A systematic review of treatment guidelines for metastatic colorectal cancer.

AIM: A systematic review of treatment guidelines for metastatic colorectal cancer (mCRC) was performed to assess recommendations for monoclonal antibody therapy in these guidelines. METHOD: Relevant papers were identified through electronic searches of MEDLINE, MEDLINE In Process, EMBASE and the Cochrane Library; through manual searches of reference lists; and by searching the Internet. RESULTS: A total of 57 relevant guidelines were identified, 32 through electronic database searches and 25 through the website searches. The majority of guidelines were published between 2004 and 2010. The country publishing the most guidelines was the USA (12), followed by the UK (10), Canada (eight), France (eight), Germany (three), Australia (two), Spain (two) and Italy (one). In addition, eight European and three international guidelines were identified. As monoclonal antibody therapy for mCRC was not introduced until 2004, no firm recommendations for monoclonal antibody therapy were made in guidelines published between 2004 and 2006. Recommendations for monoclonal antibody therapy first appeared in 2007 and evolved as more data became available. The most recent international, European and US guidelines recommend combination chemotherapy with the addition of a monoclonal antibody for the first-line treatment of mCRC. Second-line treatment depends on the first-line regimen used. For chemoresistant mCRC, cetuximab or panitumumab are recommended as monotherapy in patients with wild-type KRAS tumours. CONCLUSION: The study indicates that recent treatment guidelines have recognized the role of monoclonal antibodies in the management of mCRC, and that treatment guidelines should be updated in a timely manner to reflect the most recently available data.

Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with cetuximab.

BACKGROUND: Systemic agents in cancer treatment were often associated with possible infusion reactions (IRs). This study estimated the incidence of IRs requiring medical intervention and assessed the clinical and economic impacts of IRs in patients with colorectal cancer (CRC) treated with cetuximab. PATIENTS AND METHODS: Details on patients with CRC receiving cetuximab in 2004-2006 were extracted from a large USA administrative claims database. IRs were identified based on the occurrence of outpatient treatment, emergency room (ER) visit, and/or hospitalization for hypersensitivity and allergic reactions. Multivariate regressions were used to examine potential risk factors and quantify the economic impact of IRs. RESULTS: A total of 1122 CRC patients receiving cetuximab were identified. The incidence of IRs requiring medical intervention was 8.4%. Sixty-eight percent of the patients had treatment disruptions and 34% discontinued cetuximab treatment. Mean adjusted costs were $13,863 for cetuximab administrations with an IR requiring ER visit or hospitalization and $6280 for those with an IR requiring outpatient treatment, compared with $4555 for those without an IR. CONCLUSIONS: The incidence rate of cetuximab-related IRs requiring medical intervention in clinical practice was found to be higher than rates reported in the product label and clinical trials. The clinical and economic impacts of these IRs are substantial.

The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain.

Metastatic bone disease (MBD) is the most common cause of cancer pain and of serious skeletal-related events (SREs) reducing quality of life. Management of MBD involves a multimodal approach aimed at delaying the first SRE and reducing subsequent SREs. The objective of the study was to characterise the hospital burden of disease associated with MBD and SREs following breast, lung and prostate cancer in Spain. Patients admitted into a participating hospital, between 1 January 2003 and 31 December 2003, with one of the required cancers were identified and selected for inclusion into the study. The index admission to hospital, incidence of patients admitted and hospital length of stay were analysed. There were 28,162 patients identified with breast, lung and prostate cancer. The 3 year incidence rates of hospital admission due to MBD were 95 per 1000 for breast cancer, 156 per 1000 for lung cancer and 163 per 1000 for prostate cancer. For patients admitted following an SRE, the incidence rates were 211 per 1000 for breast cancer, 260 per 1000 for lung cancer and 150 per 1000 for prostate cancer. This study has shown that cancer patients consume progressively more hospital resources as MBD and subsequent SREs develop.

Association between androgen-deprivation therapy and incidence of diabetes among males with prostate cancer.

OBJECTIVES: Previous research has documented an increase in metabolic syndrome among patients who use androgen-deprivation therapy (ADT). Given that metabolic syndrome is related to diabetes, this research examined whether use of ADT was associated with an increase in the incidence of diabetes. METHODS: A retrospective, claims database was used to compare men diagnosed with prostate cancer who received ADT (N = 1231) with men diagnosed with prostate cancer who did not receive ADT (N = 7250). Unjustified comparisons among the cohorts were examined using chi-square statistics for categorical variables and t-statistics for continuous variables. A multivariate logistic regression was estimated to examine the association between receipt of ADT and the incidence of diabetes, while controlling for a wide range of factors that also potentially affect the probability of being newly diagnosed with diabetes. RESULTS: Descriptive statistics revealed that the patients who initiated ADT were significantly older (P <0.01), in poorer health (P <0.01), and more likely to have a prior diagnosis of hypertension (P = 0.04). Results from the multivariate regression indicate that for men diagnosed with prostate cancer, demographic characteristics, comorbid conditions, prior statin use, and receipt of ADT all affect the probability of incident diabetes. While controlling for other factors, the estimated relative risk of incident diabetes associated with the receipt of ADT was 1.36 (P = 0.01). CONCLUSIONS: Results from this study suggest that among prostate cancer patients, those initiating ADT are more likely to develop incident diabetes within 1 year. This finding supports previous research that established the relationship between ADT and metabolic syndrome.

Impact of abciximab versus eptifibatide on length of hospital stay for PCI patients.

The purpose of this study is to compare the profile of percutaneous coronary intervention (PCI) patients who receive abciximab versus eptifibatide, as well as to compare the effect of abciximab versus eptifibatide on hospital length of stay. Retrospective data were obtained from HCIA's Clinical Pathways Database on 5,446 coronary angioplasty patients who were administered either abciximab or eptifibatide. Estimation was conducted via a two-stage sample selection model. In the first stage, a probit regression was employed to determine which factors were associated with a higher probability of being administered abciximab versus eptifibatide. In the second stage, a negative binomial model was used to estimate the impact of a wide range of factors (selection of GPIIb/IIIa, patient demographics, insurance provider, health conditions, admission information, and hospital characteristics) on total hospital length of stay, as well as on postprocedural length of stay. After controlling for high-risk indications and other sources of selection bias, results indicate that receipt of abciximab was associated with a significantly shorter length of total hospital stay (0.83 fewer days; P < 0.001) than receipt of eptifibatide. Additionally, receipt of abciximab was found to be associated with a significantly shorter postprocedural hospital length of stay (0.48 fewer days; P = 0.002) compared to receipt of eptifibatide. Results of this study indicate that PCI patients who are administered abciximab versus eptifibatide have a significantly shorter length of hospital stay (both total and postprocedural). This finding is important since hospital length of stay reflects the occurrence of complications and has been found to be directly related to the resources consumed during in-patient management of patients. Cathet Cardiovasc Intervent 2001;53:296-303.

Impact of abciximab versus tirofiban on hospital length of stay for PCI patients.

The purpose of this retrospective study was to examine in a naturalistic setting the effect of abciximab versus tirofiban on hospital length of stay for patients undergoing percutaneous coronary intervention (PCI). Retrospective data were obtained from HCIASach's Clinical Pathways Database on 5,560 PCI patients who were administered either abciximab or tirofiban. Multivariate analysis was used to control for a wide range of factors (GPIIb/IIIa selection, patient demographics, insurance provider, health conditions, admission information, and hospital characteristics) that may influence hospital length of stay. Estimation was conducted via a two-stage sample selection model. After controlling for high-risk indications and sources of selection bias, results indicate that receipt of abciximab was associated with significantly shorter lengths of hospital stays compared to tirofiban (1.01 fewer days; p < 0.001). In a subgroup analysis of patients having an acute myocardial infarction (AMI; n = 2,593), receipt of abciximab was also found to be associated with significantly shorter hospital stays compared to tirofiban (0.60 fewer days; p < 0.001). Results of this study indicate that patients who are administered abciximab versus tirofiban have significantly shorter hospital stays. This reduction in length of stay may imply potential cost offsets for PCI patients who receive abciximab.

A comparison of abciximab use in MCO and non-MCO populations.

OBJECTIVE: To compare abciximab use in managed care organization (MCO) patients and non-MCO patients undergoing coronary angioplasty, specifically (1) the factors influencing abciximab use, (2) the impact of abciximab on hospital length of stay (LOS), and (3) differences in results in MCO and non-MCO patients. STUDY DESIGN: A retrospective observational study based on data from 87 US hospitals on 13,384 angioplasty patients. PATIENTS AND METHODS: Multivariate analysis was used to control for a wide range of factors (patient demographics, health conditions, admission information, and hospital characteristics) that may influence the likelihood of receiving abciximab and hospital length of stay (LOS). Estimation was conducted via a 2-stage sample selection model. RESULTS: Comorbidities, hospital characteristics, and geographic regions influenced abciximab use in MCO and non-MCO populations. In the non-MCO population, women and minority group members were significantly less likely than white male patients to receive abciximab. Both MCO and non-MCO angioplasty patients who were given abciximab had significantly shorter LOSs (0.66 +/- 0.27 fewer days and 0.87 +/- 0.13 fewer days, respectively) than did patients who were not given this drug. CONCLUSIONS: Access to care for MCO and non-MCO populations differed. Non-MCO women and minorities were less likely than non-MCO white men to receive abciximab, but this difference was not observed in the MCO population. After controlling for high-risk indications and selection bias, MCO and non-MCO patients who received abciximab had significantly shorter LOSs than did those who did not receive abciximab. This finding is consistent with the many clinical trials that have observed a reduction in ischemic complications associated with abciximab use.

Early adolescent peer orientation and adjustment during high school.

The long-term consequences of early adolescents' orientation toward peers for their adjustment during high school were assessed. Approximately 1,200 adolescents completed questionnaires in the 7th grade and in the 10th or 12th grades; course grades were also obtained from the students' school records. Early adolescents who were willing to sacrifice their talents, school performance, and parents' rules engaged in greater problem behavior and evidenced lower academic achievement than did other adolescents during high school. The poorer adjustment of adolescents with this extreme orientation toward peers was mediated by their reported involvement in deviant peer groups. In contrast, a tendency to seek advice from peers more than from parents during early adolescence had little implication for later adjustment. Discussion focuses on the need to consider the role of peer dependence along with the effects of supportive friendships during adolescence.

Abciximab provides cost-effective survival advantage in high-volume interventional practice.

BACKGROUND: Placebo-controlled randomized trials of platelet glycoprotein (GP) IIb/IIIa blockade during percutaneous coronary intervention have demonstrated efficacy of these agents for reducing the risk of periprocedural ischemic events. However, cost-effectiveness of this adjunctive pharmacotherapy has been scrutinized. Extrapolation of cost-efficacy observations from clinical trials to "real world" interventional practice is problematic. METHODS: Consecutive percutaneous coronary interventions (n = 1472) performed by Ohio Heart Health Center operators at The Christ Hospital, Cincinnati, Ohio, in 1997 were analyzed for procedural and long-term (6-month) outcomes and charges. Observations on cost and efficacy (survival) were adjusted for nonrandomized abciximab allocation by means of "propensity scoring" methods. RESULTS: Abciximab therapy was associated with a survival advantage to 6 months after percutaneous coronary intervention. The average reduction in mortality rate at 6 months was 3.4% (unadjusted) and 4.9% when adjusted for nonrandomization. The average charge increment to 6 months was $1512 (unadjusted) and $950 when adjusted for nonrandomization. Patients deriving the greatest reduction in mortality rates also had a reduction in total cardiovascular charges to 6 months. Distinguishing demographics of this population included multivessel coronary intervention, coronary stent deployment, intervention within 1 week of myocardial infarction, and lower left ventricular ejection fraction. The average cost per life-year gained in this study was $2875 for all patients (unadjusted) and $1243 when adjusted for nonrandomization. CONCLUSIONS: Abciximab provides a cost-effective survival advantage in high-volume interventional practice that compares favorably with currently accepted standards. Clinical and procedural demographics associated with increased cost-effectiveness included multivessel coronary intervention, stent deployment, recent (<1 week) myocardial infarction, and impaired left ventricular function.

Shorter hospital stays for angioplasty patients who receive abciximab.

The purpose of this retrospective study is to examine the effect of abciximab treatment on hospital length of stay for patients undergoing angioplasty in a naturalistic setting. Multivariate analysis was used to control for a wide range of factors (patient demographics, insurance provider, health conditions, admission and discharge information, and hospital characteristics) that may influence length of stay. Estimation was conducted on a sample of 13,384 angioplasty patients via a two-stage sample selection model. In addition, the model was re-estimated for a subgroup of 4,800 patients who underwent angioplasty and were also diagnosed with acute myocardial infarction. The study finds that patients in poorer health were more likely to receive abciximab. After adjusting for high-risk indications and selection bias, results also indicate that angioplasty patients (n = 13,384) who are given abciximab have a significantly shorter length of stay (0.89+/-0.12 fewer days) than those patients who did not receive abciximab. In a subgroup analysis of patients who had an acute myocardial infarction (n = 4,800), patients receiving abciximab were also found to have significantly shorter hospital stays (0.54+/-0.26 fewer days) than patients who did not receive abciximab. These results indicate that there are potential economic benefits for hospitals administering abciximab.

Association between abciximab and length of stay in intensive care for patients undergoing percutaneous coronary intervention. A 2-stage econometric model in a naturalistic setting.

OBJECTIVE: To examine the effect of abciximab treatment on intensive care length of stay for patients undergoing percutaneous coronary intervention (PCI). DESIGN AND SETTING: A retrospective study conducted in a naturalistic setting. METHODS: A 2-stage econometric model was used to control for the influence of possible selection bias across categories of patients and for both observable and unobservable factors correlated with each patient's treatment selection and length of stay in intensive care. Multivariate analysis was applied to control for a wide range of factors (patient demographics, insurance provider, health conditions, admission and discharge information, and hospital characteristics) that may influence intensive care length of stay. Retrospective data were obtained from HCIA's Clinical Pathways Database. PARTICIPANTS: Patients (n = 13,364) who were hospitalised in any of 87 hospitals across the US over the period from October 1, 1995 to December 1, 1996. RESULTS: After controlling for high-risk indications and selection bias, results indicated that administration of abciximab was associated with a significantly shorter length of stay in intensive care compared with not administering a GPIIb/IIIa inhibitor (0.45 fewer days; p < or = 0.0001). In a subgroup analysis of patients having an acute myocardial infarction (n = 4793), administration of abciximab was also associated with a significantly shorter intensive care stay (0.27 fewer days; p < 0.0001). CONCLUSION: Results of this study indicate that the administration of abciximab is associated with a reduction in the length of stay in intensive care. This reduction implies potential cost offsets for patients undergoing PCI who receive abciximab.

Designing naturalistic prospective studies of economic and effectiveness outcomes associated with novel antipsychotic therapies.

The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical services utilization, thereby reducing direct medical costs associated with treatment. Creating the most valid design to prospectively examine the effectiveness and costs of competing pharmacotherapies requires a dialectic of opposing research paradigms. The final protocol must represent a series of decisions that strike a careful balance between being scientifically sound (internal validity) and generalizable to the real world of clinical treatment (external validity). The results must be useful to decision-makers in determining to what extent reductions in healthcare expenditures can offset higher drug acquisition costs within their type of treatment environment. This article is a review of several methodological challenges in the design of medical effectiveness trials, including whether to blind the study, definition of the patient population, degree of physician discretion in treatment, and how to collect and analyze data for patients who discontinue their originally assigned medication. The article also provides a discussion of how clinical practices can inform decisions made to meet these challenges. The issues are illustrated through a prospective study designed to evaluate the cost-effectiveness of the newer antipsychotics in general and olanzapine in particular. Cost-effectiveness studies of novel antipsychotic medications, particularly those with naturalistic designs, will increase in importance as the use of these second-generation agents continues to expand.

What are minimal important changes for asthma measures in a clinical trial?

In this study, the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures, in order to identify the threshold where changes in clinical asthma measures are perceivable by patients. The study included 281 asthmatic patients, aged 18-63 yrs, in a randomized, placebo-controlled clinical trial of a leukotriene antagonist. Changes were related in: 1) asthma symptom scores; 2) inhaled beta-agonist use; 3) forced expiratory volume in one second (FEV1); and 4) peak expiratory flow (PEF) to a global question that queried overall change in asthma since starting the study drug. Additional analyses examined differences in the group reporting minimal improvement by treatment (active treatment versus placebo), sex and age groups. The average minimal patient perceivable improvement for each measure was: 1) -0.31 points for the symptom score on a scale of 0-6; 2) -0.81 puffs x day(-1) for inhaled beta-agonist use; 3) 0.23 L for FEV1; and 4) 18.79 L x min(-1) for PEF. In general placebo-treated patients and older patients, who reported minimal improvement, experienced less mean improvement from baseline than active-treated patients and younger patients, who reported minimal improvement. Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes. However, interpretation should be carried out cautiously when reporting a single value as a clinically important change.

Measurement characteristics of two asthma symptom diary scales for use in clinical trials.

The measurement characteristics of two asthma symptom diary scales developed for use as health outcome measures in clinical trials of asthma therapy were investigated. A daytime diary scale was designed to capture the frequency and inconvenience of daytime asthma symptoms and their effects on activities, and a nocturnal asthma symptom diary scale was designed to capture awakenings with asthma symptoms. The internal consistency, reliability, validity and responsiveness of both asthma diary scales were assessed in 346 adult asthma patients in two placebo-controlled clinical trials of an investigational asthma therapy, a leukotriene biosynthesis inhibitor. The daytime symptom scale showed sufficient internal consistency (0.90-0.92), and the daytime and nocturnal symptom scales showed sufficient test retest reliability (0.69-0.87). Construct validity was demonstrated by generally moderate-to-strong correlations for changes in the diary scales with changes in other measures of asthma status, such as forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and puffs of beta-agonist inhaler. Both scales demonstrated significant responsiveness to change in asthma due to therapy in one of the clinical trials. Based on these results, the daytime and nocturnal asthma symptom diary scales show measurement characteristics appropriate for use as asthma outcome measures in clinical trials of asthma therapy.

Psychosocial resources, adolescent risk behaviour and young adult adjustment: is risk taking more dangerous for some than others?

Longitudinal analyses examined the extent to which adolescent alcohol use, illegal drug use, and antisocial behaviour predicted adjustment and risk behaviour during young adulthood, and whether psychosocial resources buffered any impact of risk-taking. American adolescents completed questionnaires in Grade 12 and 2 years later (n = 694). Personal and social resources predicted success in occupational, relational, and health domains. High school risk behaviours predicted decreased success in relational domains, and alcohol use predicted higher educational attainment, independent of the relations with psychosocial resources. Interactions of resources with risk behaviours predicting adjustment were inconsistent, but resources predicted decreased risk behaviours in young adulthood among adolescent risk-takers. Discussion focuses on the value of, and challenges to, research on consequences of adolescent risk taking.

Validation of a questionnaire for comparing the tolerability of ophthalmic medications.

PURPOSE: The Comparison of Ophthalmic Medications for Tolerability (COMTOL) questionnaire was developed for use in clinical trials to compare the tolerability of topical ophthalmic medications used in the treatment of glaucoma. The questionnaire captures the frequency and bother of common side effects (i.e., ocular and other local effects, and effects on visual function) of topical therapy for lowering intraocular pressure. In addition, the questionnaire measures the extent to which these side effects and any associated limitations in routine living activities interfere with health-related quality of life, medication compliance, and patient satisfaction with the medication. This study was designed to assess the measurement characteristics of the COMTOL questionnaire. METHODS: The internal consistency, reliability, reproducibility, construct validity, discriminant validity, and responsiveness of the questionnaire were assessed in 70 adult patients with glaucoma in a clinical trial comparing timolol and pilocarpine. RESULTS: The questionnaire showed good-to-excellent internal consistency (0.73 to 0.98), reliability (0.76 to 0.94), and reproducibility (0.75 to 0.93). In general, there was a strong correlation in the expected direction between the frequency and bother of side effects and patient-perceived global measures. The questionnaire discriminated between patients receiving timolol and patients receiving pilocarpine. The questionnaire demonstrated significant responsiveness to change. CONCLUSIONS: The COMTOL questionnaire showed acceptable measurement characteristics for inclusion as a tolerability measure to supplement spontaneous adverse event reporting in clinical trials of topical ophthalmic therapy.

Effect of pharmacologic lipid lowering on health-related quality of life in older persons: results from the Cholesterol Reduction in Seniors Program (CRISP) Pilot Study.

OBJECTIVE: To determine the effect of lovastatin therapy on health-related quality of life in older persons. DESIGN: A prospective, randomized, double blind clinical trial. SETTING: Four university medical center research clinics. PARTICIPANTS: There were 431 men and women, primarily 65 years of age or older, with low density lipoprotein levels greater than 159 mg/dL and less than 221 mg/dL. Exclusion criteria included a Mini-Mental state score less than 24 or presence of recent cardiovascular events or other serious chronic disease likely to shorten survival. INTERVENTION: All participants were administered the National Cholesterol Education Program step one diet and were then randomized to placebo, 20 mg lovastatin, or 40 mg lovastatin. MEASUREMENTS: Areas of health-related quality of life assessed in the Cholesterol Reduction in Seniors Program (CRISP) included: (1) physical functioning, (2) sleep behavior, (3) social support, (4) depression, (5) cognitive function, and (6) health perception. Three global change questions asked the patients to judge change in general health since starting the study diet or the study medication and change in ability to function or care for self. Although some patients were followed for a total of 12 months, all participants were followed for 6 months, and 6-month data have been used for the primary analysis in this paper. RESULTS: Patients treated with 20 mg of lovastatin had a 17% and 24% reduction in total cholesterol and LDL-cholesterol, respectively. Patients treated with the 40-mg lovastatin dose achieved reductions of 20% for total cholesterol and 28% for LDL-cholesterol. Complaints of possible adverse events were remarkably similar in the two active treatment groups and the placebo group. At 6 months of follow-up there were no statistically significant differences found in mean change scores from baseline between treatment groups on the health-related quality of life measures (physical functioning, sleep, social support, depression, cognitive function scales, health perception) or global questions. CONCLUSIONS: This study demonstrates that lovastatin was extremely well tolerated in an older cohort, both with regard to symptoms and to health-related quality of life.

A multirater validation study to assess the reliability of acne lesion counting.

BACKGROUND: Despite widespread use of acne lesion counting, little has been published on its reliability, particularly for multiple raters. OBJECTIVE: Our purpose was to assess reliability of acne lesion counting with the use of a five-segment facial template. METHODS: After training, 12 raters each evaluated 12 patients in randomized order, in the morning and again in the afternoon, and recorded counts for different types of lesions on a five-segment facial template. RESULTS: Individual raters could reproduce their total lesion counts (reliability estimates, 0.81 to 0.97). Variability between raters was high, and overall reliability estimated across raters was 0.61. For a subgroup of commonly trained raters, overall reliability was higher (0.80). CONCLUSION: The reliability of acne lesion counting is excellent when performed by the same trained rater over time. The high variability between raters appears to be reduced by standardized training. Because fewer lesions are counted with less variation, use of a template may have contributed to the high within-rater reliability.