Justine Rochon

Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG

PURPOSE Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients. METHODS Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS). RESULTS Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted. CONCLUSION Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.

Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens.

PURPOSE Despite the progress that has been achieved, long-term survival rates in patients with advanced ovarian cancer are still disappointing. One attempt to improve results could be the addition of non-cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines were among the candidates for incorporation as a third drug into first-line regimens. PATIENTS AND METHODS We performed a prospectively randomized phase III study comparing carboplatin-paclitaxel (TC; area under the curve 5/175 mg/m2, respectively) with epirubicin 60 mg/m2 added to the same combination (TEC) in previously untreated patients with advanced epithelial ovarian cancer. All drugs were administered intravenously on day 1 of a 3-week schedule for a planned minimum of six courses. RESULTS Between November 1997 and February 2000, 1,282 patients were randomly assigned to receive either TC (635 patients) or TEC (647 patients), respectively. Grade 3/4 hematologic and some nonhematologic toxicities (nausea/emesis, mucositis, and infections) occurred significantly more frequently in the TEC arm. Accordingly, quality-of-life analysis showed inferiority of TEC versus TC. Median progression-free survival time was 18.4 months for the TEC arm and 17.9 months for the TC arm (hazard ratio [HR], 0.95; 95% CI, 0.83 to 1.07; P = .3342). Median overall survival time was 45.8 months for the TEC arm and 41.0 months for the TC arm (HR, 0.93; 95% CI, 0.81 to 1.08; P = .3652). Similar nonsignificant differences were observed when strata were analyzed separately. CONCLUSION Addition of epirubicin to TC did not improve survival or time to treatment failure in patients with advanced epithelial ovarian cancer; therefore, it cannot be recommended for clinical use in this population.

Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: A systematic review

OBJECTIVE Ovarian cancer outcome varies among different institutions, regions, and countries. This systematic review summarizes the available data evaluating the impact of different physician and hospital characteristics on outcome in ovarian cancer patients. METHODS A MEDLINE database search for pertinent publications was conducted and reference lists of each relevant article were screened. Experts in the field were contacted. Selected studies assessed the relationship between physician and/or hospital specialty or volume and at least one of the outcomes of interest. The primary outcome was survival. Additional parameters included surgical outcome (debulking), completeness of staging, and quality of chemotherapy. The authors independently reviewed each article and applied the inclusion/exclusion criteria. The quality of each study was assessed by focusing on strategies to control for important prognostic factors. RESULTS Forty-four articles met inclusion criteria. Discipline and sub-specialization of the primary treating physician were identified as the most important variable associated with superior outcome. Evidence showing a beneficial impact of institutional factors was weaker, but followed the same trend. Hospital volume was hardly related to any outcome parameter. CONCLUSIONS The limited evidence available showed considerable heterogeneity and has to be interpreted cautiously. Better utilization of knowledge about institutional factors and well-established board certifications may improve outcome in ovarian cancer. Patients and primary-care physicians should select gynecologic oncologists for primary treatment in countries with established sub-specialty training. Policymakers, insurance companies, and lay organizations should support development of respective programs.

Absolute Cardiovascular Disease Risk and Shared Decision Making in Primary Care: A Randomized Controlled Trial

PURPOSE We wanted to determine the effect of promoting the effective communication of absolute cardiovascular disease (CVD) risk and shared decision making through disseminating a simple decision aid for use in family practice consultations. METHODS The study was based on a pragmatic, cluster randomized controlled trial (phase III) with continuing medical education (CME) groups of family physicians as the unit of randomization. In the intervention arm, 44 physicians (7 CME groups) consecutively recruited 550 patients in whom cholesterol levels were measured. Forty-seven physicians in the control arm (7 CME groups) similarly included 582 patients. Four hundred sixty patients (83.6%) of the intervention arm and 466 patients (80.1%) of the control arm were seen at follow-up. Physicians attended 2 interactive CME sessions and received a booklet, a paper-based risk calculator, and individual summary sheets for each patient. Control physicians attended 1 CME-session on an alternative topic. Main outcome measures were patient satisfaction and participation after the index consultation, change in CVD risk status, and decisional regret at 6 months’ follow-up. RESULTS Intervention patients were significantly more satisfied with process and result (Patient Participation Scale, difference 0.80, P<.001). Decisional regret was significantly lower at follow-up (difference 3.39, P = .02). CVD risk decreased in both groups without a significant difference between study arms. CONCLUSION A simple transactional decision aid based on calculating absolute individual CVD risk and promoting shared decision making in CVD prevention can be disseminated through CME groups and may lead to higher patient satisfaction and involvement and less decisional regret, without negatively affecting global CVD risk.

The Ariadne principles: how to handle multimorbidity in primary care consultations

Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient’s preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.Please see related article: http://www.biomedcentral.com/1741-7015/12/222.

To test or not to test: Preliminary assessment of normality when comparing two independent samples

BackgroundStudent’s two-sample t test is generally used for comparing the means of two independent samples, for example, two treatment arms. Under the null hypothesis, the t test assumes that the two samples arise from the same normally distributed population with unknown variance. Adequate control of the Type I error requires that the normality assumption holds, which is often examined by means of a preliminary Shapiro-Wilk test. The following two-stage procedure is widely accepted: If the preliminary test for normality is not significant, the t test is used; if the preliminary test rejects the null hypothesis of normality, a nonparametric test is applied in the main analysis.MethodsEqually sized samples were drawn from exponential, uniform, and normal distributions. The two-sample t test was conducted if either both samples (Strategy I) or the collapsed set of residuals from both samples (Strategy II) had passed the preliminary Shapiro-Wilk test for normality; otherwise, Mann-Whitney’s U test was conducted. By simulation, we separately estimated the conditional Type I error probabilities for the parametric and nonparametric part of the two-stage procedure. Finally, we assessed the overall Type I error rate and the power of the two-stage procedure as a whole.ResultsPreliminary testing for normality seriously altered the conditional Type I error rates of the subsequent main analysis for both parametric and nonparametric tests. We discuss possible explanations for the observed results, the most important one being the selection mechanism due to the preliminary test. Interestingly, the overall Type I error rate and power of the entire two-stage procedure remained within acceptable limits.ConclusionThe two-stage procedure might be considered incorrect from a formal perspective; nevertheless, in the investigated examples, this procedure seemed to satisfactorily maintain the nominal significance level and had acceptable power properties.

A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial

BackgroundPeritoneal carcinomatosis is regarded as a common sign of advanced tumor stage, tumor progression or local recurrence of appendiceal and colorectal cancer and is generally associated with poor prognosis. Although survival of patients with advanced stage CRC has markedly improved over the last 20 years with systemic treatment, comprising combination chemotherapy +/− monoclonal antibodies, the oncological outcome—especially of the subgroup of patients with peritoneal metastases—is still unsatisfactory. In addition to systemic therapy, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are specific treatment options for a selected group of these patients and may provide an additional therapeutic benefit in the framework of an interdisciplinary treatment concept.Methods/designThe COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial investigating perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal carcinomatosis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life (QoL) and histopathological regression after preoperative chemotherapy.DiscussionThe COMBATAC trial is designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy plus cetuximab and CRS plus bidirectional HIPEC with intraperitoneal oxaliplatin.Trial registrationClinicalTrials.gov Identifier: NCT01540344, EudraCT number: 2009-014040-11

How to improve drug dosing for patients with renal impairment in primary care - a cluster-randomized controlled trial

BackgroundPatients with chronic kidney disease (CKD) are at increased risk for inappropriate or potentially harmful prescribing. The aim of this study was to examine whether a multifaceted intervention including the use of a software programme for the estimation of creatinine clearance and recommendation of individual dosage requirements may improve correct dosage adjustment of relevant medications for patients with CKD in primary care.MethodsA cluster-randomized controlled trial was conducted between January and December 2007 in small primary care practices in Germany. Practices were randomly allocated to intervention or control groups. In each practice, we included patients with known CKD and elderly patients (≥70 years) suffering from hypertension. The practices in the intervention group received interactive training and were provided a software programme to assist with individual dose adjustment. The control group performed usual care. Data were collected at baseline and at 6 months. The outcome measures, analyzed across individual patients, included prescriptions exceeding recommended maximum daily doses, with the primary outcome being prescriptions exceeding recommended standard daily doses by more than 30%.ResultsData from 44 general practitioners and 404 patients are included. The intervention was effective in reducing prescriptions exceeding the maximum daily dose per patients, with a trend in reducing prescriptions exceeding the standard daily dose by more than 30%.ConclusionsA multifaceted intervention including the use of a software program effectively reduced inappropriately high doses of renally excreted medications in patients with CKD in the setting of small primary care practices.Trial registrationCurrent Controlled Trials ISRCTN02900734

Multimorbidity's research challenges and priorities from a clinical perspective: The case of ‘Mr Curran’

ABSTRACT Older patients, suffering from numerous diseases and taking multiple medications are the rule rather than the exception in primary care. A manifold of medical conditions are often associated with poor outcomes, and their multiple medications raise additional risks of polypharmacy. Such patients account for most healthcare expenditures. Effective approaches are needed to manage such complex patients in primary care. This paper describes the results of a scoping exercise, including a two-day workshop with 17 professionals from six countries, experienced in general practice and primary care research as well as epidemiology, clinical pharmacology, gerontology and methodology. This was followed by a consensus process investigating the challenges and core questions for multimorbidity research in primary care from a clinical perspective and presents examples of the best research practice. Current approaches in measuring and clustering multimorbidity inform policy-makers and researchers, but research is needed to provide support in clinical decision making. Multimorbidity presents a complexity of conditions leading to individual patients needs and demanding complex processes in clinical decision making. The identification of patterns presupposes the development of strategies on how to manage multimorbidity and polypharmacy. Interventions have to be complex and multifaceted, and their evaluation poses numerous methodological challenges in study design, outcome measurement and analysis. Overall, it can be seen that complexity is a main underlying theme. Moreover, flexible study designs, outcome parameters and evaluation strategies are needed to account for this complexity.

Clinical research in epithelial ovarian cancer and patients’ outcome

We evaluated the relationship between the outcome of newly diagnosed ovarian cancer patients treated in 1123 German gynecology departments in 2001, and their participation in clinical trials through two German cooperative study groups. In addition, we evaluated other potential factors predicting outcome including hospital volume. The analysis was based on 476 patients from 165 hospitals and 3-year follow-up. Patients treated in study hospitals had a higher chance of receiving treatment according to national guidelines. This included a higher chance of receiving optimal staging in early stage disease and of receiving the recommended combination of surgical debulking and combination chemotherapy in advanced disease. On multivariable Cox model analysis, overall survival was significantly worse in patients treated in non-study hospitals.