Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

A phase III, randomized, double blinded trial of platinum based chemotherapy with or without atezolizumab followed by niraparib maintenance with or without atezolizumab in patients with recurrent ovarian, tubal, or peritoneal cancer and platinum treatment free interval of more than 6 months: ENGOT-Ov41/GEICO 69-O/ANITA Trial.

BACKGROUND: Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity. PRIMARY OBJECTIVE: To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months. TRIAL DESIGN: The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab. MAJOR INCLUSION/EXCLUSION CRITERIA: Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1. PRIMARY ENDPOINT: The primary endpoint for this study is progression free survival. SAMPLE SIZE: Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023. TRIAL REGISTRATION: Clinicaltrials.gov NCT03598270.

Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.

BACKGROUND: Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS: Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS: Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency. (Funded by GlaxoSmithKline; PRIMA/ENGOT-OV26/GOG-3012 ClinicalTrials.gov number, NCT02655016.).

Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial.

BACKGROUND: Platinum-based chemotherapy is the foundation of treatment for platinum-sensitive recurrent ovarian cancer, but has substantial toxicity. Bevacizumab and maintenance poly(ADP-ribose) polymerase (PARP) inhibitors both significantly improve efficacy versus standard therapy, primarily in terms of progression-free survival, and offer the potential for chemotherapy-free treatment. AVANOVA2 compared niraparib and bevacizumab versus niraparib alone as definitive treatment for platinum-sensitive recurrent ovarian cancer. METHODS: This open-label, randomised, phase 2, superiority trial in 15 university hospitals in Denmark, Sweden, Finland, Norway, and the USA enrolled women aged 18 years or older with measurable or evaluable high-grade serous or endometrioid platinum-sensitive recurrent ovarian cancer. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2, and had to have previously received platinum-containing therapy for primary disease but ≤1 prior non-platinum-containing regimen for recurrent disease. Previous treatment with bevacizumab or first-line maintenance PARP inhibitors was permitted. Eligible patients were randomly assigned 1:1 (by random permuted blocks with block sizes of two and four, no masking), stratified by homologous recombination deficiency status and chemotherapy-free interval, to receive once-daily oral niraparib 300 mg alone or with intravenous bevacizumab 15 mg/kg once every 3 weeks until disease progression. The primary endpoint was progression-free survival, assessed by the investigators in the intention-to-treat population after events in at least 62 patients. Safety was analysed in all patients who received at least one dose of study drug. This ongoing trial is registered with ClinicalTrials.gov, number NCT02354131. FINDINGS: Between May 23, 2016, and March 6, 2017, 97 patients were enrolled and randomly assigned: 48 to niraparib plus bevacizumab and 49 to single-agent niraparib. Median follow-up was 16·9 months (IQR 15·4-20·9). Niraparib plus bevacizumab significantly improved progression-free survival compared with niraparib alone (median progression-free survival 11·9 months [95% CI 8·5-16·7] vs 5·5 months [3·8-6·3], respectively; adjusted hazard ratio [HR] 0·35 [95% CI 0·21-0·57], p<0·0001). Grade 3 or worse adverse events occurred in 31 (65%) of 48 patients who received niraparib plus bevacizumab and 22 (45%) of 49 who received single-agent niraparib. The most common grade 3 or worse adverse events in both groups were anaemia (7 [15%] of 48 vs 9 [18%] of 49) and thrombocytopenia (5 [10%] vs 6 [12%]), and hypertension in the combination group (10 [21%] vs 0). Niraparib plus bevacizumab was associated with increased incidences of any-grade proteinuria (10 [21%] of 48 patients vs 0) and hypertension (27 [56%] of 48 vs 11 [22%] of 49) compared with niraparib alone. No treatment-related deaths occurred. INTERPRETATION: The efficacy observed with this chemotherapy-free combination of approved agents in women with platinum-sensitive recurrent ovarian cancer warrants further evaluation. A randomised phase 3 trial investigating niraparib plus bevacizumab versus chemotherapy plus bevacizumab in platinum-sensitive recurrent ovarian cancer is planned. FUNDING: Nordic Society of Gynaecological Oncology and Tesaro.

Postponement of Death by Statin Use: a Systematic Review and Meta-analysis of Randomized Clinical Trials.

BACKGROUND: The average postponement of the outcome (gain in time to event) has been proposed as a measure to convey the effect of preventive medications. Among its advantages over number needed to treat and relative risk reduction is a better intuitive understanding among lay persons. OBJECTIVES: To develop a novel approach for modeling outcome postponement achieved within a trial's duration, based on published trial data and to present a formalized meta-analysis of modeled outcome postponement for all-cause mortality in statin trials. METHODS: The outcome postponement was modeled on the basis of the hazard ratio or relative risk, the mortality rate in the placebo group and the trial's duration. Outcome postponement was subjected to a meta-analysis. We also estimated the average outcome postponement as the area between Kaplan-Meier curves. Statin trials were identified through a systematic review. RESULTS: The median modeled outcome postponement was 10.0 days (interquartile range, 2.9-19.5 days). Meta-analysis of 16 trials provided a summary estimate of outcome postponement for all-cause mortality of 12.6 days, with a 95% postponement interval (PI) of 7.1-18.0. For primary, secondary, and mixed prevention trials, respectively, outcome postponements were 10.2 days (PI, 4.0-16.3), 17.4 days (PI, 6.0-28.8), and 8.5 days (PI, 1.9-15.0). CONCLUSIONS: The modeled outcome postponement is amenable to meta-analysis and may be a useful approach for presenting the benefits of preventive interventions. Statin treatment results in a small increase of average survival within the duration of a trial. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered in PROSPERO [CRD42016037507] .

Programmed Death Ligand-1 expression in stage II colon cancer - experiences from a nationwide populationbased cohort.

BACKGROUND: Patients suffering from high risk stage II colon cancer (CC) may benefit from adjuvant onco-therapy, but additional prognostic markers are needed for better treatment stratification. We investigated the prognostic value of Programmed Death Ligand-1 (PD-L1) in a true population-based cohort of patients with stage II CC. METHODS: PD-L1 expression on tumour cells was evaluated by immunohistochemistry in 572 colon cancers. Whole sections from tumour blocks representing the deepest invasive front of the primary tumour were used for analysis. A cut-off of 5% positivity was used for dichotomizing the data. The prognostic value was investigated in Cox proportional hazard models for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Overall, 6% of the tumours were classified as high PD-L1. High PD-L1 was related to female gender (p = 0.028), high malignancy grade (< 0.001), right side localization (p < 0.001) and microsatellite instability (MSI) (p < 0.001). Thirty-one (18%) of the MSI and 4 (1%) of the microsatellite stable tumours were classified as high PD-L1, respectively. PD-L1 expression provided no prognostic value as a single marker. In patients with MSI tumours, high PD-L1 expression had no significant impact regarding OS or RFS. CONCLUSIONS: PD-L1 expression in tumour cells of stage II CC did not provide any prognostic impact, neither in the entire population-based cohort nor in the group of MSI patients. Additional investigations of the immunogenic microenvironment are needed for evaluating the prognostic information in CC.

Dementia and road traffic accidents among non-institutionalized older people in Denmark: A Danish register-based nested case-control study.

AIM: We used register-based data to estimate the effect of all-type dementia on road traffic accidents (RTAs) risk, combined with comorbidities or sedative medicines, among non-institutionalized older people in Denmark. METHODS: The source population was all residents in Denmark aged 65 years and older, alive as of January 1, 2008 ( n = 853,228). Cases were those who had any type of RTA in 2009-2014. Each case was matched for age, sex and geographic location to 4-6 controls. All-type dementia was ascertained using the International Classification of Diseases version 10 (ICD-10) diagnosis supplemented with prescribed medicine records. Eight chronic diseases were selected to assess comorbidities. Four types of medicines were categorized as sedative medicines for analysis. Conditional logistic regression with adjustment for education and marital status as well as either the number of comorbidities or sedative medications use was performed using STATA software. RESULTS: Older people with dementia had lower RTAs risk compared to their controls (odds ratio = 0.43, 95% confidence interval (0.32-0.60), p < 0.001). Significant interaction was observed between dementia and the number of comorbidities for RTAs estimation. CONCLUSIONS: The significantly lower RTAs risk for older individuals with dementia observed in our study may be due to people with dementia living at home having a lower frequency of outdoor activities; that is, less exposure to traffic. However, this, together with the interaction between dementia and comorbidities as well as sedative medications, should be investigated further.

Effectiveness of a comprehensive interactive eHealth intervention on patient-reported and clinical outcomes in patients with an implantable cardioverter defibrillator [ACQUIRE-ICD trial]: study protocol of a national Danish randomised controlled trial.

BACKGROUND: In Denmark and other countries, there has been a shift in the management of patients with an implantable cardioverter defibrillator (ICD) with remote device monitoring largely replacing in-hospital visits. Less patient-nurse and patient-physician interaction may lead to gaps in patients' quality of care and impede patients' adaptation to living successfully with the ICD. A comprehensive eHealth intervention that include goal-setting, monitoring of symptoms of depression, anxiety, and quality of life, psychological treatment, information provision, supportive tools, online dialogues with nursing staff and access to an online community network, may help fill these gaps and be particularly beneficial to patients who suffer from anxiety and depression. This study will evaluate the effectiveness of the ACQUIRE-ICD care innovation, a comprehensive and interactive eHealth intervention, on patient-reported and clinical outcomes. METHODS: The ACQUIRE-ICD study is a multicenter, prospective, two-arm, unblinded randomised controlled superiority trial that will enroll 478 patients implanted with a first-time ICD or ICD with cardiac synchronisation therapy (CRT-D) from the six implanting centers in Denmark. The trial will evaluate the clinical effectiveness and cost-effectiveness of the ACQUIRE-ICD care innovation, as add-on to usual care compared with usual care alone. The primary endpoint, device acceptance, assessed with the Florida Patient Acceptance Survey, is evaluated at 12 months' post implant. Secondary endpoints, evaluated at 12 and 24 months' post implant, include patient-reported outcomes, return to work, time to first ICD therapy and first hospitalisation, mortality and cost-effectiveness. DISCUSSION: The effectiveness of a comprehensive and interactive eHealth intervention that relies on patient-centred and personalised tools offered via a web-based platform targeted to patients with an ICD has not been assessed so far. The ACQUIRE-ICD care innovation promotes and facilitates that patients become active participants in the management of their disease, and as such addresses the need for a more patient-centered disease-management approach. If the care innovation proves to be beneficial to patients, it may not only increase patient empowerment and quality of life but also free up time for clinicians to care for more patients. TRIAL REGISTRATION: The trial has been registered on https://clinicaltrials.gov/ct2/show/NCT02976961 on November 30, 2016 with registration number [ NCT02976961 ].

The Prognostic Value of Tumor-Infiltrating lymphocytes in Stage II Colon Cancer. A Nationwide Population-Based Study.

BACKGROUND: Additional prognostic markers are needed for better treatment stratification of stage II colon cancer (CC). We investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in a true population-based cohort of patients with stage II CC. MATERIAL AND METHODS: A total of 573 patients were included. Tumor blocks representing the deepest invasive part of the primary tumor were used for analysis. CD3+ and CD8+ TILs at the invasive front were evaluated by immunohistochemistry on whole tumor sections. The invasive area was manually outlined, and Visiopharm Integrator System software was used for quantification. Data were dichotomized for comparison with clinical data. The prognostic value was investigated in Cox proportional-hazard models for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Low CD3+ or CD8+ TILs were significantly associated with poor RFS and OS (P = .0021 and P ≤ .0009, respectively, log-rank test). In multiple Cox regression analysis, low CD3+ and CD8+ TILs were associated with reduced RFS with hazard ratio (HR) = 1.386 (95% CI 1.039-1.850), P = .026, and HR = 1.394 (95% CI 1.029-1.890), P = .032, respectively, independent of age, T-stage, localization, perforation, and microsatellite instability (MSI). In the subgroups of patients with low CD3+ or CD8+ TILs, there was no difference in survival between patients with MSI and microsatellite-stable tumors, (P = .821 and P = .907, respectively). CONCLUSION: Low CD3+ and CD8+ TILs in the invasive area are both related to inferior prognosis of stage II CC, and we recommend either of these parameters to be considered as additional high-risk factor.

The prognostic value of tumour stroma ratio and tumour budding in stage II colon cancer. A nationwide population-based study.

PURPOSE: High-risk patients with stage II colon cancer (CC) may benefit from adjuvant chemotherapy, but additional prognostic markers are needed for better stratification. We investigated the prognostic value of tumour stroma ratio (TSR) and tumour budding (TB). METHODS: A nationwide population-based cohort of 573 patients with stage II CC was included. TSR was scored on hematoxylin and eosin sections as low TSR (> 50% stroma) and high TSR (≤ 50% stroma). TB was evaluated in hotspots on pan-cytokeratin stained sections in 10 high power fields (HPF) at the invasive front and classified by the mean number of buds per HPF as high grade budding (≥ 10 buds) or low-grade budding (< 10 buds). The prognostic value was investigated in Cox proportional hazard models for recurrence-free survival (RFS) and overall survival (OS). RESULTS: Low TSR was associated with worse RFS (HR = 1.342 (95% CI 1.006-1.791), p = 0.045) and OS (HR = 1.376 (95% CI 1.016-1.862), p = 0.039). Furthermore, an association was found between low TSR and microsatellite stabile tumours (p < 0.001). The mean number of buds per HPF was associated to TSR with increasing number of buds related to a lower TSR (p = 0.026). No statistically significant prognostic impact of TB regarding OS or RFS was detected. CONCLUSIONS: TSR provided valuable prognostic information, and adding TSR to the current risk stratification may contribute to better patient selection. The estimates of TSR and TB were found to be associated, but no prognostic value of TB was documented.

Does heterogeneity matter in the estimation of tumour budding and tumour stroma ratio in colon cancer?

BACKGROUND: Tumour budding (TB) and Tumour Stroma Ratio (TSR) may be rewarding in the treatment stratification of patients with stage II colon cancer. However, lack of standardization may exclude these parameters from being used in a clinical setting. The purpose of this methodologic study was to compare stereology with semi-quantitative estimations of TSR, to investigate the intra-tumoural heterogeneity of TB and TSR, and to assess the intra- and inter-observer agreement. METHODS: Three paraffin embedded tumour blocks, one of them representing the deepest invasive front, were selected from each of 43 patients treated for stage II colon cancer. TSR was estimated in H&E sections semi-quantitatively using conventional microscopy, and stereologically on scanned slides, using the newCAST stereology platform. TB was scored across 10 high power fields at the invasive front in cytokeratin AE1/AE3 stained sections. RESULTS: Subjective, semi-quantitative estimates of TSR significantly correlated to the stereological estimates, with the best correlation found for sections with the deepest invasive tumour penetration (σ = 0.621, p < 0.001). Inter-observer agreement was moderate to substantial for both TB (Κappa = 0.46-0.73) and TSR (Κappa = 0.70-0.75). The Intraclass correlation coefficient (ICC) for TSR varied from 0.322 based on stereological hotspot estimation to 0.648 for the semi-quantitative evaluation. For TB, ICC varied from 0.646 based on continuous data to 0.698 based on categorical data (cut-off: 10 buds). Thus, the intra-tumoural heterogeneity for both TB and the semi-quantitative estimation of TSR was low. CONCLUSION: We recommend using only one tissue section representing the deepest invasive tumour area for estimation of TSR. For TB we recommend using one tissue section; however due to low representation of high-budding tumours, results must be considered with caution.

Computer-assisted stereology and automated image analysis for quantification of tumor infiltrating lymphocytes in colon cancer.

BACKGROUND: Precise prognostic and predictive variables allowing improved post-operative treatment stratification are missing in patients treated for stage II colon cancer (CC). Investigation of tumor infiltrating lymphocytes (TILs) may be rewarding, but the lack of a standardized analytic technique is a major concern. Manual stereological counting is considered the gold standard, but digital pathology with image analysis is preferred due to time efficiency. The purpose of this study was to compare manual stereological estimates of TILs with automatic counts obtained by image analysis, and at the same time investigate the heterogeneity of TILs. METHODS: From 43 patients treated for stage II CC in 2002 three paraffin embedded, tumor containing tissue blocks were selected one of them representing the deepest invasive tumor front. Serial sections from each of the 129 blocks were immunohistochemically stained for CD3 and CD8, and the slides were scanned. Stereological estimates of the numerical density and area fraction of TILs were obtained using the computer-assisted newCAST stereology system. For the image analysis approach an app-based algorithm was developed using Visiopharm Integrator System software. For both methods the tumor areas of interest (invasive front and central area) were manually delineated by the observer. RESULTS: Based on all sections, the Spearman's correlation coefficients for density estimates varied from 0.9457 to 0.9638 (p < 0.0001), whereas the coefficients for area fraction estimates ranged from 0.9400 to 0.9603 (P < 0.0001). Regarding heterogeneity, intra-class correlation coefficients (ICC) for CD3+ TILs varied from 0.615 to 0.746 in the central area, and from 0.686 to 0.746 in the invasive area. ICC for CD8+ TILs varied from 0.724 to 0.775 in the central area, and from 0.746 to 0.765 in the invasive area. CONCLUSIONS: Exact objective and time efficient estimates of numerical densities and area fractions of CD3+ and CD8+ TILs in stage II colon cancer can be obtained by image analysis and are highly correlated to the corresponding estimates obtained by the gold standard based on stereology. Since the intra-tumoral heterogeneity was low, this method may be recommended for quantifying TILs in only one histological section representing the deepest invasive tumor front.

Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer: a phase III, randomised, multicentre trial (Ovaresist).

BACKGROUND: Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. METHODS: Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). RESULTS: Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. CONCLUSIONS: Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.

Satisfaction with sex life in sexually active heterosexual couples dealing with breast cancer: a nationwide longitudinal study.

BACKGROUND: A breast cancer (BC) diagnosis can profoundly affect the sex life of patient and partner within a couple. The purpose of the present study is to examine whether individual and partner sexual functioning, affectionate behavior, emotional closeness and depressive symptoms are associated with change over time in satisfaction with sex life of sexually active heterosexual couples dealing with BC and to explore whether the associations differ between patients and partners after adjustment for basic sociodemographic characteristics, comorbidity and BC treatment. MATERIAL AND METHODS: Women with BC and their male partners participated in a longitudinal study (Time 1, ≤4 months after surgery; Time 2, 5 months later). Participants completed items from the PROMIS® Sexual Function and Satisfaction measure (version 1.0), two items measuring affectionate behavior, a single item measuring emotional closeness and the Center for Epidemiologic Studies-Depression Scale. Registers provided sociodemographic and medical information. Multilevel models were used, which take the interdependency of couples' scores into account. RESULTS: A total of 287 sexually active couples were included in the analyses. Less vaginal discomfort and more vaginal lubrication were associated with increases in patients' satisfaction with sex life. Patients' and partners' satisfaction increased with higher ratings of their own orgasm ability and of partners' timing of ejaculation. Patients' reports of affectionate behavior were positively associated with their partners' satisfaction, and vice versa for partners. Patients' satisfaction increased the more emotional closeness their partner experienced. Partners' depressive symptoms were negatively associated with their satisfaction. Sociodemographic factors and BC treatment were not significantly associated with change in satisfaction. CONCLUSION: Satisfaction with sex life in sexually active couples dealing with BC needs to be seen as a couple issue. Health professionals should take the partner into account when addressing sexuality issues. Couples' functioning and relationship-related factors may be promising targets for couple interventions.

Medical engagement and organizational characteristics in general practice.

BACKGROUND: Medical engagement is a mutual concept of the active and positive contribution of doctors to maintaining and enhancing the performance of their health care organization, which itself recognizes this commitment in supporting and encouraging high quality care. A Medical Engagement Scale (MES) was developed by Applied Research Ltd (2008) on the basis of emerging evidence that medical engagement is critical for implementing radical improvements. OBJECTIVES: To study the importance of medical engagement in general practice and to analyse patterns of association with individual and organizational characteristics. DESIGN AND SETTING: A cross-sectional study using a sampled survey questionnaire and the official register from the Danish General Practitioners' Organization comprising all registered Danish GPs. METHOD: The Danish version of the MES Questionnaire was distributed and the survey results were analysed in conjunction with the GP register data. RESULTS: Statistically adjusted analyses revealed that the GPs' medical engagement varied substantially. GPs working in collaboration with colleagues were more engaged than GPs from single-handed practices, older GPs were less engaged than younger GPs and female GPs had higher medical engagement than their male colleagues. Furthermore, GPs participating in vocational training of junior doctors were more engaged than GPs not participating in vocational training. CONCLUSION: Medical engagement in general practice varies a great deal and this is determined by a complex interaction between both individual and organizational characteristics. Working in collaboration, having staff and being engaged in vocational training of junior doctors are all associated with enhanced levels of medical engagement among GPs.

Vaginal vault recurrences of endometrial cancer in non-irradiated patients - Radiotherapy or surgery.

BACKGROUND: The treatment of locally recurrent endometrial cancer is based on limited evidence. The standard treatment is radiotherapy (RT) which is effective for local control and the effect has been documented in prospective studies. Investigations of surgical treatment (ST) of recurrences are few and limited to previously irradiated patients or patients with advanced disease. Investigation of surgical treatment for isolated vaginal vault recurrence is practically nonexistent. The aim of this study is to evaluate the efficacy of RT and ST in a non-irradiated group with recurrent endometrial cancer limited to the vaginal vault. METHODS: Patients treated for recurrent endometrial cancer at Odense University Hospital, Denmark between 2003 and 2012 were identified, n = 118. Thirty-three patients had an isolated vaginal vault recurrence and were treated with either RT, ST or both. Re-recurrence rates and survival rates were calculated at 2 year follow-up using Fishers exact test. RESULTS: Twenty-six patients were treated with RT, 5 with ST, 2 with both. The mean (SD) follow-up-time was 4.4 years (2.99) (RT) and 3.9 years (0.90) (ST). Two year re-recurrence rates were 40% (RT) (95 CI 9.2-48%) and 0% (ST) (95 CI 0-60%). Two-year survival rates were 83% (RT) (95 CI 71-100%) and 100% (ST) (95 CI 40-100%) ST had one re-recurrence at 2.3 years. CONCLUSION: This study indicates that ST is an appropriate treatment for locally recurrent endometrial cancer. Our study involves a limited number of patients and is made retrospectively, therefore prospective and ideally randomized trials evaluating both survival and complications are warranted.

Generic switching and non-persistence among medicine users: a combined population-based questionnaire and register study.

BACKGROUND: Generic substitution means that one medicinal product is replaced by another product containing the same active substance. It is strictly regulated with respect to its bioequivalence, and all products must have undergone appropriate studies. Although generic substitution is widely implemented, it still remains to be answered how generic switch influences persistence to long-term treatment, and if it is modified by patients' concerns about medicine and views on generic medicine. This study focuses on users of antidepressants and antiepileptics, and their experience of generic switching. METHODS: The study was an observational cohort study. By use of a prescription database, we identified patients who had redeemed prescriptions on generically substitutable drugs, and a questionnaire was mailed to them. We analyzed predictors of discontinuation in relation to generic switch and patients' attitudes towards generic medicines and concerns about their medicine. RESULTS: Patients who experience their first-time switch of a specific drug were at higher risk of non-persistence, Hazard Ratio 2.98, 95% CI (1.81;4.89) versus those who have never switched, and 35.7% became non-persistent during the first year of follow-up. Generic switching did not influence persistence considerably in those having previous experience with generic switching of the specific drug. Stratified analyses on users of antidepressants and antiepileptics underpin the results, showing higher risk of non-persistence for first-time switchers for both drug categories. CONCLUSION: In conclusion, patients who are first-time switchers of a specific drug were at higher risk of non-persistence compared to never switchers and those having experienced previous generic switching.

Discontinuation of antiplatelet treatment and risk of recurrent stroke and all-cause death: a cohort study.

BACKGROUND: We wished to examine the impact of antiplatelet drug discontinuation on recurrent stroke and all-cause mortality. METHODS: We identified a cohort of incident ischaemic stroke patients in a Danish stroke registry, 2007-2011. Using population-based registries we assessed subjects' drug use and followed them up for stroke recurrence, or all-cause death. Person-time was classified by antiplatelet drug use into current use, recent use (≤150 days after last use), and non-use (>150 days after last use). Lipid-lowering drug (LLD) use was classified by the same rules. We used Cox proportional hazard models to calculate the adjusted hazard ratio (HR) and corresponding 95% confidence intervals (CIs) for the risk of recurrent stroke or death associated with discontinuation of antiplatelet or LLD drugs. RESULTS: Among 4,670 stroke patients followed up for up a median of 1.5 years, 237 experienced a second stroke and 600 died. Compared with current antiplatelet drug use, both recent use (1.3 (0.8-2.0)), and non-use (1.3 (0.8-1.9)) were associated with increased recurrent stroke risk. The corresponding HRs of death were 1.9 (1.4-2.5) for recent and 1.8 (1.4-2.3) for non-use of antiplatelet drugs. Recent statin use was associated with markedly increased risk of death (2.1 (1.7-2.6)), and only marginally with recurrent stroke (1.2 (0.9-1.6)). CONCLUSIONS: Antiplatelet drug discontinuation may be associated with an increased recurrent stroke risk. Our results on death risk indicate that non-pharmacological biases, such as 'sick stopper', may threaten the validity of this risk estimate.

Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists.

PURPOSE: We present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. METHODS: We used a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of ≥4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome definitions, and other drugs. RESULTS: We identified 513 VKA users with at least 1 INR measurement ≥4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared to warfarin (IRR, 3.37; 95%CI, 2.50-4.53 and IRR, 1.46; 95%CI, 1.20-1.76, respectively). We observed larger IRRs with stricter outcome definitions. Concomitant tramadol and VKA exposure was also associated with an increased rate of low INR measurements (i.e., <1.5; IRR, 1.70; 95%CI, 1.37-2.13). Morphine and, to some extent, oxycodone, penicillin, beta-blockers, and inhaled beta-agonists were associated with high INR. CONCLUSIONS: The approach successfully identified an interaction between tramadol and VKA. However, associations observed for other drugs with no known VKA interaction suggest that the current approach may have too low specificity to be useful as a screening tool, at least for drugs for which time-varying confounding may be present.