Do androgen-directed therapies improve outcomes in prostate cancer patients undergoing radical prostatectomy? A systematic review and meta-analysis

IntroductionApproximately 50% of patients with non-metastatic prostate cancer are treated with radical prostatectomy (RP). While some men will be cured with surgery alone, a substantial proportion will experience cancer recurrence. Androgen-directed therapy (ADT) is an effective adjuvant therapy for patients treated with prostate radiation. Comparatively, the efficacy of ADT in surgical patients has not been well-studied.MethodsA systematic search of MEDLINE, Embase, and the Cochrane Library from inception to July 2020 was performed. Randomized trials comparing ADT with RP vs. prostatectomy alone in patients with clinically localized prostate cancer were included. Neoadjuvant ADT and adjuvant ADT interventions were assessed separately. The primary outcomes were cancer recurrence-free survival (RFS) and overall survival (OS). Pathological outcomes following neoadjuvant ADT were also evaluated.ResultsFifteen randomized trials met eligibility criteria; 11 evaluated neoadjuvant ADT (n=2322) and four evaluated adjuvant ADT (n=5205). Neoadjuvant ADT (three months of treatment) did not improve RFS (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.74–1.11) or OS (HR 1.22, 95% CI 0.62–2.41). Neoadjuvant ADT significantly decreased the risk of positive surgical margins (relative risk [RR] 0.48, 95% CI 0.41–0.56) and extraprostatic tumor extension (RR 0.75, 95% CI 0.64–0.89). Adjuvant ADT improved RFS (HR 0.65, 95% CI 0.45–0.93) but did not improve OS (HR 1.02, 95% CI 0.84–1.24).ConclusionsNeoadjuvant ADT causes a pathological downstaging of prostate tumors but has not been found to delay cancer recurrence nor extend survival. Few studies have evaluated adjuvant ADT. Trials are needed to determine the benefits and harms of intermediate- or long-term adjuvant ADT for RP patients.     

Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer

Background

Some evidence indicates that androgen-deprivation therapy (ADT) increases the risk of diabetes and cardiovascular disease. To date, few studies have investigated whether this therapy also increases the risk of cerebrovascular events.

Objective

To determine whether different types of ADT increase the risk of stroke/transient ischaemic attacks (TIAs) in patients with prostate cancer.

Design, setting, and participants

We conducted a population-based cohort study using a nested case-control analysis within the United Kingdom's General Practice Research Database population. The cohort included all patients at least 40 yr of age newly diagnosed with prostate cancer between January 1, 1988, and December 31, 2008, and followed until December 31, 2009. Cases consisted of those who experienced a first-ever stroke/TIA during follow-up. Up to 10 controls were matched to each case on age, year of cohort entry, and duration of follow-up.

Measurements

Adjusted rate ratios (RRs) of stroke/TIA associated with the use of different ADTs (gonadotropin-releasing hormone [GnRH] agonists, oral antiandrogens, combined androgen blockade, bilateral orchiectomy, and others) were estimated using conditional logistic regression.

Results and limitations

The cohort included 22 310 patients with prostate cancer, followed for a mean of 3.9 yr, where 938 patients experienced a first-ever stroke/TIA (rate: 10.7 per 1000/yr). Compared with nonusers of ADT, current users of GnRH agonists (adjusted RR: 1.18; 95% confidence interval [CI], 1.00–1.39), oral antiandrogens (adjusted RR: 1.47; 95% CI, 1.08–2.01), and those who underwent bilateral orchiectomy (adjusted RR: 1.77; 95% CI, 1.25–2.39) were at an increased risk of stroke/TIA. No statistically significant increased risks were observed for patients on combined androgen blockade and other ADTs, but the small numbers do not rule out a possible association.

Conclusions

The results of this large population-based study provide additional evidence that different forms of ADT may increase the risk of stroke/TIA.     

Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism

Background

Previous studies demonstrate that androgen-deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and orchiectomy for prostate cancer (PCa) is associated with cardiovascular disease. However, few studies have examined its effect on the peripheral vascular system.

Objective

To study the risk of peripheral artery disease (PAD) and venous thromboembolism associated with ADT for PCa.

Design, settings, and participants

This was a population-based observational study of 182 757 US men ≥66 yr of age who were diagnosed with nonmetastatic PCa from 1992 to 2007, with a median follow-up of 5.1 yr, of whom 47.8% received GnRH agonists and 2.2% orchiectomy.

Measurements

We used Cox proportional hazards models with time-varying treatment variables to adjust for demographic and tumor characteristics in assessing whether treatment with GnRH agonists or orchiectomy were associated with PAD and/or venous thromboembolism.

Results and limitations

GnRH agonist use was associated with an increased risk of incident PAD (adjusted hazard ratio [HR]: 1.16; 95% confidence interval [CI], 1.12–1.21) and incident venous thromboembolism (adjusted HR: 1.10; 95% CI, 1.04–1.15). In addition, orchiectomy was associated with an increased risk of peripheral arterial disease (adjusted HR: 1.13; 95% CI, 1.02–1.26) and venous thromboembolism (adjusted HR: 1.27; 95% CI, 1.11–1.45). Limitations include the observational study design and the inability to assess the use of oral antiandrogens.

Conclusions

ADT for nonmetastatic PCa is associated with an increased risk of PAD and venous thromboembolism. Additional research is needed to better understand the potential risks and benefits of ADT, so that this treatment can be targeted to patients for whom the benefits are clearest.     

Aromatase inhibitors use and risk for cardiovascular disease in breast cancer patients: A population-based cohort study

BackgroundPrior studies regarding use of Aromatase inhibitors (AIs) and risk for cardiovascular disease (CVD) have shown conflicting results. This retrospective cohort study aimed to investigate whether AIs use affects risk for CVD events in postmenopausal breast cancer survivors.MethodsUsing a retrospective cohort study design, four CVD outcomes; heart failure or cardiomyopathy, arrhythmia, acute ischemic heart disease and ischemic stroke or Transient Ischemic Attack were compared with uni- and multivariate Cox regression analyses according to exposure to endocrine therapy (use of AI, tamoxifen or AI/tamoxifen sequentially) or no endocrine therapy.ResultsIn total 15815 postmenopausal women, surgically treated to early breast cancer during 2006–2012, were included. No significantly increased risk for CVD events was observed in patients with AI use in the whole cohort. However, two subgroup analyses showed increased risk for CVD events in the AI/tamoxifen sequential group; heart failure in patients older than 75 years (Hazard Ratio (HR) 2.44; 95% Confidence Interval (CI): 1.32–4.54) and arrhythmia in patients without prior CVD (HR 1.45; 95% CI: 1.01–2.10). An increased risk for arrhythmia and acute ischemic heart disease in patients with at least four years of AI treatment compared with no or short-time exposure was observed (HR 2.12; 95% CI: 1.40–3.25 for arrhythmia; HR 2.03; 95% CI: 1.15–3.58 for ischemic heart disease).ConclusionOur results indicate an increased risk for ischemic heart disease and arrhythmia in patients treated for more than four years with AIs. This should be considered in the risk-benefit assessment concerning endocrine therapy.     

Androgen deprivation therapy and the risk of tenosynovitis in prostate cancer patients

Objectives

Androgen deprivation therapy (ADT) use in prostate cancer (PCa) patients has been reported to have an association with rheumatoid arthritis. We aimed to assess the impact of ADT on the subsequent risk of tenosynovitis.

Methods

Using data from the National Health Insurance Research Database of Taiwan between 2001 and 2013, 3309 patients with PCa were identified. Among them, 729 ADT patients comprised the study group with 729 matched non-ADT controls. We used a 1:1 propensity score matched analysis. The demographic characteristics and comorbidities of the patients were analyzed; Cox proportional hazards regression was used to calculate the hazard ratios (HR) for the risk of tenosynovitis.

Results

There were 224 (15.3%) patients with newly diagnosed tenosynovitis. Compared with non-ADT patients, ADT patients had a lower risk of subsequent tenosynovitis with an adjusted HR of 0.38 [95% confidence interval (CI) 0.28–0.51; P?<?0.001].

Conclusions

ADT use apparently did not increase the risk of tenosynovitis in patients with PCa. Further studies are warranted to assess the clinical significance.

     

Quality of life in low-income men after surgical castration for metastatic prostate cancer

ObjectiveTo compare health-related quality of life in men who underwent surgical vs. medical castration for metastatic prostate cancer.MethodsWe analyzed data from a prospective cohort of men enrolled in a statewide public health program that provides care for prostate cancer among low-income, uninsured men from 2001 to 2020. Outcome measures included the RAND SF-12 and the UCLA Prostate Cancer Index (PCI) at baseline and every 6 months. We used generalized estimating equations to assess the independent impact of surgical vs. medical castration on health-related quality of life.ResultsAmong men with metastatic prostate cancer, 27 underwent orchiectomy, and 274 underwent medical castration. Median cohort age at enrollment was 61.3 years (IQR 56–65); 239 (79%) men had less than a high school education. Average follow-up was 8 months (range 0–45) since study enrollment. Seventy percent of patients within the surgical castration group had their orchiectomy prior to study enrollment (median months since orchiectomy at study enrollment was 9 months, IQR 1–43). Similarly, 59% of patients within the medical castration group had begun ADT prior to study enrollment (median months since ADT initiation at study enrollment was 4 months, IQR 1–12). The majority (66%) had metastatic disease at diagnosis. The 2 groups did not differ in age, race/ethnicity, education, monthly income, baseline PSA, Gleason score, or percent metastatic at diagnosis. SF-12 domains did not differ between those who underwent surgical vs. medical castration (on average throughout follow-up, physical component difference -2.0, 95% CI -8.0–3.9 and mental component difference -1.0, 95% CI -5.4–+3.4). Patients treated with orchiectomy reported better urinary function than those who underwent medical castration (+16 point, 95%CI 5.3–26).ConclusionsSurgical castration did not negatively impact general or disease-specific quality of life. The finding of improved urination after orchiectomy merits further inquiry. This may inform urologists’ discussion of surgical vs. medical options for men with castration-sensitive metastatic prostate cancer.     

Impact of adjuvant androgen deprivation therapy after radical prostatectomy on the survival of patients with pathological T3b prostate cancer

Study Type – Therapy (case series)
Level of Evidence 4 What’s known on the subject? and What does the study add? Adjuvant hormonal therapy is known to improve cancer specific survival in prostate cancer patients with lymph node positive disease. This study suggests that surgically treated prostate cancer patients with seminal vesical invasion (pT3b) may have improved cancer specific survival if treated with adjuvant androgen deprivation therapy, similar to lymph node positive patients.

OBJECTIVE

To determine the impact of adjuvant androgen deprivation therapy (ADT) on survival in patients with seminal vesicle invasion (pT3b) at radical prostatectomy.

PATIENTS AND METHODS

We reviewed 12 115 patients who underwent radical prostatectomy between 1987 and 2002 to identify patients with pT3bN0 prostate cancer who received adjuvant ADT (n= 191). These patients were matched by clinical and pathological variables to a group of patients with pT3b prostate cancer who did not receive adjuvant ADT. Median postoperative follow‐up was 10 years. Clinical endpoints included biochemical progression‐free survival (BPFS), local recurrence‐free survival (LRFS), systemic progression‐free survival (SPFS), cancer‐specific survival (CSS) and overall survival.

RESULTS

Patients who underwent adjuvant ADT experienced improved 10‐year BPFS (60% vs 16%, P < 0.001), LRFS (87% vs 76%, P= 0.002), SPFS (91% vs 78%, P= 0.004) and CSS (94% vs 87%, P= 0.037). Overall survival was not significantly different between groups (75% vs 69%, P= 0.12). Both luteinizing hormone‐releasing hormone agonists (hazard ratio, 0.26; 95% CI, 0.15–0.46; P < 0.001) and bilateral orchiectomy (hazard ratio, 0.13; 95% CI, 0.06–0.31; P < 0.001) improved BPFS. When stratified by type of ADT (hormonal therapy vs orchiectomy), there was no difference in survival outcomes.

CONCLUSIONS

Adjuvant ADT improves local, and systemic control after radical prostatectomy for pT3b prostate cancer. There is no difference in survival between patients receiving medical hormonal therapy vs patients undergoing orchiectomy. Given the lack of improvement in overall survival, continued investigation is needed to identify the cohort of pT3b patients at highest risk for cancer progression and therefore most likely to benefit from a multimodal treatment approach.     

Significant financial differences of chemical and surgical androgen deprivation in a contemporary cohort

BackgroundAndrogen deprivation therapy (ADT) remains a cornerstone of treatment for advanced prostate cancer. Few men elect for surgical castration via bilateral orchiectomy. We sought to compare the relative difference in financial charges between chemical and surgical ADT in men.MethodsBilling data was obtained for patients with metastatic prostate cancer receiving chemical ADT and who had bilateral orchiectomy from 2014–2019. Men had chosen intervention based on personal preference. We compared charges of ADT administration for chemical ADT and overall charges for bilateral orchiectomy. We determined the time chemical ADT patient charges surpassed those of surgical charges, as well as the net present value (NPV) of hypothetical savings for electing surgery over various ADT agents.ResultsOne hundred and thirty-seven patients receiving chemical ADT and 7 patients who had undergone bilateral orchiectomy were analyzed. Median and mean surgical charges were $13,000. By 38 weeks following treatment initiation, 50% of chemical ADT patients had surpassed surgical charges, with 95% at 2 years. The NPV in savings for a median patient varied between ADT agent and was highest at $167,000 for leuprolide.ConclusionsIn less than a year, the median chemical ADT patient charges were greater than surgical castration. The NPV of electing surgery over ADT was the highest with leuprolide. Despite under-utilization, surgical castration remains a medically appropriate and cost-effective option for permanent ADT.     

Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer

Background

Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa).

Objective

To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population.

Design, setting, and participants

Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results–Medicare database.

Outcomes measurements and statistical analyses

Patient in both treatment arms (ADT vs no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up.

Results and limitations

Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p < 0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p < 0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18–1.31; p < 0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96–1.29; p = 0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design.

Conclusions

ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI.

Patient summary

The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients.     

Insulinemic and Inflammatory Dietary Patterns and Risk of Prostate Cancer

BackgroundHyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk.ObjectiveTo determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality.Design, setting, and participantsWe prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986–2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr.Outcome measurements and statistical analysisTotal, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns—empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern—and prostate cancer risk estimated using Cox proportional hazard regression.Results and limitationsDuring 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01–1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00–1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06–1.35) for advanced, 1.22 (1.04–1.42) for fatal, and 1.20 (1.04–1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00–1.35).ConclusionsHyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease.Patient summaryAvoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.     

The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy

BackgroundStudies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT).ObjectiveTo perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes.Design, setting, and participantsPatients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate.Outcome measurements and statistical analysisThe primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT.Results and limitationsOf 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53–0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48–0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication.ConclusionsIn men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted.Patient summaryWe found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.     

Patient-reported Quality of Life in Patients with Primary Metastatic Prostate Cancer Treated with Androgen Deprivation Therapy with and Without Concurrent Radiation Therapy to the Prostate in a Prospective Randomised Clinical Trial; Data from the HORRAD Trial

BackgroundA survival benefit was demonstrated for patients with low-volume metastatic prostate cancer (mPCa) when local radiotherapy was added to androgen deprivation therapy (ADT).ObjectiveTo determine the effect of ADT combined with external beam radiotherapy (EBRT) to the prostate on health-related quality of life (HRQoL) of patients with primary bone mPCa.Design, setting, and participantsThe HORRAD trial is a multicentre randomised controlled trial recruiting 432patients with primary bone mPCa between 2004 and 2014.InterventionPatients were randomised to ADT with EBRT or to ADT alone.Outcome measurements and statistical analysisPatients completed two validated HRQoL questionnaires (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core Module (QLQ-C30) and EORTC Quality of Life Questionnaire Prostate Module [QLQ-PR25]) at baseline and at 3, 6, 12, and24 mo after the initiation of treatment. The effect of both treatments was evaluated based on mixed-effect models.Results and limitationsPatient characteristics and HRQoL scores at baseline were similar in both arms. At baseline, 98% of patients completed the questionnaires, compared with 58% at 24 mo. Patients reported significantly more diarrhoea (difference between the groups 10.8; 95% confidence interval [CI] 7.3–14.2), bowel symptoms (4.5; 95% CI 2.1–6.8), and urinary symptoms (11.9; 95% CI 8.9–14.8) after EBRT and ADT compared with ADT alone (all between-arm difference p < 0.001). Urinary complaints levelled at 6 mo. At 2 yr, only bowel symptom scores were significantly different (8.0; 95% CI 4.8–11.1, p ≤ 0.001), but 68% of patients in the radiotherapy group did not report clinically relevant worsening of their bowel symptom scores.ConclusionsPatients with bone mPCa reported temporary modest urinary and bowel symptoms after combined treatment with EBRT of the prostate and ADT compared with ADT alone. For some patients (22%), deterioration of bowel functions remains at 2 yr, whereas general HRQoL does not deteriorate..Patient summaryThis study investigated the effect of radiotherapy to the prostate added to hormonal therapy on patient-reported health-related quality of life (HRQoL) in patients with primary bone metastatic prostate cancer. Most patients reported only temporary urinary and bowel symptoms. In 22% of patients, bowel symptoms remained at 2 yr, whereas general HRQoL did not deteriorate.     

PSA nadir and time to PSA nadir during initial androgen deprivation therapy as prognostic factors in metastatic castration-resistance prostate cancer patients treated with docetaxel

Prostate-specific antigen nadir (nPSA) and time to nPSA (TTN) have been proved to be associated with the prognosis of prostate cancer. In this study, we explored the prognosis effect of nPSA and TTN during initial androgen deprivation therapy (ADT) in patients with metastatic castration-resistant prostate cancer (mCRPC) after treatment with docetaxel-based chemotherapy. The data of 153 mCRPC patients received docetaxel followed by ADT were retrospectively reviewed. Multivariate Cox regression analysis demonstrated that TTN (overall survival (OS): Hazard ratio [HR] 0.096, 95% confidence interval [CI] 0.045–0.206, p < .001; progression-free survival (PFS): HR 0.128, 95% CI 0.078–0.211, p < .001) and nPSA (OS: HR 2.849, 95% CI 1.318–6.157, p = .008; PFS: HR 1.573, 95% CI 1.008–2.454, p = .046) acted as independent predictors of chemotherapy prognosis. Kaplan-Meier analysis showed that patients with nPSA ≥ 0.2 ng/ml or TTN < 6.5 months had shorter OS and PFS. These results suggest that TTN and nPSA during ADT can affect the prognosis of docetaxel-based chemotherapy prognosis post-castration resistance in patients with mCRPC, and higher nPSA and shorter TTN lead to poor chemotherapy prognosis. What is more, TTN has a greater impact during ADT on the prognosis of chemotherapy than nPSA.     

Radical prostatectomy versus external beam radiation therapy for high-grade,clinically localized prostate cancer: Emulation of a target clinical trial

PurposeThe comparative effectiveness of surgery and radiation therapy for high-grade, clinically localized prostate cancer remains a seminal, open question in urologic oncology, with no randomized controlled trials to inform management. We therefore emulated a hypothetical target clinical trial of radical prostatectomy (RP) versus external beam radiotherapy (EBRT) for high-grade, clinically localized prostate cancer.Materials and MethodsWe conducted observational analyses using the National Cancer Database from 2006-2015 to emulate a target clinical trial in men 55-69 years with cT1-3cN0cM0, PSA<20 ng/mL, Gleason 8 to 10 prostate adenocarcinoma treated with RP or 75 to 81 Gy EBRT with androgen deprivation therapy (EBRT+ADT). The associations of treatment type with overall survival (OS) were estimated using Cox regression with stabilized inverse probability weights (IPW).ResultsA total of 26,806 men formed the study cohort (RP: 23,990; EBRT+ADT: 2,816). Baseline characteristics were well-balanced after IPW-adjustment. Median follow-up was 48.4 (IQR 25.5-76.2) months. After IPW-reweighting, RP was associated with improved OS compared to EBRT+ADT (HR 0.54;95% CI 0.48-0.62; P<0.001), with 5- and 10-year OS of 93% vs 87%, and 76% vs 60%, respectively. RP was associated with improved OS across all categories of Gleason score, PSA, cT stage, age, and Charlson comorbidity index examined. In sensitivity analyses adjusting for biopsy tumor volume and a biopsy-specific Gleason score, RP remained associated with improved OS compared to EBRT+ADT (HR 0.62;95% CI 0.49-0.78; P<0.001).ConclusionsIn observational analyses designed to emulate a target clinical trial of men with high-grade, clinically localized prostate cancer, RP was associated with improved OS compared with EBRT+ADT.     

Does Local Treatment of the Prostate in Advanced and/or Lymph Node Metastatic Disease Improve Efficacy of Androgen-Deprivation Therapy? A Systematic Review

Context

Androgen-deprivation therapy (ADT) plays a pivotal role in the management of locally advanced and metastatic prostate cancer (PCa). When and for how long to apply ADT have remained controversial issues.

Objective

To review randomised studies of ADT (orchiectomy or luteinising hormone-releasing hormone analogues) in PCa—both immediate and deferred/adjuvant studies—to elucidate a possible interaction between local treatment and ADT.

Evidence acquisition

Published randomised studies on ADT in various stages of PCa were included in this review.

Evidence synthesis

Studies of immediate versus deferred ADT without local treatment consistently showed only limited benefit for overall survival (OS; hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.83–0.97) and cancer-specific survival (CSS; HR: 0.79; 95% CI, 0.71–0.89). In contrast, ADT as an adjuvant to radiation therapy in patients with high-risk localised disease or locally advanced disease was associated with substantial OS and CSS benefits. A similar benefit was seen in patients with proven systemic disease (node-positive patients after radical prostatectomy). Overall, the data suggest a clinically important survival benefit (HR for OS: 0.69; 95% CI, 0.61–0.79) when a local treatment has been applied to the primary tumour. Possible mechanisms of this therapeutic effect are discussed.

Conclusions

We conclude that an interaction between local treatment and ADT is suggested by this systematic review. In patients with advanced and aggressive disease who are at a high risk to die from PCa and who are treated for their primary tumour with curative intent, immediate and sustained ADT improves OS and CSS significantly. The local therapy in T3 and/or lymph node–positive disease is an essential part of the optimal treatment. However, this intensive treatment is unnecessary in a substantial number of patients with T3 and/or N1 disease with a slow natural history or high competing death risk.     

The oncologic impact of hormone replacement therapy in premenopausal breast cancer survivors: A systematic review

SynopsisThis is the first systematic review to investigate the risk of recurrence in breast cancer survivors <50 years old who have used hormone replacement therapy (HRT).BackgroundThe risk of HRT in premenopausal breast cancer survivors is unclear. Due to the higher incidence of estrogen receptor negative tumours in women <50, the potential for HRT to promote breast cancer recurrence may differ from older age groups.MethodsWe performed a search of Medline, EMBASE and CINAHL through June 2016. For the observational studies relative risk (RR) and 95% confidence interval (CI) were calculated for the recurrence rate among HRT users and nonusers. A random effects model was used to estimate the combined RR using the Mantel-Haenszel method.ResultsFour papers satisfied our inclusion criteria. 3477 subjects were analyzed. On pooled meta-analysis of breast cancer recurrence in the observational studies, no significant association was found between HRT and risk of recurrence (RR 1.04 [95% CI 0.45, 2.41]). The randomized controlled trial (RCT) included found an increased risk of recurrence with HRT among women <50 (HR 1.56 [95% CI 1.1–2.2]). However, among women of all ages with an estrogen receptor negative tumour there was no significant difference in recurrence when compared to hormone receptor positive tumours (HR 1.15 [95% CI 0.7–1.8, p = 0.55]).DiscussionThis review on HRT in breast cancer survivors <50 revealed conflicting results between randomized and observational study data. Further studies are warranted to investigate the association between HRT and recurrence rates in younger breast cancer survivors.     

Association of reimbursement policy and urologists׳ characteristics with the use of medical androgen deprivation therapy for clinically localized prostate cancer

ObjectivesPhysician characteristics and changes in drug reimbursement rates have been shown to influence practice patterns regardless of clinical guidelines, patient, clinical, or sociodemographic factors. We concurrently examined the association between urologists? characteristics and non–evidence-based use of primary medical androgen deprivation therapy (ADT) for clinically localized patients with prostate cancer, before and after the 2003 Medicare Modernization Act?s reductions in ADT reimbursement rates.Methods and materialsThe Surveillance, Epidemiology, and End Results-Medicare–linked database and the American Medical Association Physician Masterfile are used in a retrospective analysis of 12,255 patients diagnosed between 2001 and 2007 with clinical stage T1-T2, low- to intermediate-grade prostate cancer, and the 1,863 urologists who treated them. Logistic multilevel regression analyses are used to evaluate the association of urologists? characteristics on ADT use among patients within 6 months of diagnosis.ResultsOverall, 3,866 (32%) patients received non–evidence-based ADT. After adjusting for patient and urologist characteristics, patients treated by urologists with no medical school affiliations, compared with those treated by urologists with major medical school affiliations, are significantly more likely to receive non–evidence-based medical ADT (odds ratio = 2.35; 95% CI: 1.71–3.23; P<0.0001). Non–US-trained urologists are also more likely to prescribe non–evidence-based medical ADT (odds ratio = 1.64; 95% CI: 1.33–2.04; P<0.0001).ConclusionsPatients treated by non–medical school–affiliated or non–US-trained urologists or both are significantly more likely to receive non–evidence-based ADT before and after the passage of the Medicare Modernization Act. Better strategies to encourage evidence-based ADT use on clinically localized patients with prostate cancer may be of benefit especially among non–medical school–affiliated or non–US-trained urologists or both.     

Brachytherapy monotherapy may be sufficient for a subset of patients with unfavorable intermediate risk prostate cancer

Purpose/objective(s)

Brachytherapy (BT) monotherapy is a well-established treatment modality for favorable intermediate risk (FIR) prostate cancer. However, patients with unfavorable intermediate risk (UIR) disease are often recommended trimodality therapy involving BT, androgen deprivation therapy (ADT), and external beam radiation therapy (EBRT). We sought to investigate the relative benefit of supplemental therapies (ADT and/or EBRT) for FIR and UIR prostate cancer in a large dataset.

Evaluation of the platelet-to-lymphocyte ratio as a prognostic indicator in a European cohort of patients with prostate cancer treated with radiotherapy

ObjectivesRecent evidence suggests that the presence of a systemic inflammatory response plays an important role in the progression of several solid tumors. The platelet-to-lymphocyte ratio (PLR) has been proposed as an easily assessable marker of systemic inflammation and has been shown to represent a prognostic marker in different cancer entities. To evaluate the prognostic value of the PLR in prostate cancer, we performed the present study.Methods and materialsData from 374 consecutive patients with prostate cancer, treated with 3D conformal radiotherapy from 1999 to 2007, were analyzed. Distant metastases–free survival (MFS), cancer-specific survival (CSS), overall survival (OS), biochemical disease–free survival, and time to salvage systemic therapy were assessed using the Kaplan-Meier method. Cox proportional hazards analysis was performed to calculate hazard ratio (HR) and 95% CI. Multivariate Cox regression analysis was performed to adjust for other covariates.ResultsUsing receiver operating characteristics analysis, the optimal cutoff level for the PLR was 190. Kaplan-Meier analyses revealed that PLR≥190 was a prognostic factor for decreased MFS (P = 0.004), CSS (P = 0.004), and OS (P = 0.024) whereas a significant association of an elevated PLR with biochemical disease–free survival (P = 0.740) and time to salvage systemic therapy (P = 0.063) was not detected. In multivariate analysis, an increased PLR remained a significant prognostic factor for poor MFS (HR = 2.24, 95% CI: 1.06–4.76, P = 0.036), CSS (HR = 3.99, 95% CI: 1.19–13.4, P = 0.025), and OS (HR = 1.87, 95% CI: 1.02–3.42, P = 0.044).ConclusionsOur findings indicate that the PLR may predict prognosis in patients with prostate cancer and may contribute to future individual risk assessment in them.     

Influence of the subtype on local recurrence risk of breast cancer with or without radiation therapy

PurposeTo investigate if intrinsic subtypes of breast cancer predict different risks of ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS) with and without postoperative radiation therapy.Patients and methodsWe randomized 381 women with a unifocal T1N0M0 breast cancer to BCS alone (197 women) or BCS plus postoperative radiation therapy (XRT) (184 women). All available histopathological material was re-analyzed with modern immunohistochemical methods (223 women). After 20 years of complete follow-up we analyzed the risk of IBTR by intrinsic breast cancer subtypes (luminal A, luminal B/HER2-negative, luminal B/HER2-positive, HER2-positive and triple negative). We used Cox regression analyses to estimate hazard ratios (HR) with 95% confidence intervals (CI).ResultsIn a multivariate analysis the luminal B/HER2-negative subtype, compared with the luminal A subtype, was associated with a higher risk of IBTR overall (HR 3.04; 95% CI 1.38–6.71) and in both the XRT-group (HR 5.08 95% CI 1.31–19.7) and the non-XRT-group (HR 2.58 95%CI 1.07–6.20); (p for interaction = 0.37). The risk of IBTR in the XRT- and non-XRT group, stratified by intrinsic subtype, revealed an absolute risk difference at 20 years to the benefit of XRT of 14% (95% CI 1.0%–26%) for luminal A, 17% (95% CI -6.0% to 39%) for luminal B/HER2 negative and 22% (95% CI -7.0–51%) for the high-risk group.ConclusionsAmong breast cancer patients treated with BCS, the luminal B/HER2-negative subtype predicts an about 3-fold higher risk for IBTR compared to other intrinsic subtypes independent of postoperative radiation therapy.