Testosterone nadir and clinical outcomes in patients with advanced prostate cancer: Post hoc analysis of triptorelin pamoate Phase III studies.

Objective: The objective of the study is to evaluate whether low nadir testosterone during treatment with triptorelin pamoate, a luteinising hormone-releasing hormone (LHRH) agonist, is associated with improved clinical outcomes in patients with advanced prostate cancer using a retrospective analysis of clinical trial data. Patients and methods: Data were pooled from three prospective, 9-12-month Phase III studies of triptorelin monotherapy in patients with advanced prostate cancer (including NCT00751790). The serum testosterone concentration suppression targets evaluated were <0.35 nmol/L (<10 ng/dl), <0.7 nmol/L (<20 ng/dl), <1.7 nmol/L (<50 ng/dl) and ≥1.7 nmol/L. Overall survival (OS) and disease-specific survival (DSS) by testosterone suppression group were assessed by Kaplan-Meier analysis, with log-rank test. The time frame for the primary analysis was Days 1-518 (median OS follow-up 254 days [range, 29-518 days]) and for the sensitivity analyses was Days 1-262. Supplementary analyses combined the ≥0.7- to <1.7-nmol/L and ≥1.7-nmol/L groups. Results: The sample size comprised 592 patients (most received triptorelin monotherapy; four reported concomitant androgen receptor-axis-targeted therapy). Nadir testosterones of <0.35, ≥0.35 to <0.7, ≥0.7 to <1.7 and ≥1.7 nmol/L were achieved by 96%, 3.2%, 0.34% and 0.17% of patients, respectively. Better OS with decreasing level of nadir testosterone was observed (p < 0.001) and this persisted after sensitivity/supplemental analyses (all p < 0.001). Differences in DSS with decreasing levels of nadir testosterone were not statistically significant in the primary analysis. Sensitivity/supplemental analysis showed better DSS with decreasing level of nadir testosterone (Days 1-262, p = 0.01; combined groups Days 1-518, p = 0.03; combined groups Days 1-262, p = 0.005). Conclusion: Low nadir testosterone achieved during treatment with the LHRH agonist triptorelin was associated with improved OS and DSS in patients with advanced prostate cancer.

Cardiovascular safety of mirabegron: analysis of an integrated clinical trial database of patients with overactive bladder syndrome.

Mirabegron is a ß3-adrenoreceptor agonist used for the treatment of overactive bladder syndrome. We evaluated the cardiovascular (CV) safety of mirabegron using pooled data from 13 studies. The analysis included 13,396 patients who received ≥1 dose of mirabegron (25 mg/50 mg) or comparator antimuscarinics (solifenacin 2.5 mg/5 mg/10 mg or tolterodine extended release 4 mg) as monotherapies, or placebo. We focused on changes in blood pressure and CV adverse events. Baseline CV risk factors had an imbalanced effect on subsequent CV adverse events. The frequency of these adverse events was comparable for overactive bladder treatments (0.4%-1.5%) and placebo (0.9%). Changes from baseline in blood pressure were similar for the overactive bladder treatments and placebo, and did not confer increased risk of CV adverse events. Multivariate analyses demonstrated that baseline CV risk factors (history of arrhythmia, history of coronary artery disease, and history of stroke/transient ischemic attack) were significantly associated with subsequent CV adverse events in the trials, whereas overactive bladder therapies were not. In conclusion, using an analytical approach to carefully control for CV characteristics of patients in these trials demonstrated no evidence of increased CV risk for mirabegron or antimuscarinics over placebo in the treatment of overactive bladder syndrome.

A randomized feasibility study of docetaxel versus vinorelbine in advanced breast cancer.

BACKGROUND: Docetaxel and vinorelbine have demonstrated efficacy in the treatment of metastatic breast cancer (MBC). This prospective feasibility study compared the efficacy of these two treatments in MBC. METHODS: Patients with MBC progressing following anthracycline treatment were randomly assigned to either docetaxel (100 mg/m(2)day 1 q3W) or vinorelbine (25mg/m(2) day 1 q2W). Patients were eligible to cross over at progression. Objective response rates (ORR), time to progression (TTP) and overall survival (OS) were measured. RESULTS: 37 patients were randomised. 2 patients were excluded due to protocol violations. Of 35 remaining patients 17 received docetaxel and 18 received vinorelbine per protocol. ORR was 12.5% and 6.0% respectively for docetaxel and vinorelbine. The median time to progression was 10.4 weeks (range 6-14 weeks) in docetaxel arm and 7.6 weeks (range 4-11 weeks) in vinorelbine arm (p = .82). The clinical benefit rate (defined as complete response, partial response plus stable disease) was 44% in the docetaxel arm and 12% in the vinorelbine arm. Based on intent to treat the median OS in the docetaxel arm was 34 weeks (95% CI, 20.7-48) and 21.2 weeks (95% CI, 17-25.4) in vinorelbine arm (p = .388). 16 patients crossed over, 5 from docetaxel to vinorelbine and 11 from vinorelbine to docetaxel. At cross over the ORR was 0% and 18% on cross over to vinorelbine and docetaxel respectively with a median TTP of 17.3 weeks (95% CI, 16.3-18.1) and 18.7 weeks (95% CI, 13.9-23.4) for those receiving vinorebine and docetaxel at cross over respectively. Vinorelbine however was much better tolerated with fewer grade 3-4 toxicity events (n = 4) than docetaxel (n = 27). DISCUSSION: While docetaxel resulted in a longer TTP and OS in this study it did not reach statistical significance. TTP duration for those patients who crossed over was similar, but overwhelmingly vinorelbine had fewer significant grade 3-4 toxicities than docetaxel. Only two previous randomized studies have compared the efficacy of single agent docetaxel and vinorelbine following prior anthracycline exposure, one in an unselected population [16], and the other, HERNATA, in HER2 positive disease with trastuzumab used in both arms [17]. The patients randomized in this study were relatively heavily pretreated with the majority having received 2-3 lines of prior treatment for their metastatic disease. The lower response rates with vinorelbine as compared to docetaxel in this study concur with results reported in other studies [16]. However, the numbers in both this study and the other unselected study [16] are small and need to be interpreted with caution. With regard to toxicity, in the present study, grade 3-4 hematological adverse events and infection were tenfold greater with docetaxel as compared with vinorelbine, consistent with results in HERNATA [17]. While others have reported a significantly higher number of overall grade 3-4 toxicities with vinorelbine [16], the fact that, as in HERNATA, discontinuations due to toxicities in that study [16] were significantly greater with docetaxel as compared to vinorelbine suggests either the toxicity data collected did not reflect the true toxicities on treatment or that docetaxel toxicities were in some way more severe or protracted leading to more numerous discontinuations [16]. Larger randomized studies are needed to determine (1) the efficacy of docetaxel versus vinorelbine in anthracycline pretreated disease and (2) the efficacy of vinorelbine after prior taxane exposure, and particularly how it may compares both with regard to efficacy and tolerability with other possible regimens that may utilized such as carboplatin-gemcitabine [20] or eribulin [21]. The longer as well as comparable TTP at cross over for both agents compared to that upfront suggests there may be enrichment at cross over of a group of patients who are not only fit for further treatment but are more likely to a derive continued benefit from additional treatment.

Management and outcome of HER2-positive early breast cancer treated with or without trastuzumab in the adjuvant trastuzumab era.

BACKGROUND: Adjuvant trastuzumab (AT) is known to significantly improve survival of women with HER2(+) early breast cancer. This study explores the use and nonuse of AT in early breast cancer, as well as the efficacy in a neoadjuvant and adjuvant population, within a routine clinical setting. PATIENTS AND METHODS: Histopathology reports of invasive breast cancer resected at Imperial College Healthcare NHS Trust (ICHT) between January 2006 and December 2008 were reviewed. HER2(+) patients were identified and their case notes reviewed. In addition, patients who received AT at our center but underwent surgery elsewhere were included in the efficacy and safety analyses. RESULTS: The local HER2(+) rate was 13.1%, with 54.5% of these patients receiving AT. A total of 128 patients received AT (85 local and 43 referrals from elsewhere). Neoadjuvant chemotherapy (CT) followed by postoperative AT was associated with a significantly increased risk of recurrence compared with adjuvant CT and then AT (hazard ratio [HR] 18.6 [95% CI, 1.8-152.2]; P = .013). The proportion of patients who were disease free at 3 years from primary therapy was 96.4% (95% CI, 89.8%-100%) for adjuvant therapy, compared with 72.0% (95% CI, 56.5%-91.6%) for neoadjuvant therapy. AT was omitted in 49 HER2(+) patients; the main reason for AT omission was clinical judgment that the breast cancer was low risk. Patients treated with AT had a significantly decreased risk of recurrence (HR 0.27 [95% CI, 0.08-0.97]; P = .04) compared with the untreated patients. The majority of untreated relapses were in patients in whom there was an original intent to use AT. The proportion alive at 3 years for adjuvant CT, neoadjuvant CT, and untreated AT was 100%, 74.5%, and 92.7% respectively. CONCLUSION: The overall efficacy and safety of AT in our routine clinical setting is comparable to the large randomized trials. HER2(+) patients who underwent neoadjuvant CT had a significantly increased risk of disease recurrence compared with patients treated with adjuvant CT followed by trastuzumab. Untreated patients had an increased risk of recurrence.

Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease.

Cilomilast (Ariflo), a new oral phosphodiesterase-4 selective inhibitor, improves lung function in chronic obstructive pulmonary disease (COPD). We have evaluated its antiinflammatory effects in 59 patients with COPD randomized to receive cilomilast, 15 mg two times a day, or placebo for 12 weeks. Induced sputum differential cell counts were obtained at baseline and at five further visits. Interleukin-8 and neutrophil elastase were measured in sputum supernatant. Bronchial biopsies obtained at baseline and at Week 10 were immunostained and counted for neutrophils, CD8+ and CD4+ T-lymphocyte subsets, and CD68+ macrophages. Cells expressing the genes for interleukin-8 and tumor necrosis factor-alpha were identified by in situ hybridization and quantified. Compared with placebo, analysis of variance (ANOVA) of the change from baseline showed that cilomilast did not alter any sputum endpoint or FEV1. However, bronchial biopsies demonstrated that cilomilast treatment was associated with reductions in CD8+ (p = 0.001; ANOVA) and CD68+ cells (p < 0.05; ANOVA). In addition, by Poisson analysis, comparison of cell counts analyzed as a ratio of active to placebo demonstrated reductions of CD8+ (48% p < 0.01) and CD68+ (47% p = 0.001) cells. This is the first demonstration of reduction by any agent of airway tissue inflammatory cells characteristic of COPD. Phosphodiesterase-4 inhibitors represent a promising new class of substances for use in antiinflammatory treatment of this disease.

Right ventricular function in adults with repaired tetralogy of Fallot assessed with cardiovascular magnetic resonance imaging: detrimental role of right ventricular outflow aneurysms or akinesia and adverse right-to-left ventricular interaction.

OBJECTIVES: We examined the relationship among biventricular hemodynamics, pulmonary regurgitant fraction (PRF), right ventricular outflow tract (RVOT) aneurysm or akinesia, and baseline and surgical characteristics in adults with repaired tetralogy of Fallot (rTOF). BACKGROUND: The precise relationship of pulmonary regurgitation with biventricular hemodynamics has been hampered by limitations of right ventricular (RV) imaging. METHODS: We assessed 85 consecutive adults with rTOF and 26 matched healthy controls using cardiovascular magnetic resonance imaging. RESULTS: Patients had higher right ventricular end-diastolic volume index (RVEDVi) (p < 0.001), right ventricular end-systolic volume index (RVESVi) (p < 0.001), right ventricular mass index (RVMi) (p < 0.001), and lower right ventricular ejection fraction (RVEF) (p < 0.001) and left ventricular ejection fraction (LVEF) (p = 0.002) compared to controls. The PRF (range 0% to 55%) independently predicted RVEDVi (p < 0.01) and the latter predicted RVESVi (p < 0.01) and RVMi (p < 0.01). The RVOT aneurysm/akinesia was present in 48/85 (56.9%) of patients and predicted RV volumes (RVEDVi, p = 0.01, and RVESVi, p = 0.03). There was a negative effect of RVOT aneurysm/akinesia and RVMi on RVEF (p < 0.01 and p = 0.02, respectively). There was only a tendency among patients with transannular or RVOT patching toward RVOT aneurysm/akinesia (p = 0.09). The LVEF correlated with RVEF (r = 0.67, p < 0.001). CONCLUSIONS: Pulmonary regurgitation and RVOT aneurysm/akinesia were independently associated with RV dilation and the latter with RV hypertrophy late after rTOF. The RVOT aneurysm/akinesia was common but related only in part to RVOT or transannular patching. Both RV hypertrophy and RVOT aneurysm/akinesia were associated with lower RVEF. Left ventricular systolic dysfunction correlated with RV dysfunction, suggesting an unfavorable ventricular-ventricular interaction. Measures to maintain or restore pulmonary valve function and avoid RVOT aneurysm/akinesia are mandatory for preserving biventricular function late after rTOF.