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Anthony V Damico - One of the best experts on this subject based on the ideXlab platform.

  • the likelihood of death from prostate cancer in men with favorable or unfavorable intermediate risk disease
    Journal of Clinical Oncology, 2014
    Co-Authors: Florence K Keane, Minghui Chen, P Kantoff, Andrew A Renshaw, Marian Loffredo, Danjie Zhang, Anthony V Damico
    Abstract:

    42 Background: Recently men with intermediate-risk prostate cancer (PC) were classified into favorable and unfavorable categories but whether the risk of PC-specific mortality (PCSM) amongst men with high-risk PC is higher compared to men with unfavorable intermediate-risk PC is unknown. Methods: In a prospective randomized trial conducted between 1995 and 2001, 206 men with intermediate or high-risk PC were randomized to 70 Gy with or without six months of Androgen Suppression therapy (AST). The subgroup of 197 patients with available information on percent positive biopsies formed the study cohort. Fine and Gray’s regression was used to assess whether men with high-risk PC had a significantly higher risk of PCSM compared to men with unfavorable intermediate-risk PC, adjusting for age, treatment, and comorbidity category. Results: After a median follow-up of 14.3 years there were 127 deaths (64.5%), of which 22 (17.3%) were from PC. There were no PC deaths in the favorable intermediate-risk group. There ...

  • hormonal therapy or external beam radiation with brachytherapy and the risk of death from prostate cancer in men with intermediate risk prostate cancer
    Clinical Genitourinary Cancer, 2012
    Co-Authors: Jonathan E Rosenberg, Ming H Chen, Paul L Nguyen, Michelle H Braccioforte, Brian J Moran, Anthony V Damico
    Abstract:

    Abstract Purpose To determine whether external-beam radiotherapy (EBRT) improves disease control compared with supplemental Androgen Suppression therapy (AST) in men with intermediate-risk prostate cancer who are being treated with brachytherapy. Patients and Methods A total of 807 men with intermediate-risk prostate cancer (T2bNXM0, Gleason ≤7, prostate-specific antigen [PSA] Results Treatment with brachytherapy and with EBRT was associated with a significant increase in the risk of PCSM compared with brachytherapy and AST (adjusted hazard ratio [HR] 4.027 [95% CI, 1.168-13.89]; P = .027) after adjusting for age and prostate cancer prognostic factors. A Gleason score of 4+3 and increasing PSA were associated with worse PCSM (adjusted HR 8.882 [95% CI, 1.095-72.04]; P = .041; and adjusted HR 8.029 [95% CI, 2.38-28.8]; P = .0014, respectively). Conclusion Supplemental AST use compared with EBRT is associated with a lower risk of PCSM in men with intermediate-risk PC undergoing brachytherapy. Prospective validation in a randomized controlled trial is needed.

  • duration of short course Androgen Suppression therapy and the risk of death as a result of prostate cancer
    Journal of Clinical Oncology, 2011
    Co-Authors: Anthony V Damico, Minghui Chen, Juanita Crook, S Malone, Allison Steigler, John Armstrong, M Dunne, P Kantoff, James W Denham
    Abstract:

    Purpose We evaluated whether the duration of Androgen Suppression therapy (AST) had an impact on the risk of prostate cancer–specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories. Patients and Methods Between February 2, 1996, and December 27, 2001, 761 men with unfavorable-risk PC were treated in Australia, New Zealand, Ireland, or the United States in a randomized trial with radiotherapy and 3, 4, or 6 months of AST (the study cohort). Competing risks regression was used to evaluate whether the duration of AST interacted with GS and was significantly associated with the risk of PCSM, adjusting for age, trial site, and PC prognostic factors. Results After a median follow-up of 10.9 years, 263 men died, 111 (42%) from PC. For all men, 6 versus 3 or 4 months of AST was associated with a reduced risk of PCSM (adjusted hazard ratio [AHR], 0.55; 95% CI, 0.36 to 0.82; P = .004). AHRs evaluating the impact of the duration of AST on the risk ...

  • Androgen Suppression and radiation vs radiation alone for prostate cancer a randomized trial
    JAMA, 2008
    Co-Authors: Anthony V Damico, Minghui Chen, Andrew A Renshaw, Marian Loffredo, P Kantoff
    Abstract:

    ContextComorbidities may increase the negative effects of specific anticancer treatments such as Androgen Suppression therapy (AST).ObjectivesTo compare 6 months of AST and radiation therapy (RT) to RT alone and to assess the interaction between level of comorbidity and all-cause mortality.Design, Setting, and Patients At academic and community-based medical centers in Massachusetts, between December 1, 1995, and April 15, 2001, 206 men with localized but unfavorable-risk prostate cancer were randomized to receive RT alone or RT and AST combined. All-cause mortality estimates stratified by randomized treatment group and further stratified in a postrandomization analysis by the Adult Comorbidity Evaluation 27 comorbidity score were compared using a log-rank test. Main Outcome MeasureTime to all-cause mortality.Results As of January 15, 2007, with a median follow-up of 7.6 (range, 0.5-11.0) years, 74 deaths have occurred. A significant increase in the risk of all-cause mortality (44 vs 30 deaths; hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.1-2.9; P = .01) was observed in men randomized to RT compared with RT and AST. However, the increased risk in all-cause mortality appeared to apply only to men randomized to RT with no or minimal comorbidity (31 vs 11 deaths; HR, 4.2; 95% CI, 2.1-8.5; P < .001). Among men with moderate or severe comorbidity, those randomized to RT alone vs RT and AST did not have an increased risk of all-cause mortality (13 vs 19 deaths; HR, 0.54; 95% CI, 0.27-1.10; P = .08). ConclusionsThe addition of 6 months of AST to RT resulted in increased overall survival in men with localized but unfavorable-risk prostate cancer. This result may pertain only to men without moderate or severe comorbidity, but this requires further assessment in a clinical trial specifically designed to assess this interaction.Trial Registration clinicaltrials.gov Identifier: NCT00116220

  • time to prostate specific antigen nadir after Androgen Suppression therapy for postoperative or postradiation psa failure and risk of prostate cancer specific mortality
    Urology, 2008
    Co-Authors: Christine S Chung, Minghui Chen, Jennifer Cullen, David G Mcleod, Peter R Carroll, Anthony V Damico
    Abstract:

    OBJECTIVES To examine whether the time to the prostate-specific antigen (PSA) nadir was associated with prostate cancer-specific mortality (PCSM) in men with PSA failure after radical prostatectomy or radiotherapy who do not achieve an undetectable PSA level (PSA level of 0.2 ng/mL or less) after 8 months of Androgen Suppression therapy (AST). METHODS The cohort included 162 men with localized prostate cancer treated with AST for an increasing PSA level after radical prostatectomy or radiotherapy. Gray's analysis was used to evaluate for an association between the time to PSA nadir after 8 months of AST and the time to PCSM, adjusting for established prognostic factors. The median age and follow-up after 8 months of AST was 71.2 and 1.8 years, respectively. RESULTS After adjusting for Gleason score, pre-AST PSA doubling time, PSA at AST, PSA nadir value, time to PSA failure, initial treatment, and age, the time to PSA nadir was significantly associated with PCSM (adjusted hazard ratio 2.53, 95% confidence interval 1.24 to 5.14, P = 0.01). Men with a PSA nadir greater than the median value of 0.9 ng/mL and the time to PSA nadir longer than the median of 4 months had significantly greater PCSM estimates (P <0.001) compared with men with a PSA nadir of 0.9 ng/mL or less. CONCLUSIONS The time to PSA nadir, combined with the PSA nadir level, can be used to identify men who are at high risk of PCSM after a short course of AST for entry onto clinical trials using novel systemic agents with AST.

James W Denham - One of the best experts on this subject based on the ideXlab platform.

  • 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 t
    Lancet Oncology, 2014
    Co-Authors: James W Denham, David Lamb, David Joseph, Chris Atkinson, David Christie, Nigel Spry, Gillian M Duchesne, J N S Matthews, Lizbeth Kenny, Sandra Turner
    Abstract:

    Summary 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.

  • 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
    Lancet Oncology, 2012
    Co-Authors: James W Denham, David Lamb, David Joseph, Sandra Turner, Chris Atkinson, Nigel Spry, Chantelle Wilcox, Keen Hun Tai, John Matthews, David Christie
    Abstract:

    Summary 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 Interpretation Compared with 6 months of Androgen Suppression, 18 months of Androgen Suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. Funding National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

  • rectal and urinary dysfunction in the trog 03 04 radar trial for locally advanced prostate cancer
    Radiotherapy and Oncology, 2012
    Co-Authors: James W Denham, David Lamb, Sandra Turner, Chris Atkinson, Nigel Spry, Gillian M Duchesne, Lizbeth Kenny, Chantelle Wilcox, John W Matthews, Keen Hun Tai
    Abstract:

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

  • duration of short course Androgen Suppression therapy and the risk of death as a result of prostate cancer
    Journal of Clinical Oncology, 2011
    Co-Authors: Anthony V Damico, Minghui Chen, Juanita Crook, S Malone, Allison Steigler, John Armstrong, M Dunne, P Kantoff, James W Denham
    Abstract:

    Purpose We evaluated whether the duration of Androgen Suppression therapy (AST) had an impact on the risk of prostate cancer–specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories. Patients and Methods Between February 2, 1996, and December 27, 2001, 761 men with unfavorable-risk PC were treated in Australia, New Zealand, Ireland, or the United States in a randomized trial with radiotherapy and 3, 4, or 6 months of AST (the study cohort). Competing risks regression was used to evaluate whether the duration of AST interacted with GS and was significantly associated with the risk of PCSM, adjusting for age, trial site, and PC prognostic factors. Results After a median follow-up of 10.9 years, 263 men died, 111 (42%) from PC. For all men, 6 versus 3 or 4 months of AST was associated with a reduced risk of PCSM (adjusted hazard ratio [AHR], 0.55; 95% CI, 0.36 to 0.82; P = .004). AHRs evaluating the impact of the duration of AST on the risk ...

  • influence of Androgen Suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions
    Journal of Clinical Oncology, 2007
    Co-Authors: Anthony V Damico, James W Denham, David Lamb, David Joseph, Minghui Chen, Juanita Crook, Samuel Z Goldhaber, S Malone, Charles Ludgate, Allison Steigler
    Abstract:

    Purpose We evaluated whether the timing of fatal myocardial infarction (MI) was influenced by the administration of Androgen Suppression therapy (AST). Patients and Methods The study cohort comprised 1,372 men who were enrolled onto three randomized trials between February 1995 and June 2001. In the three trials, the men were randomly assigned to receive radiation therapy with 0 versus 3 versus 6, 3 versus 8, or 0 versus 6 months of AST. Fine and Gray's regression was used to determine the clinical factors associated with the time to fatal MI, and estimates of time to fatal MI were calculated using a cumulative incidence method. When comparing the cumulative incidence estimates using Gray's k-sample P values, increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST. Results Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not rece...

David Joseph - One of the best experts on this subject based on the ideXlab platform.

  • 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 t
    Lancet Oncology, 2014
    Co-Authors: James W Denham, David Lamb, David Joseph, Chris Atkinson, David Christie, Nigel Spry, Gillian M Duchesne, J N S Matthews, Lizbeth Kenny, Sandra Turner
    Abstract:

    Summary 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.

  • 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
    Lancet Oncology, 2012
    Co-Authors: James W Denham, David Lamb, David Joseph, Sandra Turner, Chris Atkinson, Nigel Spry, Chantelle Wilcox, Keen Hun Tai, John Matthews, David Christie
    Abstract:

    Summary 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 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.

  • combined resistance and aerobic exercise program reverses muscle loss in men undergoing Androgen Suppression therapy for prostate cancer without bone metastases a randomized controlled trial
    Journal of Clinical Oncology, 2010
    Co-Authors: Daniel A Galvao, David Joseph, Nigel Spry, Dennis R Taaffe, Robert U Newton
    Abstract:

    Purpose Androgen Suppression therapy (AST) results in musculoskeletal toxicity that reduces physical function and quality of life. This study examined the impact of a combined resistance and aerobic exercise program as a countermeasure to these AST-related toxicities. Patients and Methods Between 2007 and 2008, 57 patients with prostate cancer undergoing AST (commenced > 2 months prior) were randomly assigned to a program of resistance and aerobic exercise (n = 29) or usual care (n = 28) for 12 weeks. Primary end points were whole body and regional lean mass. Secondary end points were muscle strength and function, cardiorespiratory capacity, blood biomarkers, and quality of life. Results Analysis of covariance was used to compare outcomes for groups at 12 weeks adjusted for baseline values and potential confounders. Patients undergoing exercise showed an increase in lean mass compared with usual care (total body, P = .047; upper limb, P < .001; lower limb, P = .019) and similarly better muscle strength (P...

  • long term effects of intermittent Androgen Suppression on testosterone recovery and bone mineral density results of a 33 month observational study
    BJUI, 2009
    Co-Authors: Nigel Spry, David Joseph, Daniel A Galvao, Robert J Davies, Shane La Bianca, Andrew Davidson, Richard L Prince
    Abstract:

    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 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.

  • reduced muscle strength and functional performance in men with prostate cancer undergoing Androgen Suppression a comprehensive cross sectional investigation
    Prostate Cancer and Prostatic Diseases, 2009
    Co-Authors: Daniel A Galvao, David Joseph, Nigel Spry, Dennis R Taaffe, Darryl Turner, Robert U Newton
    Abstract:

    This study examined the effects of Androgen Suppression therapy (AST) on upper and lower body muscle strength and a range of direct measures of physical performance using a cross-sectional design with 118 men (48 men undertaking AST for prostate cancer and 70 healthy aged-matched controls) from a single tertiary center. Primary end points included muscle strength for the upper- and lower-body; functional performance--repeated chair rise, usual and fast 6-m walk, 6-m backwards walk and 400-m walk time; and dual-energy X-ray absorptiometry assessment--whole body, regional soft tissue composition and bone mineral density (BMD). Men on AST had significantly reduced muscle strength for the upper- and lower-body and impaired functional performance compared to controls (P<0.05). As expected, AST patients had significantly lower whole-body and hip BMD and higher percent of body fat than controls (P<0.05), and tended to have lower whole-body lean mass (-2.3 kg, P=0.077). Appendicular skeletal muscle was positively associated with upper-body (r=0.400-0.606, P<0.001) and lower-body (r=0.549-0.588, P<0.001) muscle strength, and strength was related to functional performance. Men undertaking AST were consistently impaired across a broad range of physical and functional musculoskeletal performance assessments compared with their age-matched normal controls. These findings are relevant for those patients considering AST for subclinical disease management, but whose physical reserve is marginal. Strategies to counter these adverse effects of AST need to be initiated so that independent living and quality of life can be maintained.

Nigel Spry - One of the best experts on this subject based on the ideXlab platform.

  • 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 t
    Lancet Oncology, 2014
    Co-Authors: James W Denham, David Lamb, David Joseph, Chris Atkinson, David Christie, Nigel Spry, Gillian M Duchesne, J N S Matthews, Lizbeth Kenny, Sandra Turner
    Abstract:

    Summary 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.

  • 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
    Lancet Oncology, 2012
    Co-Authors: James W Denham, David Lamb, David Joseph, Sandra Turner, Chris Atkinson, Nigel Spry, Chantelle Wilcox, Keen Hun Tai, John Matthews, David Christie
    Abstract:

    Summary 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 Interpretation Compared with 6 months of Androgen Suppression, 18 months of Androgen Suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. Funding National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

  • rectal and urinary dysfunction in the trog 03 04 radar trial for locally advanced prostate cancer
    Radiotherapy and Oncology, 2012
    Co-Authors: James W Denham, David Lamb, Sandra Turner, Chris Atkinson, Nigel Spry, Gillian M Duchesne, Lizbeth Kenny, Chantelle Wilcox, John W Matthews, Keen Hun Tai
    Abstract:

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

  • combined resistance and aerobic exercise program reverses muscle loss in men undergoing Androgen Suppression therapy for prostate cancer without bone metastases a randomized controlled trial
    Journal of Clinical Oncology, 2010
    Co-Authors: Daniel A Galvao, David Joseph, Nigel Spry, Dennis R Taaffe, Robert U Newton
    Abstract:

    Purpose Androgen Suppression therapy (AST) results in musculoskeletal toxicity that reduces physical function and quality of life. This study examined the impact of a combined resistance and aerobic exercise program as a countermeasure to these AST-related toxicities. Patients and Methods Between 2007 and 2008, 57 patients with prostate cancer undergoing AST (commenced > 2 months prior) were randomly assigned to a program of resistance and aerobic exercise (n = 29) or usual care (n = 28) for 12 weeks. Primary end points were whole body and regional lean mass. Secondary end points were muscle strength and function, cardiorespiratory capacity, blood biomarkers, and quality of life. Results Analysis of covariance was used to compare outcomes for groups at 12 weeks adjusted for baseline values and potential confounders. Patients undergoing exercise showed an increase in lean mass compared with usual care (total body, P = .047; upper limb, P < .001; lower limb, P = .019) and similarly better muscle strength (P...

  • long term effects of intermittent Androgen Suppression on testosterone recovery and bone mineral density results of a 33 month observational study
    BJUI, 2009
    Co-Authors: Nigel Spry, David Joseph, Daniel A Galvao, Robert J Davies, Shane La Bianca, Andrew Davidson, Richard L Prince
    Abstract:

    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 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.

Sandra Turner - One of the best experts on this subject based on the ideXlab platform.

  • 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 t
    Lancet Oncology, 2014
    Co-Authors: James W Denham, David Lamb, David Joseph, Chris Atkinson, David Christie, Nigel Spry, Gillian M Duchesne, J N S Matthews, Lizbeth Kenny, Sandra Turner
    Abstract:

    Summary 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.

  • 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
    Lancet Oncology, 2012
    Co-Authors: James W Denham, David Lamb, David Joseph, Sandra Turner, Chris Atkinson, Nigel Spry, Chantelle Wilcox, Keen Hun Tai, John Matthews, David Christie
    Abstract:

    Summary 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 Interpretation Compared with 6 months of Androgen Suppression, 18 months of Androgen Suppression causes additional detrimental changes at the 18 month follow-up in some PRO scores but not in global quality-of-life scores. However, with the exception of HTRS, these differences resolved by 36 months. The use of zoledronic acid every 3 months over 18 months does not result in additional detrimental changes, but the use of a brachytherapy boost to achieve radiation dose escalation in the prostate can adversely affect emotional function and financial problems. Funding National Health and Medical Research Council of Australia, Novartis Pharmaceuticals Australia, Abbott Pharmaceuticals Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Hunter Medical Research Institute, Calvary Mater Radiation Oncology Fund, and Maitland Cancer Appeal.

  • rectal and urinary dysfunction in the trog 03 04 radar trial for locally advanced prostate cancer
    Radiotherapy and Oncology, 2012
    Co-Authors: James W Denham, David Lamb, Sandra Turner, Chris Atkinson, Nigel Spry, Gillian M Duchesne, Lizbeth Kenny, Chantelle Wilcox, John W Matthews, Keen Hun Tai
    Abstract:

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