Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

BACKGROUND:
Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE--an international, open-label, randomised controlled trial--uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A).
METHODS:
Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544.
FINDINGS:
2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·94 (95% CI 0·74-1·20). [corrected]. 2-year FFS was 51% (95% CI 46-56) in arm A and 51% (95% CI 43-58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20-27] patients in arm A and 64 [25%, 19-30] in arm D). The most common grade 3-5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee.
INTERPRETATION:
Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival.

Neoadjuvant hormone therapy for radical prostate radiotherapy:bicalutamide monotherapy vs. luteinizing hormone-releasing hormone agonist monotherapy: a single-institution matched-pair analysis

The purpose of this study was to compare the prostate-specific antigen (PSA) response to either neoadjuvant bicalutamide (BC) monotherapy or neoadjuvant luteinizing hormone-releasing hormone agonist (LHRHa) monotherapy and the subsequent effect on biochemical failure-free survival (BFFS) in men receiving radical radiotherapy (RT) for localized prostate cancer.

Hormone therapy and intraocular pressure in nonglaucomatous eyes

Objective: The influence of sex hormones on intraocular pressure (IOP) has been the focus of recent debate. Previous studies investigating the effects of hormone therapy (HT) on IOP in postmenopausal women have produced conflicting results but have been limited by small numbers of participants. The aim of our study was to compare IOP in women without glaucoma taking HT with those not taking HT. Methods: A prospective cross-sectional study of postmenopausal women visiting a single ophthalmic medical practitioner was conducted. All women with a history of intraocular disease, a family history of glaucoma, or refractive error exceeding ±5 diopters were excluded. Applanation tonometry was used to measure IOP, and participants were then asked if they were current HT users. Results: A total of 263 participants were recruited, of whom 91 reported current use of HT; 172 had never used HT. Within the HT group, 33 were taking an estrogen-therapy and 58 were taking a estrogen-progesterone therapy. Mean IOP in the HT group was significantly lower than that in the non-HT group; the mean difference was 1.41 mm Hg (P <0.001). This difference remained statistically significant after statistical correction for age, use of systemic ß-blockers, and time of IOP measurement. There was no significant difference in mean IOP between women taking combined versus those taking estrogen-only preparations. Conclusions: Our study showed that IOP was significantly lower in women taking HT than in those who had never taken HT, even after removing other possible influences on IOP. The IOP-lowering effect of HT deserves further investigation to explore whether it may represent a possible new therapeutic modality for glaucoma. © 2010 by The North American Menopause Society.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Risk factors (excluding hormone therapy) for endometrial hyperplasia: a systematic review.

Objective: To conduct a systematic review of risk factors associated with the development of Endometrial Hyperplasia (EH).

Data sources: Ovid MEDLINE, EMBASE and Web of Science databases were searched from inception to 30 June 2015.

Study eligibility: Fifteen observational studies that reported on EH risk in relation to lifestyle factors (n=14), medical history (n=11), reproductive and menstrual history (n=9) and measures of socio-economic status (n=2) were identified. Pooled relative risk estimates and corresponding 95% confidence intervals (CI) were able to be derived for EH and Body Mass Index (BMI), smoking, diabetes and hypertension, using random effects models comparing high versus low categories.

Results: The pooled relative risk for EH when comparing women with the highest versus lowest BMI was 1.82 (95% CI 1.22–2.71; n=7 studies, I2=90.4%). No significant associations were observed for EH risk for smokers compared with non-smokers (RR 0.88, 95% CI 0.66-1.17; n=3, I2=0.0%), hypertensive versus normotensive women (RR 1.51, 95% CI 0.72–3.15; n=5 studies, I2=79.1%), or diabetic versus non-diabetic women (RR 1.77, 95% CI 0.79–3.96; n=5 studies, I2=31.8%) respectively although the number of included studies was limited. There were mixed reports on the relationship between age and risk of EH. Too few studies reported on other factors to reach any conclusions in relation to EH risk.

Conclusions: A high BMI was associated with an increased risk of EH, providing additional rationale for women to maintain a normal body weight. No significant associations were detected for other factors and EH risk, however relatively few studies have been conducted and few of the available studies adequately adjusted for relevant confounders. Therefore, further aetiological studies of endometrial hyperplasia are warranted.

Development of a multi-gene PCR assay for the prediction of the response to hormone therapy in breast cancer

Deux tiers des cancers du sein expriment des récepteurs hormonaux ostrogéniques (tumeur ER-positive) et la croissance de ces tumeurs est stimulée par l’estrogène. Des traitements adjuvant avec des anti-estrogènes, tel que le Tamoxifen et les Inhibiteurs de l’Aromatase peuvent améliorer la survie des patientes atteinte de cancer du sein. Toutefois la thérapie hormonale n’est pas efficace dans toutes les tumeurs mammaires ER-positives. Les tumeurs peuvent présenter avec une résistance intrinsèque ou acquise au Tamoxifen. Présentement, c’est impossible de prédire quelle patiente va bénéficier ou non du Tamoxifen. Des études préliminaires du laboratoire de Dr. Mader, ont identifié le niveau d’expression de 20 gènes, qui peuvent prédire la réponse thérapeutique au Tamoxifen (survie sans récidive). Ces marqueurs, identifié en utilisant une analyse bioinformatique de bases de données publiques de profils d’expression des gènes, sont capables de discriminer quelles patientes vont mieux répondre au Tamoxifen. Le but principal de cette étude est de développer un outil de PCR qui peut évaluer le niveau d’expression de ces 20 gènes prédictif et de tester cette signature de 20 gènes dans une étude rétrospective, en utilisant des tumeurs de cancer du sein en bloc de paraffine, de patients avec une histoire médicale connue. Cet outil aurait donc un impact direct dans la pratique clinique. Des traitements futiles pourraient être éviter et l’indentification de tumeurs ER+ avec peu de chance de répondre à un traitement anti-estrogène amélioré. En conséquence, de la recherche plus appropriée pour les tumeurs résistantes au Tamoxifen, pourront se faire.

Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women

Context: Evidence is limited on the effects of different patterns of use of postmenopausal hormone therapy on fracture incidence and particularly on the effects of ceasing use. Objective: To investigate the effect of different patterns of hormone therapy use on fracture incidence. Design, Setting, and Participants: Prospective study of 138737 postmenopausal women aged 50 to 69 years recruited from the UK general population in 19961998 (the Million Women Study) and followed up for 1.9 to 3.9 years (average, 2.8 years) for fracture incidence. Main Outcome Measure: Adjusted relative risk (RR) for incident fracture (except fracture of the fingers, toes, and ribs) in hormone therapy users compared with never users at baseline. Results: A total of 5197 women (3.7%) reported 1 or more fractures, 79% resulting from falls. Current users of hormone therapy at baseline had a significantly reduced incidence of fracture (RR, 0.62; 95% confidence interval [CI], 0.58-0.66; P<.001). This protection was evident soon after hormone therapy began, and the RR decreased with increasing duration of use (P=.001). Among current users at baseline the RR of fracture did not vary significantly according to whether estrogen-only, estrogen-progestin, or other types of hormones were used (RR [95% CI], 0.64 [0.58-0.71], 0.58 [0.53-0.64], and 0.67 [0.56-0.80], respectively; P=19), nor did it vary significantly according to estrogen dose or estrogen or progestin constituents. The RR associated with current use of hormone therapy did not vary significantly according to 11 personal characteristics of study participants, including their age at menopause, body mass index, and physical activity. Past users of hormone therapy at baseline experienced no significant protection against fractures (RR, 1.07; 95% CI, 0.99-1.15); incidence rates returned to those of never-users within about a year of ceasing use. Conclusions: All types of hormone therapy studied confer substantial protection against fracture while they are used. This protection appears rapidly after use commences and wears off rapidly after use ceases. The older women are, the greater is their absolute reduction in fracture incidence while using hormone therapy.

Polymer therapeutics designed for a combination therapy of hormone-dependent cancer

Designer drug: A polymer therapeutic was designed for a combination therapy of breast cancer. N-(2-Hydroxypropyl)methacrylamide was used as the model polymer platform to prepare a unimolecular polymer conjugate (see picture, radius of gyration: 12.8 nm) that combines an endocrine (the aromatase inhibitor aminoglutethimide, blue) and a chemotherapeutic agent (the anthraxcycline antibiotic doxorubicin, red).

Adjuvant therapy with GnRH agonists/tamoxifen in breast cancer should be a good council for patients with hormone receptor-positive tumours and wish to preserve fertility

Infertility represents one of the main long-term consequences of the chemotherapy used for the adjuvant treatment of breast cancer. Approximately 60-65% of breast cancers express the nuclear hormone receptor in premenopausal women. Adjuvant endocrine therapy is an integral component of care for patients with hormone receptor-positive (HR+) tumours. The GnRH agonist (GnRHa) alone or in combination with tamoxifen produces results at least similar to those obtained with the different chemotherapy protocols in patients with HR+ breast cancer with respect to recurrence-free survival and overall survival. It is time to indicate adjuvant therapy with GnRHa associated with tamoxifen for patients with breast cancer (HR+ tumours) if they want to preserve their reproductive function. The evaluation of ovarian reserve tests: follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH), inhibin B, antral follicle count (AFC) and ovarian volume 6 months, and 1 year after the end of therapy with GnRHa/tamoxifen must be realised. The recurrence-free survival and overall survival should be analysed. The major implication of this hypothesis will be to avoid adjuvant chemotherapy for patients with breast cancer (HR+ tumours) that request fertility preservation. It is expected that ovarian function should not be altered in almost all cases and subsequent pregnancy a real possibility. (C) 2012 Elsevier Ltd. All rights reserved.

Effect of hormone therapy on postural balance in postmenopausal women

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Improvement of embryo production by the replacement of the last two doses of porcine follicle-stimulating hormone with equine chorionic gonadotropin in Sindhi donors

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of combined hormonal and insulin therapy on the steroid hormone receptors and growth factors signalling in diabetic mice prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)