption 1.1 mL/kg/min, P = 0.004), muscular strength (4.0-25.9 kg, P ≤ 0.026), lower body function (-1.1 s, P < 0.001), total cholesterol: high-density lipoprotein-cholesterol ratio (-0.52, P = 0.028), sexual function (15.2, P = 0.028), fatigue (3.1, P = 0.042), psychological distress (-2.2, P = 0.045), social functioning (3.8, P = 0.015) and mental health (3.6-3.8, P ≤ 0.022). There were no significant group differences for any other outcomes. CONCLUSION: Commencing a supervised exercise programme involving aerobic and resistance exercise when initiating ADT significantly reduced treatment toxicity, while improving social functioning and mental health. Concurrent prescription of supervised exercise when initiating ADT is therefore advised to minimise morbidity associated with severe hypogonadism.

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.

Mediators of the resistance and aerobic exercise intervention effect on physical and general health in men undergoing androgen deprivation therapy for prostate cancer.

BACKGROUND: The objective of the current study was to identify mediators of the effects of a combined resistance and aerobic exercise program on perceived physical and general health in men undergoing androgen deprivation therapy for prostate cancer. METHODS: In total, 57 patients with prostate cancer undergoing androgen deprivation therapy were randomly assigned to 12 weeks of resistance and aerobic exercise or usual care. The outcome measures of physical and general health were assessed by standardized questionnaires. Linear regression analyses were conducted on the residual change scores of the variables. The mediating effects of fatigue, muscle strength, and functional performance on the intervention's effect on physical and general health were examined using the product of coefficients method. Bootstrapping was used to calculate the 95% confidence intervals (95% CIs). RESULTS: The exercise intervention was found to significantly improve physical (beta, 5.03; 95% CI, 1.01-9.04) and general health (beta, 12.89; 95% CI, 2.24-23.54). Upper body muscle strength and walking speed significantly mediated the intervention effect on physical health (beta, 2.65; 95% CI, 0.64-5.54), accounting for 53% of the total effect. Walking speed and fatigue were found to be mediators in the intervention effect on general health (beta, 7.52; 95% CI, 2.16-16.92), accounting for 51% of the total effect. CONCLUSIONS: The intervention effects on physical and general health were explained by different mediating mechanisms. Walking speed mediated the intervention effect on both physical and general health. The intervention effect on physical health was further mediated by upper body strength, whereas the effect on general health was mediated by fatigue.

Improving sexual health in men with prostate cancer: randomised controlled trial of exercise and psychosexual therapies.

BACKGROUND: Despite being a critical survivorship care issue, there is a clear gap in current knowledge of the optimal treatment of sexual dysfunction in men with prostate cancer. There is sound theoretical rationale and emerging evidence that exercise may be an innovative therapy to counteract sexual dysfunction in men with prostate cancer. Furthermore, despite the multidimensional aetiology of sexual dysfunction, there is a paucity of research investigating the efficacy of integrated treatment models. Therefore, the purpose of this study is to: 1) examine the efficacy of exercise as a therapy to aid in the management of sexual dysfunction in men with prostate cancer; 2) determine if combining exercise and brief psychosexual intervention results in more pronounced improvements in sexual health; and 3) assess if any benefit of exercise and psychosexual intervention on sexual dysfunction is sustained long term. METHODS/DESIGN: A three-arm, multi-site randomised controlled trial involving 240 prostate cancer survivors will be implemented. Participants will be randomised to: 1) 'Exercise' intervention; 2) 'Exercise + Psychosexual' intervention; or 3) 'Usual Care'. The Exercise group will receive a 6-month, group based, supervised resistance and aerobic exercise intervention. The Exercise + Psychosexual group will receive the same exercise intervention plus a brief psychosexual self-management intervention that addresses psychological and sexual well-being. The Usual Care group will maintain standard care for 6 months. Measurements for primary and secondary endpoints will take place at baseline, 6 months (post-intervention) and 1 year follow-up. The primary endpoint is sexual health and secondary endpoints include key factors associated with sexual health in men with prostate cancer. DISCUSSION: Sexual dysfunction is one of the most prevalent and distressing consequences of prostate cancer. Despite this, very little is known about the management of sexual dysfunction and current health care services do not adequately meet sexual health needs of survivors. This project will examine the potential role of exercise in the management of sexual dysfunction and evaluate a potential best-practice management approach by integrating pharmacological, physiological and psychological treatment modalities to address the complex and multifaceted aetiology of sexual dysfunction following cancer. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613001179729.