Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality.

Methods: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users.

Results: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92).

Conclusions: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers.

Keywords: Colorectal cancer; Breast cancer; Prostate cancer; Mortality; Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Beta-blocker usage after malignant melanoma diagnosis and survival: a population-based nested case-control study

Background: Beta-blockers have potential antiangiogenic and antimigratory activity. Studies have demonstrated a survival benefit in patients with malignant melanoma treated with beta-blockers.

Objectives: To investigate the association between postdiagnostic beta-blocker usage and risk of melanoma-specific mortality in a population-based cohort of patients with malignant melanoma.

Methods: Patients with incident malignant melanoma diagnosed between 1998 and 2010 were identified within the U.K. Clinical Practice Research Datalink and confirmed using cancer registry data. Patients with malignant melanoma with a melanoma-specific death (cases) recorded by the Office of National Statistics were matched on year of diagnosis, age and sex to four malignant melanoma controls (who lived at least as long after diagnosis as their matched case). A nested case–control approach was used to investigate the association between postdiagnostic beta-blocker usage and melanoma-specific death and all-cause mortality. Conditional logistic regression was applied to generate odds ratios (ORs) and 95% confidence intervals (CIs) for beta-blocker use determined from general practitioner prescribing.

Results: Beta-blocker medications were prescribed after malignant melanoma diagnosis to 20·2% of 242 patients who died from malignant melanoma (cases) and 20·3% of 886 matched controls. Consequently, there was no association between beta-blocker use postdiagnosis and cancer-specific death (OR 0·99, 95% CI 0·68–1·42), which did not markedly alter after adjustment for confounders including stage (OR 0·87, 95% CI 0·56–1·34). No significant associations were detected for individual beta-blocker types, by defined daily doses of use or for all-cause mortality.

Conclusions: Contrary to some previous studies, beta-blocker use after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in this U.K. population-based study.

The challenge to health professionals when carers resist truth telling at the end of life: a qualitative secondary analysis

Aims and objectives: To draw out the similar complexities faced by staff around
truth-telling in a children’s and adult population and to interrogate the dilemmas faced by staff when informal carers act to block truth-telling.

Background: Policy encourages normalisation of death, but carers may act to protect or prevent the patient from being told the truth. Little is known about the impact on staff.

Design: Secondary analysis of data using a supra-analysis design to identify commonality of experiences.

Methods: Secondary ‘supra-analysis’ was used to transcend the focus of two primary studies in the UK, which examined staff perspectives in a palliative children’s and a palliative adult setting, respectively. The analysis examined new theoretical questions relating to the commonality of issues independently derived in each primary study. Both primary studies used focus groups. Existing empirical data were analysed thematically and compared across the studies.

Results: Staff reported a hiding of the truth by carers and sustained use of activities aimed at prolonging life. Carers frequently ignored the advance of end of life, and divergence between staff and carer approaches to truth-telling challenged professionals. Not being truthful with patients had a deleterious effect on staff, causing anger and feelings of incompetence.

Conclusions: Both children’s and adult specialist palliative care staff found themselves caught in a dilemma, subject to policies that promoted openness in planning for death and informal carers who often prevented them from being truthful with patients about terminal prognosis. This dilemma had adverse psychological effects upon many staff.

Relevance to clinical practice: There remains a powerful death-denying culture in
many societies, and carers of dying patients may prevent staff from being truthful with their patients. The current situation is not ideal, and open discussion of this problem is the essential first step in finding a solution.

Public knowledge and perceptions of connected health

Rationale, aims and objectives: This study aims to examine the public's knowledge and perceptions of connected health (CH).

Methods: A structured questionnaire was administered by face-to-face interview to an opportunistic sample of 1003 members of the public in 11 shopping centres across Northern Ireland (NI). Topics included public knowledge of CH, opinions about who should provide CH and views about the use of computers in health care. Multivariable analyses were conducted to assess respondents' willingness to use CH in the future.

Results: Sixty-seven per cent of respondents were female, 31% were less than 30 years old and 22% were over 60 years. Most respondents had never heard of CH (92%). Following a standard definition, the majority felt CH was a good idea (≈90%) and that general practitioners were in the best position to provide CH; however, respondents were equivocal about reductions in health care professionals' workload and had some concerns about the ease of device use. Factors positively influencing willingness to use CH in the future included knowledge of someone who has a chronic disease, residence in NI since birth and less concern about the use of information technology (IT) in health care. Those over 60 years old or who felt threatened by the use of IT to store personal health information were less willing to use CH in the future.

Conclusion: Increased public awareness and education about CH is required to alleviate concerns and increase the acceptability of this type of care.

Potentially inappropriate prescribing among older people in the United Kingdom

Background: Potentially inappropriate prescribing (PIP) in older people is associated with increases in morbidity, hospitalisation and mortality. The objective of this study was to estimate the prevalence of and factors associated with PIP, among those aged ≥70 years, in the United Kingdom, using a comprehensive set of prescribing indicators and comparing these to estimates obtained from a truncated set of the same indicators.

Methods: A retrospective cross-sectional study was carried out in the UK Clinical Practice Research Datalink (CPRD), in 2007. Participants included those aged ≥ 70 years, in CPRD. Fifty-two PIP indicators from the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria were applied to data on prescribed drugs and clinical diagnoses. Overall prevalence of PIP and prevalence according to individual STOPP criteria were estimated. The relationship between PIP and polypharmacy (≥4 medications), comorbidity, age, and gender was examined. A truncated, subset of 28 STOPP criteria that were used in two previous studies, were further applied to the data to facilitate comparison.

Results: Using 52 indicators, the overall prevalence of PIP in the study population (n = 1,019,491) was 29%. The most common examples of PIP were therapeutic duplication (11.9%), followed by use of aspirin with no indication (11.3%) and inappropriate use of proton pump inhibitors (PPIs) (3.7%). PIP was strongly associated with polypharmacy (Odds Ratio 18.2, 95% Confidence Intervals, 18.0-18.4, P < 0.05). PIP was more common in those aged 70–74 years vs. 85 years or more and in males. Application of the smaller subset of the STOPP criteria resulted in a lower PIP prevalence at 14.9% (95% CIs 14.8-14.9%) (n = 151,598). The most common PIP issues identified with this subset were use of PPIs at maximum dose for > 8 weeks, NSAIDs for > 3 months, and use of long-term neuroleptics.

Conclusions: PIP was prevalent in the UK and increased with polypharmacy. Application of the comprehensive set of STOPP criteria allowed more accurate estimation of PIP compared to the subset of criteria used in previous studies. These findings may provide a focus for targeted interventions to reduce PIP.

Implementing change in the neonatal unit: Part 1 – The evidence base

Pain management in premature and sick babies has long been recognised as a vital component of neonatal care; however practices pertaining to pain assessment and administration of analgesia remain variable in Neonatal Units (NNU). Sucrose has been identified as an effective agent in reducing pain during minor painful procedures in premature babies but the uptake has been modest.This article is the first of two, and will describe the rationale for implementation of sucrose administration as a measure for pain relief for minor procedures in one neonatal unit in Northern Ireland. Current literature relating to use of sucrose willbe utilised in generating debate and discussion around the implementation of Clinical Practice Guidelines (CPG) for Sucrose use.

A narrow-band ultraviolet B course improves vitamin D balance and alters cutaneous CYP27A1 and CYP27B1 mRNA expression levels in haemodialysis patients supplemented with oral vitamin D

Background: Chronic kidney disease (CKD) patients on dialysis are prone to vitamin D insufficiency despite oral vitamin D supplementation. Here, we studied whether narrow-band ultraviolet B (NB-UVB) exposures improve vitamin D balance.

Methods: 14 haemodialysis patients and 15 healthy subjects receiving oral cholecalciferol 20 µg daily got nine NB-UVB exposures on the entire body. Serum 25-hydroxyvitamin D (25(OH)D) was measured by radioimmunoassay. Cutaneous mRNA expression levels of CYP27A1 and CYP27B1, two enzymes required for hydroxylation of vitamin D into its active metabolite, were also measured.

Results: The baseline serum 25(OH)D concentration was 57.6 ± 18.2 nmol/l in the CKD patients and 74.3 ± 14.8 nmol/l in the healthy subjects. The NB-UVB course increased serum 25(OH)D by 14.0 nmol/l (95% CI 8.7-19.5) and 17.0 nmol/l (CI 13.7-20.2), respectively. At baseline the CKD patients showed significantly increased CYP27B1 levels compared to the healthy subjects.

Conclusions: A short NB-UVB course is an efficient way to improve vitamin D balance in CKD patients on dialysis who are receiving oral vitamin D supplementation. The increased cutaneous CYP27B1 levels in the CKD patients suggest that the loss of renal activity of this enzyme is at least partially compensated for by the skin.

'Conditional candour' and 'knowing me': an interpretive description study on patient preferences for physician behaviours during end-of-life communication

OBJECTIVE: To understand patients' preferences for physician behaviours during end-of-life communication.

METHODS: We used interpretive description methods to analyse data from semistructured, one-on-one interviews with patients admitted to general medical wards at three Canadian tertiary care hospitals. Study recruitment took place from October 2012 to August 2013. We used a purposive, maximum variation sampling approach to recruit hospitalised patients aged ≥55 years with a high risk of mortality within 6-12 months, and with different combinations of the following demographic variables: race (Caucasian vs non-Caucasian), gender and diagnosis (cancer vs non-cancer).

RESULTS: A total of 16 participants were recruited, most of whom (69%) were women and 70% had a non-cancer diagnosis. Two major concepts regarding helpful physician behaviour during end-of-life conversations emerged: (1) 'knowing me', which reflects the importance of acknowledging the influence of family roles and life history on values and priorities expressed during end-of-life communication, and (2) 'conditional candour', which describes a process of information exchange that includes an assessment of patients' readiness, being invited to the conversation, and sensitive delivery of information.

CONCLUSIONS: Our findings suggest that patients prefer a nuanced approach to truth telling when having end-of-life discussions with their physician. This may have important implications for clinical practice and end-of-life communication training initiatives.

Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients

Background: This is an update of a review last published in Issue 5, 2010, of The Cochrane Library. Reducing weaning time is desirable in minimizing potential complications from mechanical ventilation. Standardized weaning protocols are purported to reduce time spent on mechanical ventilation. However, evidence supporting their use in clinical practice is inconsistent. Objectives: The first objective of this review was to compare the total duration of mechanical ventilation of critically ill adults who were weaned using protocols versus usual (non-protocolized) practice.The second objective was to ascertain differences between protocolized and non-protocolized weaning in outcomes measuring weaning duration, harm (adverse events) and resource use (intensive care unit (ICU) and hospital length of stay, cost).The third objective was to explore, using subgroup analyses, variations in outcomes by type of ICU, type of protocol and approach to delivering the protocol (professional-led or computer-driven). Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2014), MEDLINE (1950 to January 2014), EMBASE (1988 to January 2014), CINAHL (1937 to January 2014), LILACS (1982 to January 2014), ISI Web of Science and ISI Conference Proceedings (1970 to February 2014), and reference lists of articles. We did not apply language restrictions. The original search was performed in January 2010 and updated in January 2014.Selection criteriaWe included randomized controlled trials (RCTs) and quasi-RCTs of protocolized weaning versus non-protocolized weaning from mechanical ventilation in critically ill adults. Data collection and analysis: Two authors independently assessed trial quality and extracted data. We performed a priori subgroup and sensitivity analyses. We contacted study authors for additional information. Main results: We included 17 trials (with 2434 patients) in this updated review. The original review included 11 trials. The total geometric mean duration of mechanical ventilation in the protocolized weaning group was on average reduced by 26% compared with the usual care group (N = 14 trials, 95% confidence interval (CI) 13% to 37%, P = 0.0002). Reductions were most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. Weaning duration was reduced by 70% (N = 8 trials, 95% CI 27% to 88%, P = 0.009); and ICU length of stay by 11% (N = 9 trials, 95% CI 3% to 19%, P = 0.01). There was significant heterogeneity among studies for total duration of mechanical ventilation (I2 = 67%, P < 0.0001) and weaning duration (I2 = 97%, P < 0.00001), which could not be explained by subgroup analyses based on type of unit or type of approach. Authors' conclusions: There is evidence of reduced duration of mechanical ventilation, weaning duration and ICU length of stay with use of standardized weaning protocols. Reductions are most likely to occur in medical, surgical and mixed ICUs, but not in neurosurgical ICUs. However, significant heterogeneity among studies indicates caution in generalizing results. Some study authors suggest that organizational context may influence outcomes, however these factors were not considered in all included studies and could not be evaluated. Future trials should consider an evaluation of the process of intervention delivery to distinguish between intervention and implementation effects. There is an important need for further development and research in the neurosurgical population.

Healthcare professionals’ response to cachexia in advanced cancer

Background: Cancer cachexia is a complex metabolic syndrome characterised by severe and progressive weight loss which is predominantly muscle mass. It is a devastating complication of advanced cancer with profound bio-psycho-social implications for patients and their families. At present, there is no curative treatment for cachexia in advanced cancer therefore, the most important healthcare response entails the minimisation of the psycho-social distress associated with it. However, the literature suggests healthcare professionals’ are missing opportunities to respond to the multi-dimensional needs of this population.

Aim: The objective of this study was to explore healthcare professionals’ experience, understanding and perception of need of patients with advanced cancer who have cachexia and their families.

Methods: An interpretative qualitative approach based on symbolic interactionism was adopted. A purposive sample of doctors, nurses, specialist nurses, and dieticians were recruited from a cancer centre in a large teaching hospital in Northern Ireland. Data collection consisted of two phases: focus group interviews followed by individual semi-structured interviews.

Results: Findings from the focus group interviews were used as a framework for the semi structured interview schedule. Results centred on the influence of a variable combination of knowledge, culture, and resources on the management of cachexia in advanced cancer. Data revealed that variation in healthcare professionals’ perceptions of cachexia in advanced cancer, along with their professional ethos, influenced their response to it in clinical practice.

Conclusions: This study has revealed that cancer cachexia is a complex and challenging syndrome which needs to be addressed from a holistic model of care to reflect the multidimensional needs of patients and their families. Effective management will require a combination of knowledge, a supportive culture, and adequate resources.

The need for qualitative methodologies in cancer cachexia research

Background: Cancer cachexia is not well understood or managed in clinical practice (Delmore 2000; Poole and Froggatt 2002). Whilst a dedicated effort has been made towards understanding the biological processes of the syndrome, little attention has been paid to its multidimensional impact. This is despite previous qualitative research, enriching our understanding of the holistic impact of the syndrome which traditional quantitative methods could not have uncovered (Reid 2007).

Aim: The aim of this study is to determine the adequacy of the existing clinical knowledge base of cancer cachexia management.

Methods: A systematic critical review of the literature on cancer cachexia was undertaken.

Results: There is a need to develop protocols for care delivery, which move beyond a purely biological approach to care towards a more holistic approach. This can only be achieved by gaining the perspectives of those who are involved in care delivery to advanced cancer patients with cachexia and their families using qualitative methodologies.

Conclusions: Cancer cachexia is a complex, challenging syndrome, which must be understood from a holistic bio-psychosocial model of care in order to meet the multidimensional needs of this client population. The perspectives of those involved in care delivery is required in order to contribute to a knowledge base which will inform the development of interventions directed at empowering patients and their families to understand cancer cachexia and recognise it as part of the disease process.

Uncovering the challenges of managing cachexia in advanced cancer: Preliminary results from semi-structured interviews with healthcare professionals in a regional cancer centre

Background: Cancer cachexia is a complex metabolic syndrome characterised by severe and progressive weight loss which is predominantly muscle mass. It is a devastating and distressing complication of advanced cancer with profound bio-psycho-social implications for patients and their families. At present there is no curative treatment for cachexiain advanced cancer therefore the most important healthcare response entails the minimisation of the psycho-social distress associated with it. However the literature suggests healthcare professionals’are missing opportunities to intervene and respond to the multi-dimensional needs of this population.

Objective:The objective of this study was to explore healthcare professionals’ response to cachexia in advanced cancer.

Methods: An interpretative qualitative approach was adopted in this study. A purposive sample of doctors, nurses, specialist nurses and dieticians were recruited from a regional cancer centre between November 2009 and November 2010. Data was collection was twofold: two multi-professional focus groups were conducted first to uncover the main themes and issues in cachexia management. This data then informed the interview schedule for the following 25 individual semi-structured interviews.

Results: Preliminary data analysis of the semi-structured interviews revealed distinct differences between disciplines in their perceptions of cancer cachexia which influenced their response to it in clinical practice. The commonality between disciplines, with the exception of palliative care, was a reliance on the biomedical approach to cancer cachexia management.

Discussion and Conclusions: Cancer cachexia is a complex and challenging syndrome which needs to be addressed from a holistic model of care to reflect the multi-dimensional needs of this patient group. The perspectives of those involved in care delivery is required in order to inform the development of interventions aimed at minimising the distress associated with this devastating syndrome.