Time to deterioration in cancer randomized clinical trials for patient-reported outcomes data: a systematic review.

PURPOSE: The time to deterioration (TTD) approach has been proposed as a modality of longitudinal analysis of patient-reported outcomes (PROs) in cancer randomized clinical trials (RCTs). The objective of this study was to perform a systematic review of how the TTD approach has been used in phase III RCTs to analyze longitudinal PRO data. METHODS: A systematic literature search was conducted in PubMed/MEDLINE, the Cochrane Library and through manual search to identify studies published between January 2014 and June 2018. All phase III cancer RCTs including a PRO endpoint using the TTD approach were considered. We collected general information about the study, PRO assessment and the TTD approach, such as the event definition, the choice of reference score and whether the deterioration was definitive or not. RESULTS: A total of 1549 articles were screened, and 39 studies were finally identified as relevant according to predefined criteria. Among these 39 studies, 36 (92.3%) were in advanced and/or metastatic cancer. Several different deterioration definitions were used in RCTs, 10 studies (25.6%) defined the deterioration as "definitive", corresponding to a deterioration maintained over time until the last PRO assessment available for each patient. The baseline score was explicitly stated as the reference score to qualify the deterioration for most studies (n = 31, 79.5%). CONCLUSION: This review highlights the lack of standardization of the TTD approach for the analysis of PRO data in RCTs. Special attention should be paid to the definition of "deterioration", and this should be based on the specific cancer setting.

Incidence and risk-factors of CHOP/R-CHOP-related cardiotoxicity in patients with aggressive non-Hodgkin's lymphoma.

WHAT IS KNOWN AND OBJECTIVE: The CHOP regimen with rituximab (R-CHOP) remains the standard for chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). The cardiotoxicity of doxorubicin appears to be a key problem in clinical practice. We studied the cardiotoxicity of CHOP/R-CHOP regimen in a retrospective series. The prognostic factors of congestive heart failure (CHF) were investigated, including the impact of empirical cardioprotection by dexrazoxane. METHODS: Patients with an aggressive NHL between 1994 and 2005 were included. Cardiac events were defined as either a decline in resting left ventricular ejection fraction (LVEF) <50%, a decline in LVEF of ≥20% from baseline or as clinical evidence of CHF. The risk of cardiotoxicity was explored by the Kaplan-Meier method. RESULTS: The study included 180 consecutive patients. During the second period of the survey, cardioprotective therapy by dexrazoxane was administered to 45% of patients. The 5-year cumulative risks of cardiac events (29% vs. 8%) and clinical CHF (17% vs. 1·5%) varied significantly between the two periods of study (1994-2000 vs. 2001-2005). In multivariate analysis, use of dexrazoxane (HR = 0·1 [0·01-0·75], P = 0·02) and age  < 60 years (HR = 0·4 [0·17-0·9], P = 0·03) appeared as protective factors of cardiac events. WHAT IS NEW AND CONCLUSION: Our study confirmed the weight of cardiac toxic effect of CHOP ± R regimen. Even if the use of dexrazoxane is highly debatable in curative situations, it may be an effective prevention of cardiotoxicity in aggressive NHL patients.

Computerized physician order entry of injectable antineoplastic drugs: an epidemiologic study of prescribing medication errors.

PURPOSE: In the context of CPOE of standardized antineoplastic drugs, the objectives of the present study were to determine the incidence of prescribing medication errors (PME) and to analyse PME related to antineoplastic treatment in university teaching hospitals. METHODS: All consecutive prescribing medication orders over 1 year were analysed prospectively. Potential clinical impact was quoted according to the Hatoum scale and risk factors identified with a logistic-regression model. RESULTS: A total of 14,854 prescriptions were analysed. The PME incidence was estimated at 1.5% [1.3-1.7], i.e. 15 errors per 1000 prescribing medication orders, with a significant or very significant potential clinical impact in 62.9% of cases. Potentially death-threatening events were avoided in 3.7% of cases. Overall, PME incidence related to significant, very significant or vital potential clinical impact was estimated to be 1.0% [0.8-1.2], i.e. 10 errors per 1000 prescribing medication orders. The most common type of error was related to antineoplastic drug dosage (61.0%): inadequate adaptation (43.1%), not taking alarms into account (16.1%), incorrect weight (0.9%), incorrect unit (0.9%). More than 20% of PME are medication errors directly linked to the prescribing medication order (choice of antineoplastic treatment, double-prescribing medication order, forgotten or not validated by a resident or senior physician). Occasional users of the CPOE system and resident physicians were identified as main PME risk factors. CONCLUSION: An epidemiologic survey of PME in the context of the use of a partial CPOE has allowed to determine the incidence and epidemiology of PME as well as the potential clinical impact they represent. Two risk factors have emerged that can be considered from an organization and software points of view. Better pharmacist's analysis of prescribing medication order within the CPOE system could possibly minimize duplication of antineoplasic drugs and the vital clinical impact associated with overdosage.

Magnesium effect on testosterone-SHBG association studied by a novel molecular chromatography approach.

A biochromatographic approach is developed to measure for the first time thermodynamic data and magnesium (Mg(2+)) effect for the binding of testosterone (TT) to sex hormone-binding globulin (SHBG) in a wide temperature range. For this, the SHBG was immobilized on a chromatographic support. It was established that this novel SHBG column was stable during an extended period of time. The affinity of TT to SHBG is high and changes slightly with the Mg(2+) concentration because the number of Mg(2+) linked to binding is low. The determination of the testosterone retention with the steroid hormone at different Mg(2+) concentrations and temperatures demonstrated that the Mg(2+) binding heat effect associated with this Mg(2+) release or uptake during this binding was in magnitude around 17kJ/mol corresponding to the model describing the electrostatic attraction that occurs between the negatively charged non specific areas of SHBG and the positively charged of magnesium. At all the magnesium concentrations studied, the DeltaH values were negative due to van der Waals interactions and hydrogen bonding which are engaged at the complex interface confirming strong TT-SHBG hydrogen bond networks. As well, the DeltaS values were all positive due to hydrophobic forces in the testosterone-SHBG complex formation. In addition our results suggest that adaptive conformational transitions contribute to the specific testosterone-SHBG complex formation. As well, in the biological Mg(2+) concentration domain, it was clearly demonstrated that there was an uncompetitive inhibition of Mg(2+) on TT-SHBG binding which led an enhancement of bioavailable TT. Our work indicated that our biochromatographic approach could soon become very attractive for study other SHBG-steroid (or phytoestrogen) binding.

[Clinical audit on the use of expensive systemic antifungals in the Besançon University Hospital]. / Audit clinique des prescriptions d'antifongiques systémiques couteux au centre hospitalier universitaire de Besançon.

UNLABELLED: The continuous improvement policy for healthcare quality requires practice evaluation. The principle of a clinical audit is to compare practice to guidelines. Prescription guidelines on antifungal agent use has been available in our hospital since 2003. It was updated in 2005 and 2006. OBJECTIVE: The aim of this study was to assess compliance to guidelines, with an audit of prescriptions: amphotericin B lipid formulation, voriconazole and caspofungin, expensive antifungals concerned by the budget allowance correlated to activity, subject to supplementary reimbursement to the coded Homogeneous Group of Diseases. METHOD: The assessment criteria were: relevance of the indication, absence of a better alternative, complying to recommended dosage, loading dose and timing. This retrospective study dealt with all prescriptions of all departments, from January to May 2007. RESULTS: Hundred and eighteen prescriptions were retrospectively analyzed for 81 patients. The rate of overall conformity was 54%. Antifungal therapy was justified for 113 prescriptions (96%). In 30% of the cases, a more efficient alternative was advised, cheaper or less toxic. The dosage and the charge dosing were right in 92% and 80% of the cases respectively. CONCLUSION: This audit allowed assessing good-use of antifungals. We showed an over-prescription of caspofungin and sometimes insufficient regimen of voriconazole dosages for children. Reporting these audit results and development of new international guidelines stress the need to update local recommendations regularly.

Hospital costs of renal transplant management.

Renal transplantation is considered to be a cost-effective therapy, but hospital medical costs are not accurately known. The aim of this work was to evaluate the costs of hospital stay for renal transplantation. This retrospective study included all patients who underwent renal transplantation between January 1, 2004, and December 31, 2005, in our University hospital. The incurred costs were determined using our center's analytical accounting (AA). The mean local cost was then compared with the median national cost of hospitalization for renal transplantation, based on a sample of participating centers contributing to the National Cost Scale (NCS) per homogenous diagnosis-related group (DRG). These mean costs were weighed against the financing obtained by national rates of the case-mix based payment system (termed T2A). Data were collected from 77 patients. Their mean length of stay was 19.4 days. AA determined the cost of management to be euro14,100 per patient. National economic approaches were significantly higher: euro16,389 for NCS and euro17,369 for national rates. Thus, the specific DRG rate (case mix index) of renal transplantation covers the expenses incurred by our center. These results are rather interesting; however, it is unlike those obtained for the management of other diseases such as acute myeloid leukemia, where T2A underestimates the actual cost by 2-4 times. Last, the hospital budget and T2A must be considered as a whole. The fact that DRGs with favorable and unfavorable pricing balance out should be taken into account.

[IFCT-0302 trial: randomised study comparing two follow-up schedules in completely resected non-small cell lung cancer]. / Protocole IFCT-0302: essai randomisé de deux schémas de surveillance dans les cancers bronchiques non à petites cellules complètement réséqués.

BACKGROUND: The authorities advocate a minimalist attitude towards the follow-up of resected bronchial carcinoma (clinical examination and chest x-ray). A survey showed that 70% of French respiratory physicians have chosen to use the CT scanner and often endoscopy. The published data are equivocal and are often based on retrospective studies. Lung cancer is a good model for a study of post-operative surveillance. Recurrences often occur in easily observed areas, they may be detected while still asymptomatic and are sometimes potentially curable. Second primary tumours may develop at the same site. METHODS: The Intergroupe Francophone de Cancerologie Thoracique (IFCT) has initiated a trial comparing simple follow-up (clinical examination, chest x-ray) with a more intensive follow-up (CT scan, fibreoptic bronchoscopy). The surveillance will take place every 6 months for 2 years and then annually until 5 years. EXPECTED RESULTS: The main aim is to determine whether intensive follow-up improves patient survival. The opposite question is equally important. If an expensive and demanding follow-up does not affect the chances of cure these results will influence our practice.

[Retrospective and comparative study of the medicoeconomical impact of a new mesh in the treatment of anterior abdominal wall incisinal hernia]. / Etude comparative rétrospective de l'impact médicoéconomique d'un renfort innovant dans la cure des éventrations de la paroi abdominale antérieure.

STUDY AIM: Determine the gain of hospitalization cost using a new intraperitoneal mesh compared to the retro-muscular pre-fascial implantation of a polyester mesh. PATIENTS AND METHODS: From January 1998 to June 2000, 52 patients with incisional hernia of the anterior abdominal wall were operated using intraperitoneal Parietex composite Mesh. The cost of surgery, anesthesia and hospitalization in this group were compared to similar data from a group of 21 patient where a Mesrsuture mesh in a prefascial retromuscular position was used. RESULTS: Parietex Composite Mesh in intraperitoneal position allows a significative reduction in surgery time, anesthesia time and hospitalization. The clinical results were confirmed by cost savings. CONCLUSION: Using new innovative medical device changing surgery technique insures significant cost saving despite its initial additional cost and increases patient's comfort during hospitalization.

Cost-effectiveness analysis of strategies introducing FDG-PET into the mediastinal staging of non-small-cell lung cancer from the French healthcare system perspective.

AIM: To determine the most cost-effective strategy using PET for mediastinal staging of potentially operable non-small-cell lung cancer (NSCLC). METHODS: Four decision strategies based on French NSCLC work-up practices for the selection of potential surgical candidates were compared, comprising CT only, PET for negative CT, PET for all with anatomical CT, and CT and PET for all cases. The medical literature was surveyed to obtain values for all variables of interest. Costs were assessed with reimbursements from the French healthcare insurance for the year 1999. Expected cost and life expectancy were calculated for all possible outcomes of each strategy. Sensitivity analysis was performed to determine the effects of changing variables on the expected cost and life expectancy. RESULTS: Compared with the CT only strategy, CT and PET for all resulted in a relative reduction of 70% of surgery for persons with mediastinal lymph node metastasis. PET for all with anatomical CT was shown to be a cost-effective alternative to the CT only, with life expectancy increased by 0.10 years and expected cost savings of 61 euros. This strategy was more favourable than PET for negative CT. Overall, sensitivity analyses showed the robustness of the results. CONCLUSION: The introduction of thoracic PET for NSCLC staging is potentially cost-effective in France. Further clinical investigation might help to validate this result.

Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin's lymphoma.

BACKGROUND: To determine the incidence of early cardiotoxicity induced by the CHOP regimen in patients with aggressive non-Hodgkin's lymphoma (NHL) and to identify associated risk factors. PATIENTS AND METHODS: A retrospective analysis included 135 consecutive patients who had been treated with the CHOP (cyclophosphamide, doxorubicin, vincristin, prednisone) regimen as first-line therapy between 1994 and 2000. The cardiac evaluation was based on a determination of the resting left ventricular ejection function (LVEF) by gated blood-pool imaging. Cardiotoxicity was defined as a significant decrease in LVEF or clinical evidence of congestive heart failure (CHF). RESULTS: Twenty-seven (20%) patients developed a cardiac event within 1 year of treatment. Among these, 14 patients had clinical signs of CHF. Three patients died suddenly from presumed cardiac causes. In multivariate analysis, a cumulative dose of doxorubicin >200 mg/m(2) [odds ratio (OR) = 4.2, P = 0.005)] and age over 50 years (OR = 2.9, P = 0.03) appeared to be significant risk factors. CONCLUSION: Early clinical and subclinical cardiotoxicity was frequent in patients receiving the CHOP regimen. The threshold of the cumulative dose of doxorubicin appeared to be low: at doses >200 mg/m(2), 27% of patients had cardiac events. Elderly patients appeared to be at higher risk. The development of cardioprotective strategies or alternative treatments are mandatory for aggressive NHL patients.

[Neurosurgical and endovascular treatment of intracranial aneurysms: a cost analysis of two different strategies at the University Hospital of Bordeaux (France)]. / Traitement neurochirurgical et endovasculaire des anévrismes intracrâniens. Approche économique de deux alternatives thérapeutiques sur le CHU de Bordeaux.

BACKGROUND: Rupture of intracranial aneurysms causes major mortality and morbidity. Moreover, treatment of this vascular malformation generates high medical costs. We compared the cost of two different strategies employed at the University of Bordeaux to prevent aneurysms from rebleeding: a classical neurosurgical technique consisting in clipping the neck of the aneurysm and a new less invasive neuroradiological technique based on embolization using platinum coils. METHOD: A micro-cost study was carried out retrospectively from May 1998 to June 2000) comparing data from 44 patients admitted for ruptured intracranial aneurysm: 22 operated patients and 22 patients treated with an endovascular approach. Each operated patient was matched with an embolized patient for clinical status at admission (World Federation of Neurological Surgeons Scale) and complications resulting from cerebral hemorrhage (hydrocephalus, vasospasm, rebleeding). RESULTS AND CONCLUSION: Our results showed the same cost for the same efficiency . Expenditures are however made differently. The endovascular technique allows a shorter hospital stay (8 days less), balancing the high cost of single use medical supplies (coils, microcatheters.). The endovascular technique has many advantages for the patients, but cannot be successful in all types of intracranial aneurysms. Both techniques remain indispensable.

The impact of resistance to methicillin in Staphylococcus aureus bacteremia on mortality.

Background: It is unclear whether methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) differ in virulence. We therefore carried out a prospective study of cases of S. aureus bacteremia over a period of 2 years at our university hospital. We report herein the results of a comparative analysis of the clinical characteristics and mortality rates associated with cases of bacteremia caused by MRSA and MSSA. Methods: Over a 2-year period, we reviewed the medical records of hospitalized patients with blood cultures positive for S. aureus. Demographic characteristics, underlying diseases, diagnosis, clinical features, severity, laboratory findings, antimicrobial treatment, and resistance to methicillin were analyzed as possible risk factors for death attributed to bacteremia. Results: The rate of mortality attributed to bacteremia was 27.3% (27 patients): 13 (43.3%) deaths were recorded for patients infected with MRSA and 14 (20.3%) for patients infected with MSSA (P=0.0339, OR=3.00 (1.08--8.46)). Two variables were significantly associated with death within 14 days of the onset of bacteremia in univariate and multivariate analyses after adjusting for antimicrobial treatment: malignant hematologic disease (protective factor; OR=0.184 (0.038--0.882)) and resistance to methicillin (risk factor; OR=2.97 (1.12--7.88)). Conclusion: This study shows that S. aureus bacteremia has a high mortality rate, especially if the strain involved is methicillin-resistant, regardless of patient age and the efficacy of antimicrobial treatment.

Incidence and risk factors of preparation errors in a centralized cytotoxic preparation unit.

OBJECTIVE: A major objective of centralized preparation is to improve the quality of the final product, and thus their safety for the patient. Few data are available concerning errors occurring during preparation and the risk factors associated with the errors. To assess risk factors associated with preparation errors in a centralized cytotoxic preparation unit. DESIGN: Medication errors were detected during preparation (self-education by technicians) or at the time of control (qualitative and semi-quantitative). For each preparation, several potential risk factors were studied. Univariate analysis was carried out using Chi-2 or Fisher exact tests. Variables with p < 0.15 associated in univariate analysis were entered in a stepwise regression model. In an overall analysis, all types of error were considered. In a second analysis, only major errors (errors associated with drug, dose or major incompatibility) were studied. RESULTS: Analysis included 30,819 preparations. Overall and major error rates were respectively 0.45% and 0.19%. The number of bottles (more than one), the volume of active solution (more than 50 ml) and the daily workload were the major risk factors identified by successive univariate and multivariate analysis. CONCLUSION: Low rates of medication errors compared to previous studies were reported. Major preparation errors were principally related to drug labeling (dose/bottle and concentration) and workload. Preparation mistakes appeared to have many causes. These results could be used to revise the general organization and determine a suitable purchasing policy.

[Cost effectiveness of GM-CSF in the treatment of acute myeloblastic leukemia in aged patients: protocol of GOELAM Sa3]. / Intérêt thérapeutique et économique du GM-CSF dans le traitement des leucémies aiguës myéloblastiques du sujet âgé: protocole GOELAM Sa3.

A cost-effectiveness analysis was carried out from a randomized placebo-controlled protocol of GM-CSF during and after remission induction treatment for elderly patients with acute myeloid leukemia (AML). A retrospective economic analysis was carried out from the hospital perspective. A total of 240 patients with de novo AML and aged 55 to 75 years were enrolled. Overall survival and disease-free survival were analysed for efficacy within five years and expressed in gained life-years. Analysis was also conducted according to the protocol stratification: 55-64-year-old and 65-75-year-old patients. Global costs were estimated on the basis of patient medical records from inclusion to death or relapse. In all, 83 patients were evaluated from three centres, Besançon, Nancy and Nantes. Costs are expressed in French francs. Overall, total cost per patient amounted to FF 641,778 for placebo patients and to FF 587,048 for GM-CSF patients. For disease free-survival, costs were FF 357,167 for placebo patients and FF 320,736 for GM-CSF patients. For overall survival and disease free-survival the cost savings by GM-CSF were, respectively, FF 54,730 and FF 36,431. In the younger patient group savings were synonymous with GM-CSF. In all cases GM-CSF strategy induced benefit expressed as savings as well as efficacy.