Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence, as part of the institute's single technology appraisal process, invited the manufacturer of ribociclib (Kisqali®, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer's decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3-not reached) vs. 14.7 months (95% confidence interval 13.0-16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.

Family history tools for primary care are not ready yet to be implemented. A systematic review.

BACKGROUND: Taking the family history helps the doctor in estimating the probability of disease in individual patients. However, significant barriers to obtaining adequate family history information remain. Tools overcoming these barriers might support family physicians in this task. OBJECTIVE: To review systematically the characteristics of existing family history tools and discuss their potential use in primary care. METHODS: Studies were identified through searches of PubMed, Embase and Cinahl from 1 January 2002 until May 2012. All authors independently screened studies and included original research papers on family history tools of which assessment had been performed or was planned. We reviewed diseases for which family history information was collected, study setting, tool design, type of family history collection, presence of risk-assessment and recommendations for management, and assessment (categorized as either validity or benefit). RESULTS: Eighteen family history tools were identified: six generic, two on cardiovascular disease and ten on cancer. The six generic tools were partly tested in primary care (3x), are mainly computerized (4x), rarely include management recommendations for the physician (1x) and were partly validated against a reference standard (genetic counsellor) (3x, plus one planned). Of the five specific tools studied in primary care, none was validated. No family history tool allows electronic transfer of family history information to electronic medical record systems. Use of a family history tool improved identification of patients at risk for disease. CONCLUSION: Several promising family history tools for primary care have been developed but large-scale implementation cannot be advised yet, based on available validation studies.

Use of diagnostic self-tests on body materials among Internet users in the Netherlands: prevalence and correlates of use.

BACKGROUND: A range of self-tests on body materials has become available to the general public, but the extent of their use has hardly been studied. This study examined how many people use diagnostic self-tests on body materials such as blood or urine, as well as the type of tests that are used, and factors associated with their use. METHODS: Cross-sectional survey. Participants were recruited from an existing Dutch Internet panel of 12,529 persons, and information was collected by means of a structured Internet-based questionnaire. Multiple logistic regression analyses were used to assess correlates of self-test use. RESULTS: Response to the survey was 63%. Sixteen percent of the respondents said they had ever used at least one self-test, with a mean of 2.1 tests per self-tester. The most frequently reported self-tests were those for diabetes and cholesterol. Self-testers generally reported lower health status and had a higher BMI than non-testers. On the other hand, they were more likely to engage in health-related behaviour such as the use of dietary supplements and homeopathic medicine. CONCLUSION: Self-testing proved to be relatively prevalent among Dutch Internet users. We therefore think that it is essential to develop appropriate information for consumers, health care providers and policymakers, about the pros and cons of self-testing and specific self-tests. More test-specific research is needed.

General practitioners' treatment orientations towards low back pain: influence on treatment behaviour and patient outcome.

BACKGROUND: In low back pain (LBP) treatment and research attention has shifted from a biomedical towards a biopsychosocial approach. Patients' LBP beliefs and attitudes were found to predict long-term outcome, and recently it has been suggested that the health care providers' ideas about LBP are also important predictors of treatment behaviour and outcome. AIMS: In the present study we examined whether (1) differences in General Practitioners' (GP) LBP treatment orientation are associated with differences in actual treatment behaviour and (2) whether treatment orientation is related to LBP outcome in patients. METHODS: Two hundred twenty two patients consulting their GP with a new episode of LBP were recruited and completed questionnaires on (among others) LBP outcome (graded chronic pain scale) at baseline, during 12 months of follow-up and at the end of the study. Data on treatment were collected from the GPs. The GPs also completed a set of questionnaires on LBP treatment orientation. Associations between measures of treatment orientation, treatment recommendations, treatment behaviour and LBP outcome were analysed. RESULTS: A biomedical treatment orientation was found to be associated with more concern about tissue damage and the effect of physical activity on pain and recovery in vignettes. No associations were found between treatment orientation measures, actual treatment behaviour and LBP outcome. CONCLUSIONS: Associations were not found as expected. Still these findings are relevant and may feed a clinically important debate on widely accepted assumptions about the role and influence of health care providers in changing patients' pain behaviours.

A new episode of low back pain: who relies on bed rest?

Bed rest has been shown to be an ineffective treatment for non-specific low back pain (LBP). Despite this, during a new episode of pain some patients still rely on bed rest. Which patients choose bed rest is however unknown. The objectives of the present study were, firstly, to assess characteristics of patients choosing bed rest in (sub)acute pain and secondly to study whether prolonged bed rest in the (sub)acute phase of pain will result in long term disability. A prospective longitudinal cohort study included 282 patients with non-specific LBP for less than 7 weeks. Main outcome measures were duration of bed rest (in three categories) and disability. Results showed that 33% of patients with (sub)acute LBP had bed rest, but only 8% stayed in bed for more than four days. An ordinal regression analysis revealed that behavioural factors (catastrophizing (OR=1.05 per bed rest category p<0.01)) and fear of injury (OR=1.05 per category p<0.01) rather than specific pain related factors (pain history (OR=0.61 per category p=0.16) and pain intensity (OR=1.00 per category p=0.63)) were associated with bed rest. Patients with prolonged bed rest in an early phase of pain were still more disabled after one year (p<0.01). Based on these results we conclude that prolonged bed rest in the early phase of pain is associated with a higher long term disability level. In preventing low back disability, GP screening for catastrophizing and fear of injury in LBP patients who had prolonged bed rest merits consideration.

The effectiveness of a treatment protocol for male lower urinary tract symptoms in general practice: a practical randomised controlled trial.

BACKGROUND: Randomised controlled trials have shown the efficacy of several treatment modalities for lower urinary tract symptoms (LUTS) in selected populations. The effectiveness in daily practice has hardly been investigated, especially in primary care and is dependent on choices between all possible treatment options and best investigated in a comprehensive study, including all treatment modalities (watchful waiting, alpha-blockers, 5-alpha-reductase inhibitors, and surgery). AIM: Assessment of the effectiveness of a comprehensive treatment protocol for LUTS in primary care. DESIGN OF STUDY: Randomised controlled trial. SETTING: Fourteen general practices in the Netherlands. INTERVENTION: treatment protocol based on a formalised expert opinion. Control condition: usual care. STUDY POPULATION: 208 subjects with moderate to severe LUTS (IPSS > or =8, median = 13). OUTCOME MEASURES: symptom severity (IPSS [International Prostate Symptom Score]), bother score (Dan-PSS [Danish Prostate Symptom Score]), and maximum urinary flow (Q(max)); incidence of acute urinary retention and urinary tract infections. RESULTS: In the intervention group markedly more subjects used an alpha-blocker at end of follow-up than in the usual care group (24% versus 6%). No significant differences were found between intervention and control group in IPSS, Q(max) or Dan-PSS. CONCLUSION: alpha-blockers and watchful waiting are the most frequent treatment modalities for LUTS in primary care. Our study showed no evidence that a protocol using well-defined indications for all possible treatment modalities based on a formalised expert opinion procedure has added value. Based on our results, we cannot recommend a broadening of the indication for alpha-blockers, which, however, seems to be the current trend.

A decision aid for GPs for the treatment of elderly male patients with lower urinary tract symptoms (LUTS).

BACKGROUND: GPs have four main treatment options for lower urinary tract symptoms (LUTS): watchful waiting, alpha-blockers, 5-alpha-reductase inhibitors or (referral for) surgery. Guidelines do not provide clear cut-off values for (combinations of) symptoms and physical examination results to decide which treatment is best. OBJECTIVE: (i) To develop a decision aid ('checklist') for GPs for the treatment of patients with LUTS. (ii) To assess its value for use in a primary care population. Materials and methods. Population-based cross-sectional study. Included were subjects with uncomplicated LUTS for whom treatment in primary care may be appropriate. [International Prostate Symptom Score (IPSS) > or = 8, no prior prostate surgery, prostate-specific antigen (PSA) value < 10 ng/ml]. For each subject the appropriateness of surgery and alpha-blocker treatment was determined using a previously validated formalized international expert panel judgement. Regression models using data available in primary care were constructed to predict the panel judgement. Subsequently these models were transformed into simple checklists. Finally, the efficiency of these checklists was calculated. RESULTS: The best checklists consisted of age, symptoms severity, type of symptoms, a quality of life score and PSA value. Assuming one would like to provide at least 95% of the subjects for whom a certain treatment is appropriate with this treatment (i.e. 'sensitivity' of the checklist > or = 95%), one can reach a positive predictive value of 50-60%. CONCLUSION: Simple checklists based on the judgement of experts regarding the most appropriate therapy can help GPs to advise their patients of a rational treatment strategy.

Childhood trauma and emotional reactivity to daily life stress in adult frequent attenders of general practitioners.

OBJECTIVES: Childhood trauma (CT) has consistently been associated with neuroticism--a personality trait reflecting vulnerability to stress. However, not much is known about the impact of a history of trauma on moment-to-moment emotions and experiences in the flow of daily life. The relationship between CT and emotional reactivity to daily life stress was investigated. METHODS: Ninety frequent attenders of general practitioners, of which 29 fulfilled criteria for CT (sexual and/or physical trauma before the age of 19 years), were studied with the Experience Sampling Method (a structured diary technique assessing current context and mood in daily life) to assess: (a) appraised subjective stress related to daily events and activities, and (b) emotional reactivity conceptualized as changes in negative affect (NA). RESULTS: Multilevel regression analysis revealed that subjects with a history of CT reported significantly increased emotional reactivity to daily life stress, as reflected in an increase in NA. This effect was significantly stronger for subjects who experienced trauma before the age of 10 years. CONCLUSION: These results confirm that CT may have long-lasting and enduring effects on adult psychological functioning, as exposed individuals continually react more strongly to small stressors occurring in the natural flow of everyday life. The finding that emotional stress reactivity is most pronounced for subjects who experienced trauma early in life confirms prior evidence suggesting that the effects of trauma are more detrimental when trauma occurs at a younger age.

Pain-related fear at the start of a new low back pain episode.

Previous research supports the fear-avoidance model in explaining chronic low back pain (LBP) disability. The aims of the present study were to determine: (1) whether fear-avoidance model variables are associated already during acute stages of LBP and (2) whether (increases in) pain-related fear are associated with other patient characteristics routinely assessed by the General Practitioner (GP). General practice patients consulting because of a new episode of LBP completed questionnaires on pain-related fear, avoidance, pain and disability. A sample of 247 acute LBP patients (median duration of current episode was 5 days) was collected. Significant associations were found between pain intensity, pain-related fear, avoidance behaviour and disability, but correlations were generally modest. A strong association was found between pain and disability. Pain-related fear was slightly higher in patients reporting low job satisfaction and in those taking bedrest. These results suggest that the fear-avoidance model as it was developed and tested in chronic LBP, might not entirely apply to acute LBP patients. Future research should focus on the transition from acute to chronic LBP and the shifts that take place between fear-avoidance model associations.

A longitudinal study on the predictive validity of the fear-avoidance model in low back pain.

Recently, fear-avoidance models have been quite influential in understanding the transition from acute to chronic low back pain (LBP). Not only has pain-related fear been found to be associated with disability and increased pain severity, but also treatment focused at reducing pain-related fear has shown to successfully reduce disability levels. In spite of these developments, there is still a lack in well-designed prospective studies examining the role of pain-related fear in acute back pain. The aim of the current study was to prospectively test the assumption that pain-related fear in acute stages successfully predicts future disability. Subjects were primary care acute LBP patients consulting because of a new episode of LBP (

Pain-related fear in acute low back pain: the first two weeks of a new episode.

The overall aim of this study was to explore the natural course of pain-related fear during the early stage of a new low back pain episode, using a prospective case series design. Specific research questions addressed the existence of typical patterns in individual time series of pain-related fear and sequential relationships between the occurrence of pain-related fear, pain and pain catastrophizing. Forty-four general practice patients who consulted their physician with a new episode of non-specific low back pain were recruited. They completed diaries on pain-related fear, pain and pain catastrophizing for 14 days following the consultation. Follow-up questionnaires on disability were completed at 3 months and 12 months. Time series analyses produced subgroups of patients with descending, stable and rising levels of pain-related fear over the 2-week period. These groups differed on baseline characteristics and outcome at follow-up. A time-shift between the occurrence of pain-events and pain-related fear or pain catastrophizing could not be demonstrated.In summary, these results fit in with previous findings in chronic patients. A relevant subgroup of patients who might benefit from early intervention could be identified. These findings support the need for further research into fear mechanisms in acute low back pain.