Safety, efficacy and survival of patients with primary malignant brain tumours (PMBT) in phase I (Ph1) trials: the 12-year Royal Marsden experience.

BACKGROUND: Primary malignant brain tumours (PMBT) constitute less than 2% of all malignancies and carry a dismal prognosis. Treatment options at relapse are limited. First-in-human solid tumour studies have historically excluded patients with PMBT due to the poor prognosis, concomitant drug interactions and concerns regarding toxicities. METHODS: Retrospective data were collected on clinical and tumour characteristics of patients referred for consideration of Ph1 trials in the Royal Marsden Hospital between June 2004 and August 2016. Survival analyses were performed using the Kaplan-Meier method, Cox proportional hazards model. Chi squared test was used to measure bivariate associations between categorical variables. RESULTS: 100pts with advanced PMBT were referred. At initial consultation, patients had a median ECOG PS 1, median age 48 years (range 18-70); 69% were men, 76% had glioblastoma; 68% were on AEDs, 63% required steroid therapy; median number of prior treatments was two. Median OS for patients treated on a Ph1 trials was 9.3 months (95% CI 5.9-12.9) versus 5.3 months (95% CI 4.1-6.1) for patients that did not proceed with a Ph1 trial, p = 0.0094. Steroid use, poor PS, neutrophil-to-lymphocyte ratio and treatment on a Ph1 trial were shown to independently influence OS. CONCLUSIONS: We report a survival benefit for patients with PMBT treated on Ph1 trials. Toxicity and efficacy outcomes were comparable to the general Ph1 population. In the absence of an internationally recognized standard second line treatment for patients with recurrent PMBT, more Ph1 trials should allow enrolment of patients with refractory PMBT and Ph1 trial participation should be considered at an earlier stage.

Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer.

OBJECTIVE: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. METHODS: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. RESULTS: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0·0149 and 0·0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0·001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. CONCLUSIONS: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.

Inter-Rater Reliability of the Phase of Illness Tool in Pediatric Palliative Care.

BACKGROUND: Phase of Illness is used to describe the stages of a patient's illness in the palliative care setting. Categorization is based on individual needs, family circumstances, and the adequacy of a care plan. Substantial (κ = .67) and moderate (κ = .52) inter-rater reliability is demonstrated when categorizing adults; however, there is a lack of similar studies in pediatrics. OBJECTIVE: To test the inter-rater reliability of health-care professionals when assigning pediatric palliative care patients to a Phase of Illness. Furthermore, to obtain user views on phase definitions, ease of assignment, feasibility and acceptability of use. METHOD: A prospective cohort study in which up to 9 health-care professionals' independently allocated 80 pediatric patients to a Phase of Illness and reported on their experiences. This study took place between June and November 2017. RESULTS: Professionals achieved a moderate level of agreement (κ = 0.50). Kappa values per phase were as follows: stable = 0.63 (substantial), unstable = 0.26 (fair), deteriorating = 0.45 (moderate), and dying = 0.43 (moderate). For the majority of allocations, professionals report that the phase definitions described patients very well (76.1%), and they found it easy to assign patients (73.5%). However, the unstable phase caused the most uncertainty. CONCLUSION: The results of this study suggest Phase of Illness is a moderately reliable, acceptable, and feasible tool for use in pediatric palliative care. Current results are similar to those found in some adult studies. However, in a quarter of cases, users report some uncertainty in the application of the tool, and further study is warranted to explore whether suggested refinements improve its psychometric properties.

Gemcitabine Re-challenge in Metastatic Soft Tissue Sarcomas: A Therapeutic Option for Selected Patients.

BACKGROUND/AIM: Treatment options for patients with metastatic soft tissue sarcomas are limited. Re-challenge with a previously successful gemcitabine-based regimen is common. There are no published data to support this practice. PATIENTS AND METHODS: We conducted a retrospective search to identify patients re-challenged with gemcitabine-based chemotherapy (GBC) from 2003 to 2015. RESULTS: Twenty-nine patients re-challenged with gemcitabine were identified. The response rate for initial GBC was 55% (n=15) and for re-challenge GBC 26% (n=6). The median progression-free survival was 11.1 months (95%CI=7.2-11.9) for initial GBC and 5.3 months (95%CI=2.0-7.5) for re-challenge GBC. Overall survival following gemcitabine re-challenge was 12.2 months (95%CI=7.0-18.2). Twelve out of 26 evaluable patients (46%) treated with re-challenge GBC experienced grade 3-4 adverse events (CTCAE 4.03) with 31% (n=8) of patients requiring dose reduction. CONCLUSION: In selected patients, gemcitabine re-challenge can be considered in advanced sarcomas, however, this approach is associated with toxicity.

Clinical outcomes of adolescents and young adults with advanced solid tumours participating in phase I trials.

BACKGROUND: Adolescent and young adult (AYA) patients with advanced solid tumours are often considered for phase I clinical trials with novel agents. The outcome of AYAs in these trials have not been described before. AIM: To study the outcome of AYA patients in phase I clinical trials. METHODS: Clinical trial data of AYAs (defined as aged 15-39 years at diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, between 2002 and 2016, were analysed. RESULTS: From a prospectively maintained database of 2631 patients treated in phase I trials, 219 AYA patients (8%) were identified. Major tumour types included gynaecological cancer (25%) and sarcoma (18%). Twenty-five (11%) had a known hereditary cancer syndrome (most commonly BRCA). Molecular characterisation of tumours (n = 45) identified mutations most commonly in TP53 (33%), PI3KCA (18%) and KRAS (9%). Therapeutic targets of trials included DNA damage repair (16%), phosphoinositide 3-kinase (PI3K) (16%) and angiogenesis (16%). Grade 3/4 toxicities were experienced in 26% of patients. Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median overall survival (OS) was 7.5 months (95% confidence interval: 6.3-9.5), and 2-year OS was 11%. Of patients with responses, 36% were matched to phase I trials based on germline or somatic genetic aberrations. CONCLUSION: We describe the outcome of the largest cohort of AYA patients treated in phase I trials. A subgroup of these patients demonstrates benefit, with several durable responses beyond 2 years. A sizeable proportion of AYA patients have cancer syndromes, significant family history or somatic molecular aberrancies which may influence novel therapeutic treatment options.

Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit.

BACKGROUND: We have previously reported a prognostic score for patients in phase I trials in the Drug Development Unit, treated at the Royal Marsden Hospital (RPS). The RPS is an objective tool used in patient selection for phase I trials based on albumin, number of disease sites and LDH. Patients with mesothelioma are often selected for phase I trials as the disease remains localised for long periods of time. We have now reviewed the clinical outcomes of patients with relapsed malignant mesothelioma (MM) and propose a specific mesothelioma prognostic score (m-RPS) that can help identify patients who are most likely to benefit from early referral. METHODS: Patients who participated in 38 phase I trials between September 2003 and November 2015 were included in the analysis. Efficacy was assessed by response rate, median overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate analyses (MVA) were carried out to develop the m-RPS. RESULTS: A total of 65 patients with advanced MM were included in this retrospective study. The PFS was 2.5 months (95% confidence interval [CI] 2.0-3.1 months) and OS was 8 months (95% CI 5.6-9.8 months). A total of four (6%) patients had RECIST partial responses, whereas 26 (40%) patients had RECIST stable disease >3 months. The m-RPS was developed comprising of three different prognostic factors: a neutrophil: lymphocyte ratio greater than 3, the presence of more than two disease sites (including lymph nodes as a single site of disease) and albumin levels less than 35 from the MVA. Patients each received a score of 1 for the presence of each factor. Patients in group A (m-RPS 0-1; n = 35) had a median OS of 13.4 months (95% CI 8.5-21.6), whereas those in group B (m-RPS 2-3; n = 30) had a median OS of 4.0 months (95% CI 2.9-7.1, P < 0.0001). A total of 56 (86%) patients experienced G1-2 toxicities, whereas reversible G3-4 toxicities were observed in 18 (28%) patients. Only 10 (15%) patients discontinued phase I trials due to toxicity. CONCLUSIONS: Phase I clinical trial therapies were well tolerated with early signals of antitumour activity in advanced MM patients. The m-RPS is a useful tool to assess MM patient suitability for phase I trials and should now be prospectively validated.

Sexual violence against adult women primary care attenders in east London.

BACKGROUND: Sexual violence against women is common. The prevalence appears to be higher in north America than Europe. However, not all surveys have differentiated the experience of forced sex by a current or former partner. Few women are thought to report these experiences to their general practitioner (GP). AIM: To measure the prevalence of rape, sexual assault, and forced sexual intercourse by a partner among women attending general practices, to test the association between these experiences of sexual violence and demographic factors, and to assess the acceptability to women of screening for sexual violence by GPs. DESIGN OF STUDY: Cross-sectional survey. METHOD: A self-administered questionnaire survey of 1207 women aged over 15 years was carried out in 13 general practices in Hackney, east London. RESULTS: Eight per cent (95% confidence interval [CI] = 6.2 to 9.6) of women have experienced rape, 9% (95% CI = 7.0 to 10.6) another type of sexual assault, and 16% (95% CI = 13.6 to 18.1) forced sex by a partner in adulthood: 24% (95% CI = 21.2 to 26.5) have experienced one or more of these types of sexual violence. Experiences of sexual violence demonstrated high levels of lifetime co-occurrence. Women forced to have sex by partners experienced the most severe forms of domestic violence. One in five women would object to routine questioning about being raped and/or sexually assaulted, and one in nine about being forced to have sex by a partner. CONCLUSION: Experiences of sexual violence are common in the lives of adult women in east London, and they represent a significant public health problem. Those women who have one experience appear to be at risk of being victims again. A substantial minority object to routine questions about sexual violence.

A retrospective audit of type 2 diabetes patients prescribed liraglutide in real-life clinical practice.

BACKGROUND: In phase 3 trials, the once-daily human glucagon-like peptide-1 analog liraglutide provided effective glycemic control with low rates of hypoglycemia, weight loss, and reduced systolic blood pressure (SBP) in patients with type 2 diabetes. Through a retrospective clinical audit, the authors aimed to assess the clinical effectiveness of liraglutide, from initiation to first hospital visit, when prescribed at a center in Northern Ireland. METHODS: Patients attending Ulster Hospital who were prescribed liraglutide (June 2009-September 2010) and assessed both at baseline and first post-initiation visit were included in the analysis. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline. Weight, blood pressure, and frequency of hypoglycemic events were also assessed. RESULTS: Data from 193 patients are reported (baseline HbA1c 9.0%, mean age 55.8 years, diabetes duration 8.8 years, 66.8% male). Average time to first visit after initiation was 13.5 weeks, at which point 174 patients (90.2%) were prescribed 1.2 mg liraglutide. Mean change in HbA1c from initiation to first visit was -0.9%, while mean body weight change was -2.4 kg and change in SBP was -2.0 mmHg. Transient gastrointestinal side effects were experienced by 11.9% of patients. The number of patients experiencing minor hypoglycemic events was low (5.7%) and no major events were reported. CONCLUSION: Data from clinical studies translate into clinical practice: liraglutide provided improved glycemic control after 13.5 weeks of treatment, accompanied by weight loss and low incidence of hypoglycemia.

Initiation of biphasic insulin aspart 30/70 in subjects with type 2 diabetes mellitus in a largely primary care-based setting in Sweden.

AIMS: Despite a wealth of clinical trial data supporting use of the premixed insulin analogue, biphasic insulin aspart 30 (BIAsp 30) in the treatment of type 2 diabetes mellitus (T2DM), there is limited documentation of its use in primary care-based clinical practice. METHODS: An observational study investigating the safety and efficacy of BIAsp 30 in routine clinical practice was conducted. Patients were followed up 3 and 6 months after initiating insulin treatment. Safety and efficacy measures were documented. RESULTS: During the course of the study, 1154 patients were included (age range 20-95 years), of whom 89% completed the 6-month follow-up period. Mean HbA(1c) at baseline was 8.8% (73mmol/mol), and had improved to 7.2% (55mmol/mol) after 6 months of treatment. The rate of total hypoglycaemia at completion of the study was 4.1 events per patient year. Major hypoglycaemic events were rare (two in total). CONCLUSIONS: BIAsp 30 was initiated safely and effectively in insulin-naïve patients with T2DM. The safety and efficacy profile observed in clinical trials was confirmed in this largely primary care-based setting in Sweden.

Ethnic variations in the experiences of mental health service users in England: results of a national patient survey programme.

BACKGROUND: Minority ethnic groups in the UK are reported to have a poor experience of mental health services, but comparative information is scarce. AIMS: To examine ethnic differences in patients' experience of community mental health services. METHOD: Trusts providing mental health services in England conducted surveys in 2004 and 2005 of users of community mental health services. Multiple regression was used to examine ethnic differences in responses. RESULTS: About 27 000 patients responded to each of the surveys, of whom 10% were of minority ethnic origin. In the 2004 survey, age, living alone, the 2004 survey, age, living alone, detention and hospital admissions were stronger predictors of patient experience than ethnicity. Self-reported mental health status had the strongest explanatory effect. In the 2005 survey, the main negative differences relative to the White British were for Asians. CONCLUSIONS: Ethnicity had a smaller effect on patient experience than other variables. Relative to the White British, the Black group did not report negative experiences whereas the Asian group were most likely to respond negatively. However, there is a need for improvements in services for minority ethnic groups, including access to talking therapies and better recording of ethnicity.

Abusive experiences and psychiatric morbidity in women primary care attenders.

BACKGROUND: Abusive experiences in childhood and adulthood increase risks of psychiatric morbidity in women and independently increase risks of further abuse over the lifetime. It is unclear which experiences are most damaging. AIMS: To measure lifetime prevalence of abusive experiences and psychiatric morbidity, and to analyse associations in women primary care attenders. METHOD: A cross-sectional, self-report survey of 1207 women attending 13 surgeries in the London borough of Hackney, UK. Independent associations between demographic measures, abusive experiences and psychiatric outcome were established using logistic regression. RESULTS: Childhood sexual abuse had few associations with adult mental health measures, in contrast to physical abuse. Sexual assault in adulthood was associated with substance misuse; rape with anxiety, depression and post-traumatic stress disorder but not substance misuse. Domestic violence showed strongest associations with most mental health measures, increased for experiences in the past year. CONCLUSIONS: Abuse in childhood and adulthood have differential effects on mental health; effects are increased by recency and severity. Women should be routinely questioned about ongoing and recent experiences as well as childhood.

Identifying domestic violence: cross sectional study in primary care.

OBJECTIVES: To measure the prevalence of domestic violence among women attending general practice; test the association between experience of domestic violence and demographic factors; evaluate the extent of recording of domestic violence in records held by general practices; and assess acceptability to women of screening for domestic violence by general practitioners or practice nurses. DESIGN: Self administered questionnaire survey. Review of medical records. SETTING: General practices in Hackney, London. PARTICIPANTS: 1207 women (>15 years) attending selected practices. MAIN OUTCOME MEASURES: Prevalence of domestic violence against women. Association between demographic factors and domestic violence reported in questionnaire. Comparison of recording of domestic violence in medical records with that reported in questionnaire. Attitudes of women towards being questioned about domestic violence by general practitioners or practice nurses. RESULTS: 425/1035 women (41%, 95% confidence interval 38% to 44%) had ever experienced physical violence from a partner or former partner and 160/949 (17%, 14% to 19%) had experienced it within the past year. Pregnancy in the past year was associated with an increased risk of current violence (adjusted odds ratio 2.11, 1.39 to 3.19). Physical violence was recorded in the medical records of 15/90 (17%) women who reported it on the questionnaire. At least 202/1010 (20%) women objected to screening for domestic violence. CONCLUSIONS: With the high prevalence of domestic violence, health professionals should maintain a high level of awareness of the possibility of domestic violence, especially affecting pregnant women, but the case for screening is not yet convincing.

Ethnic differences in prisoners. 1: criminality and psychiatric morbidity.

BACKGROUND: In England and Wales, persons of African-Caribbean origin are more likely to be both imprisoned and admitted to secure hospitals. AIMS: To estimate population-based rates of imprisonment in different ethnic groups, and compare criminal behaviour and psychiatric morbidity. METHOD: We examined Home Office data on all persons in prison, and carried out a two-stage cross-sectional survey of 3142 remanded and sentenced, male and female, prisoners in all penal establishments in England and Wales in 1997. RESULTS: We confirmed high rates of imprisonment for Black people and lower rates for South Asians. Different patterns of offending and lower prevalence of psychiatric morbidity were observed in Black prisoners. CONCLUSIONS: Despite increased risks of imprisonment, African-Caribbeans show less psychiatric morbidity than White prisoners. This contrasts with the excess of African-Caribbeans in secure hospitals, an inconsistency possibly in part due to the effects of ethnic groups on admission procedures.

Ethnic differences in prisoners. 2: risk factors and psychiatric service use.

BACKGROUND: The high rates of psychiatric morbidity in prisoners vary between ethnic groups. AIMS: To compare early environmental risks, stressful daily living experiences and reported use of psychiatric services in prisoners from different ethnic groups. METHOD: Cross-sectional survey of 3142 prisoners in all penal establishments in England and Wales in 1997. RESULTS: Fewer Black and South Asian male prisoners reported childhood traumas and conduct disorder, and fewer Black prisoners experienced stressful prison experiences, than White prisoners. Fewer Black women had received previous psychiatric treatment, and fewer Black men had their psychiatric problems identified in prison. Black prisoners were less likely to have received psychiatric treatment than Whites. CONCLUSIONS: The lower prevalence of psychiatric morbidity observed in Black prisoners corresponds with reduced exposure to risk factors. Higher rates of imprisonment might be explained by higher rates of conduct disorder, adolescent-onset criminality and disadvantage within the criminal justice system.