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Thread: (O) Locally Advanced Prostate Cancer

  1. #11
    Ten year final results of the TROG 03.04 (RADAR) randomised phase 3 trial evaluating duration of androgen suppression ▒ zoledronate for locally advanced prostate cancer [2018]



    Background: We investigated whether 18 months of androgen suppression (AS) plus radiotherapy (RT) ▒ 18 months of zoledronate (Z) is more effective than 6 months of neoadjuvant AS plus RT ▒ Z. Methods: Eligible men with T2a-4, N0, M0 prostatic adenocarcinomas with PSA ≥10 and Gleason score (GS) ≥7 in T2a cases were randomly allocated in a 2x2 factorial trial design to 6 months neo-adjuvant AS using leuprolide (22.5mg i.m. 3 monthly) and radiation (control arm) or followed by treatment factor 1- 12 months AS (22.5mg i.m. 3 monthly), or accompanied by the second treatment factor 2- 18 months Z (4mg i.v. 3 monthly) starting at randomisation, or by both treatment factors. Patients were stratified by centre, baseline PSA, tumour stage, GS, and use of a brachytherapy boost. The primary endpoint was prostate cancer-specific mortality (PCSM). Secondary endpoints included time to PSA, local, distant, bone and soft tissue progressions (PSA, LP, DP, BP and STP) and time to secondary therapeutic intervention and all-cause mortality (STI and ACM). Endpoints were analysed by intention to treat using competing risks methodology. ACM was analysed using Cox regression. Results: Between October 2003 and August 2007 1071 men were randomised with median age 68.7 years. Median follow-up was 10.4 years (IQR 7.9-11.7). No significant interaction was observed between AS and Z. Significant reductions were observed favouring 12 months AS for the primary endpoint: PCSM sHR 0.70 (0.50-0.97), p = 0.035; and for the secondary endpoints: BP sHR 0.61 (0.45-0.83), p = 0.001; DP sHR 0.71 (0.56-0.90), p = 0.004; PSA sHR 0.65 (0.53-0.78 ), p < 0.001; LP sHR 0.60 (0.39-0.92), p = 0.021; and STI sHR 0.66 (0.53-0.81), p < 0.0001. There were also non-significant reductions favouring 12 months AS in STP (sHR 0.85 [0.62-1.16], p = 0.30) and ACM (HR 0.84 [0.69-1.03], p = 0.10). The addition of 18 months Z did not influence any outcome significantly. Conclusions: 18 months AS+RT is an effective option for locally advanced prostate cancer but the use of 18 months Z is not beneficial. Clinical trial information: NCT00193856.
    [Emphasis mine]
    Last edited by DjinTonic; 05-09-2018 at 12:58 PM.

  2. #12
    Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017



    In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics.

    To present the report of APCCC 2017.

    Design, setting, and participants
    Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; “oligometastatic” prostate cancer; castration-na´ve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions.

    Outcome measurements and statistical analysis
    The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process.

    Results and limitations
    Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data.

    The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them.

    Patient summary
    The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.
    Last edited by DjinTonic; 05-03-2018 at 12:13 PM.

  3. #13
    Survival after radical prostatectomy or radiotherapy for locally advanced (cT3) prostate cancer



    No prospective data examined the effect of radical prostatectomy (RP) vs. external beam radiotherapy (EBRT) in locally advanced prostate cancer (PCa). We aimed to compare survival outcomes of RP and EBRT in patients harboring cT3N0-1 PCa.

    Within the SEER database (2004-2014), we identified 5500 cT3N0-1 PCa patients. Cumulative incidence plots and competing-risks regression models (CRRs) tested cancer-specific mortality (CSM) and other cause of mortality (OCM) according to treatment type. The multivariable relationship between baseline prostate-specific antigen (PSA) values and 10-year CSM after either RP or EBRT was graphically depicted using the LOESS smoothing method. Sensitivity analyses were performed in cT3N0-only patients, after OCM propensity score matching, and through landmark analyses.

    Ten-year CSM and OCM rates were significantly higher after EBRT (15.8 and 28.2%) than RP (8.1 and 10.4%) (all p < 0.0001). In multivariable CRRs, RP yielded lower CSM [hazard ratio (HR): 0.64] than EBRT. Significantly lower 10-year CSM rate was recorded after RP vs. EBRT through the entire range of baseline PSA values. The same results were recorded in cT3N0 subgroup, as well as after OCM propensity score matching. Finally, landmark analyses at 6, 12, 24, and 36 months rejected the effect of favorable survival bias after RP.

    CSM was significantly lower after RP than EBRT in cT3N0-1 PCa. A lower CSM was recorded throughout the entire range of baseline PSA and even in cT3N0 subgroup, as well as after OCM propensity score matching and landmark analyses.
    [Emphasis mine]

  4. #14
    Radiotherapy Plus Total Androgen Block Versus Radiotherapy Plus LHRH Analog Monotherapy for Non-metastatic Prostate Cancer



    Patients with locally advanced prostate cancer are generally treated with radiotherapy (RT) which can be combined with hormonal therapy. RT plus monotherapy with luteinizing hormone-releasing hormone (LHRH) analog triptorelin was compared to RT plus total androgen block (TAB).

    A retrospective study was carried out on patients with locally advanced prostate cancer comparing RT plus monotherapy versus RT plus TAB.

    For overall survival, no differences between patients receiving RT with monotherapy and those treated with TAB were observed. A trend favoring use of TAB was found for progression-free survival. No differences in late gastrointestinal and genitourinary toxicities were reported.

    This study suggests that monotherapy with LHRH is as effective as TAB, which is important in selecting appropriate treatment considering that TAB can have higher risks of adverse events and reduce the quality of life of patients.

  5. #15
    Bone-targeted therapies to reduce skeletal morbidity in prostate cancer
    [2018, Full Text]

    (Click on Full Text link at upper right)


    Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.

  6. #16
    Long-term androgen deprivation, with or without radiotherapy, in locally-advanced prostate cancer: Updated results from a phase III randomized trial


    Background: We previsously reported results of a randomized phase III trial comparing androgen-deprivation therapy (ADT) combined with external beam radiation therapy (EBRT) and ADT alone in patients treated with localized cancer. We report here long-term oncological outcomes of this trial. Methods: In this multicenter phase III trial, patients with biopsy-proven locally advanced prostate cancer (T3-4) randomly assigned to ADT alone or ADT+EBRT. In both arms, leuprorelin 11.25 mg, subcutaneous, was started within seven days of randomization and continued every three months for three years and oral flutamide (750 mg/day) was administered during the first month. For the ADT-EBRT arm, the whole pelvis was treated at a dose of 46+/-2 Gy and the prostate with a boost from 20 Gy to 28 Gy. Primary endpoint was progression-free Survival (PFS) which included biochemical and clinical events and deaths. Secondary endpoints included overall survival (OS), disease-specific survival (DSS), locoregional progression free survival (LPFS), metastasis-free survival (MFS), biochemical progression free survival (BPFS) and tolerance. Competing-risk analysis was used whenever appropriate. Results: With a median follow-up of 7.3 years, 263 patients were included in the Intent-to-treat analyses. The 8-year PFS rate was significantly higher in the ADT+EBRT arm than in the ADT arm (47.9% versus 7.0%; hazard ratio: 0.27, p < 0.0001). The risk of death from prostate cancer was significantly reduced for ADT+EBRT arm as compared to ADT alone (sub-hazard ratio (SHR): 0.48; p = 0.02). The 8-year OS rate was respectively 56.8% in the ADT arm and 65.1% in the ADT+EBRT arm (p = 0.43). LPFS was significantly in favor of ADT+EBRT arm (SHR = 0.61; p = 0.01). MFS was comparable between both arms (p = 0.88 ). Analysis of toxicities revealed acute lower tolerance (mainly gastro-intestinal and genito-urinary) in the ADT+EBRT arm with a gradual decrease in intensity during follow up from 6 months after the end of EBRT. Conclusions: These long-term results confirm the oncological benefit of combining EBRT with ADT in the treatment of locally advanced prostate cancer. Clinical trial information: NCT01122121.

  7. #17
    Health-related quality of life (HRQoL) deterioration and pain progression in men with non-metastatic castration-resistant prostate cancer (M0 CRPC): Results from the PROSPER study



    Background: The Phase 3 PROSPER trial (NCT02003924) showed a statistically significant improvement in metastasis-free survival (MFS) with enzalutamide (ENZA; n = 933) vs. placebo (PBO; n = 468 ) in asymptomatic men with M0 CRPC and prostate-specific antigen doubling time ≤10 months. We report the results of the HRQoL and pain evaluations. Methods: Functional Assessment of Cancer Therapy–Prostate (FACT-P) and Brief Pain Inventory, Short Form, were used to assess HRQoL and pain at baseline (BL) and every 16 weeks during treatment. Pain progression was defined as ≥2 points in pain severity items and mean scores increase from BL; HRQoL improvement/deterioration as an increase/decrease from BL using pre-established thresholds for clinically meaningful difference. Time to first confirmed (at two consecutive visits) and unconfirmed HRQoL deterioration/pain progression were assessed using Kaplan-Meier estimates and Cox proportional hazards models under censoring not at random assumption. Results: BL characteristics and scores were similar between arms with low pain (median 0) and high HRQoL (median FACT-P total score, 121). Decrease in attrition rate was greater in PBO vs. ENZA mainly due to disease progression (53% vs. 68% at week 49, respectively). Most patients reported no change or improvement in HRQoL. Proportion of patients with pain progression at week 49 was similar between ENZA (11–20%) and PBO (14–21%). Lower risk of pain progression was observed with ENZA vs. PBO in the confirmed analysis (hazard ratio [HR] 0.78–0.93; p > 0.05). Nominal statistically significant lower risk of deterioration was observed with ENZA for FACT-P total, FACT Advanced Prostate Symptom Index, prostate cancer subscale (PCS), and emotional well-being (EWB) in the confirmed (HR 0.75, 0.77, 0.77, 0.69, respectively; p < 0.05) and for PCS and EWB in the unconfirmed (HR 0.82, 0.80, respectively; p < 0.05) analyses. Conclusions: In PROSPER, ENZA significantly delayed MFS vs. PBO without worsening HRQoL and significantly reduced the risk of clinically meaningful HRQoL deterioration in several FACT-P domains. Pain progression was similarly low in both arms. Clinical trial information: NCT02003924.

  8. #18
    Systemic treatments for high-risk localized prostate cancer



    The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration-resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials.

  9. #19
    Definitive Radiation Therapy and Survival in Clinically Node-Positive Prostate Cancer



    The survival benefit of combined radiation therapy (RT) and androgen deprivation therapy (ADT) compared with ADT alone for clinically lymph node-positive prostate cancer remains controversial.

    We identified patients with clinically node-positive, nonmetastatic prostate cancer diagnosed between 2000 and 2015 and treated with ADT (n = 450) or ADT-RT (n = 198 ) from a national Veterans Affairs database. We compared prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) between treatment groups using multivariable competing-risks regression and Cox regression, respectively. An interaction term between ADT-RT and prostate-specific antigen (PSA) level (dichotomized about the median) was included in the multivariable models.

    ADT-RT was associated with improved PCSM among patients with PSA levels less than the median of 26 ng/mL (sub-distribution hazard ratio, 0.50; 95% confidence interval [CI] 0.28-0.88; P = .02) but not greater than the median (hazard ratio [HR], 1.15; 95% CI 0.67-1.96; P = .62) (P = .038 for interaction). ADT-RT was also associated with improved ACM among patients with PSA levels less than the median (HR, 0.38; 95% CI 0.25-0.57; P < .001) but not greater than the median (HR, 0.91; 95% CI 0.60-1.38; P = .66) (P = .004 for interaction).

    Definitive treatment with ADT-RT is associated with improved PCSM and ACM among patients with clinically node-positive prostate cancer and lower baseline PSA levels. Patients with clinically node-positive disease appear to be a heterogeneous cohort, with a subset who may achieve long-term survival with combined RT and ADT.

  10. #20
    Elderly patients aged ≥ 75 years with locally advanced prostate cancer may benefit from local treatment: a population-based propensity score-adjusted analysis



    To evaluate whether elderly patients aged ≥ 75 years with locally advanced prostate cancer (LAPC) may benefit from local treatment (LT).

    Elderly patients aged ≥ 75 years with non-metastatic cT3–4 LAPC who were treated with LT [radical prostatectomy (RP), radiation therapy (RT)] or non-LT (NLT) were identified. After propensity score matching (PSM), cancer-specific mortality (CSM) and other-cause mortality (OCM) rates were assessed. In the assessment of LT vs. NLT and RP vs. RT, multivariable competing risk regression (MVA CRR) analysis was used.

    368 and 482 paired patients were matched for LT vs. NLT and RP vs. RT, respectively. 5 and 10 years CSM rates were 9.4 vs. 18.5% in LT and 24.9 vs. 29.3% in NLT-treated patients, respectively (P < 0.0001). 5 and 10 years CSM rates were 3.4% vs. 8.6% in RP and 6.7% vs. 15.1% in RT-treated patients, respectively (P = 0.10). In the MVA CRR model, after PSM, NLT resulted in higher CSM rates in Gleason score 8–10 [subhazard ratio (sHR) = 2.83, P < 0.001], cT3b/4 (sHR = 3.97/2.56, P = 0.003/0.002), cN0 (sHR = 2.52, P < 0.001) or PSA > 10 ng/ml [sHR (PSA = 10.1–20 ng/ml) = 4.59, P = 0.03; sHR (PSA > 20 ng/ml) = 2.77, P = 0.001] patients compared with LT. However, no statistically significant difference in CSM was observed between RP and RT, except for cT3a patients in whom higher CSM rates were noted for RT compared with RP (sHR = 3.91, P = 0.02).

    LAPC patients may benefit from local treatment despite advanced age. However, this benefit was only seen in patients with cT3b/4, Gleason score 8–10, cN0 or PSA > 10 ng/ml.
    [Emphasis mine]


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