Catherine Rioufol

Chemotherapeutic errors in hospitalised cancer patients: attributable damage and extra costs

BackgroundIn spite of increasing efforts to enhance patient safety, medication errors in hospitalised patients are still relatively common, but with potentially severe consequences. This study aimed to assess antineoplastic medication errors in both affected patients and intercepted cases in terms of frequency, severity for patients, and costs.MethodsA 1-year prospective study was conducted in order to identify the medication errors that occurred during chemotherapy treatment of cancer patients at a French university hospital. The severity and potential consequences of intercepted errors were independently assessed by two physicians. A cost analysis was performed using a simulation of potential hospital stays, with estimations based on the costs of diagnosis-related groups.ResultsAmong the 6, 607 antineoplastic prescriptions, 341 (5.2%) contained at least one error, corresponding to a total of 449 medication errors. However, most errors (n = 436) were intercepted before medication was administered to the patients. Prescription errors represented 91% of errors, followed by pharmaceutical (8%) and administration errors (1%). According to an independent estimation, 13.4% of avoided errors would have resulted in temporary injury and 2.6% in permanent damage, while 2.6% would have compromised the vital prognosis of the patient, with four to eight deaths thus being avoided. Overall, 13 medication errors reached the patient without causing damage, although two patients required enhanced monitoring. If the intercepted errors had not been discovered, they would have resulted in 216 additional days of hospitalisation and cost an estimated annual total of 92, 907€, comprising 69, 248€ (74%) in hospital stays and 23, 658€ (26%) in additional drugs.ConclusionOur findings point to the very small number of chemotherapy errors that actually reach patients, although problems in the chemotherapy ordering process are frequent, with the potential for being dangerous and costly.

ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

Background: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. Primary objective: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. Methodology: Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. Results: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. Conclusion: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. Trial Registration: ClinicalTrials.gov Identifier #NCT01507480

Predictors of prescription errors involving anticancer chemotherapy agents

AIM The majority of medication errors that harm patients relate to the prescribing process. Our study aimed to identify the predictors of prescription errors involving anticancer chemotherapy agents. METHODS All consecutive antineoplastic prescriptions from June 2006 to May 2008 were analysed, with medication errors being captured. Potential risk factors for medication prescribing errors were defined in relation to the patient, chemotherapy regimen and hospital organisation. The relationship between these risk factors and observed medication errors or dose medication errors was assessed by univariate and multivariate logistic-regression analyses. RESULTS Among the 17,150 chemotherapy prescriptions, 540 contained at least one error (3.15%). The following independent predictors of risk of medication errors were identified: patients with a body surface area >2m(2) (odds ratio (OR): 1.3, 95% confidence interval (CI) 1.01-1.67, p=0.04), protocols with more than three drugs (OR: 1.91, 95%CI 1.59-2.31, p<0.001), protocols involving carboplatin (OR: 2.33, 95%CI 1.85-2.95, p<0.001), protocols requiring at least one modification by the physician (OR: 1.32, 95%CI 1.09-1.61, p=0.005), inpatient care (OR: 1.58, 95%CI 1.28-1.93, p<0.001) and prescriptions by a resident physician (OR: 1.83, 95%CI 1.50-2.22, p<0.001). The risk of medication dose prescribing errors was significantly associated with three independent factors: protocols involving carboplatin (OR: 4.47, 95%CI 3.45-5.79, p<0.001), protocols with more than three drugs (OR: 2.4, 95%CI 1.92-3.00, p<0.001) and protocols requiring at least one modification (OR: 1.33, 95%CI 1.04-1.69, p=0.02). CONCLUSION In this epidemiologic study, the independent risk factors identified should be targeted for preventive measures in order to improve anticancer agent prescriptions and reduce the risk of medication errors.

Suspicion of Drug-Drug Interaction between High-Dose Methotrexate and Proton Pump Inhibitors: A Case Report – Should the Practice Be Changed?

We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate.

EPICC study: evaluation of pharmaceutical intervention in cancer care.

In cancer care, clinical pharmacists contribute to improving prevention and management of drug‐related problems (DRPs). The 3‐year EPICC study (Evaluation of Pharmaceutical Intervention in Cancer Care) aimed to collect and analyse pharmaceutical interventions (PIs) in oncology.

Biosimilar monoclonal antibodies in lymphoma: a critical appraisal

Rituximab, an anti-CD20 monoclonal antibody, revolutionized the treatment of lymphoma. Although newer generation anti-CD20 monoclonal antibodies are being examined, patent expiries and patient demand have fueled the development of rituximab biosimilars. The development of such agents is both an important and difficult undertaking. By definition, although they aim to have safety and efficacy comparable with their reference agents, biosimilars are not exact replicas of those agents, and small changes in nonclinical and preclinical properties may ultimately affect in vivo activity. Consideration must be given to the complex mechanisms of action, sensitive patient populations that may be treated, and appropriate clinical trial endpoints. Furthermore, extrapolation of indications is multifaceted, deserving close examination. This review represents a critical look at biosimilars in lymphoma and their safety, efficacy and long-term effects on patient outcomes.

Obinutuzumab for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a frequent hematological malignancy that is incurable using standard approaches. Two anti-CD20 monoclonal antibodies (mAb), rituximab and ofatumumab, have been approved for CLL treatment. A new glycoengineered type II humanized anti-CD20 mAb, obinutuzumab (GA101), has been developed and demonstrates increased activity against B-cell malignancies by inducing direct cell death and better antibody-dependent cellular cytotoxicity. In a recent randomized Phase III study in patients with newly diagnosed CLL and coexisting conditions, obinutuzumab plus chlorambucil demonstrated significant improvement in progression-free survival and several other outcome parameters, in contrast to rituximab plus chlorambucil. Grade 3–4 infusion-related reactions and neutropenia occurred more frequently in patients who received obinutuzumab compared with those who received rituximab; however, the rate of serious infections was similar. Obinutuzumab represents a promising new option for patients with CLL and must be investigated with other chemotherapy regimens or with new targeted agents.

Improving Cancer Patient Care with Combined Medication Error Reviews and Morbidity and Mortality Conferences

Background: To reduce the occurrence of medication errors, a systemic approach was developed combining anti-neoplastic medication error reviews and morbidity and mortality conferences (M&MCs). We report the first experience of implementing this strategy in oncology. Methods: The case reports submitted to combined reviews were prepared by physicians and pharmacists, and medication error(s) were described and chronological and root-cause analyses were performed. Results: Ten combined reviews were conducted, which involved the departments of haematology, medical oncology, pneumology, gastroenterology and clinical oncology pharmacy. A total of 91 errors were analysed, of which 3 had reached the patient. Thirty-four corrective actions were proposed; 53% consisted of changes in practice, 35% in procedural reminders and 12% in on-ward education sessions. Conclusions: The combination of medication error reviews and M&MCs appears to be an efficient means of improving cancer patient safety and personnel proficiency. This multidisciplinary work is indispensable to improve future patient management through the critical analysis of past medical errors.

Pharmacokinetically based estimation of patient compliance with oral anticancer chemotherapies: in silico evaluation.

Background and objectivesMore and more anticancer chemotherapies are now available as oral formulations. This relatively new route of administration in oncology leads to problems with patient education and non-compliance. The aim of this study was to explore the performances of the ‘inverse problem’, namely, estimation of compliance from pharmacokinetics. For this purpose, we developed and evaluated a method to estimate patient compliance with an oral chemotherapy in silico (i) from an a priori population pharmacokinetic model; (ii) with limited optimal pharmacokinetic information collected on day 1; and (iii) from a single pharmacokinetic sample collected after multiple doses.MethodsPopulation pharmacokinetic models, including estimation of all fixed and random effects estimated on a prior dataset, and sparse samples taken after the first dose, were combined to provide the individual POSTHOC Bayesian pharmacokinetic parameter estimates. Sampling times on day 1 were chosen according to a D-optimal design. Individual pharmacokinetic profiles were simulated according to various dose-taking scenarios.To characterize compliance over the n previous dosing times (supposedly known without error), 2n different compliance scenarios of doses taken/not taken were considered. The observed concentration value was compared with concentrations predicted from the model and each compliance scenario. To discriminate between different compliance profiles, we used the Euclidean distance between the observed pharmacokinetic values and the predicted values simulated without residual errors.This approach was evaluated in silico and applied to imatinib and capecitabine, the pharmacokinetics of which are described in the literature, and which have quite different pharmacokinetic characteristics (imatinib has an elimination half-life of 17 hours, and α-fluoro-β-alanine [FBAL], the metabolite of capecitabine, has an elimination half-life of 3 hours). 1000 parameter sets were drawn according to population distributions, and concentration values were simulated at several timepoints under various compliance patterns to compare with the predicted ones. In addition, several simulation scenarios were run in order to explore the impact of the quality of the error model, interoccasion variability (IOV), error in the number of pills taken, and the performance of the compliance estimation method.ResultsThe best compliance estimate was obtained with pharmacokinetic samples taken 5 hours after the last dose. Performance of the method varied between simulation scenarios. In both the imatinib and capecitabine basic simulations, patient compliance was correctly estimated on the two last scheduled doses (with better results for imatinib). The magnitude of the error model also had a great impact on the quality of the compliance estimate.ConclusionsWe highlight the effect of three parameters on the quality of compliance estimates based on limited pharmacokinetic information: the plasma elimination half-life, interdose interval and magnitude of the error model. Nevertheless, the pharmacokinetic method is not informative enough and should be used with electronic monitoring, which provides additional information on compliance. Our method will be used in a future phase IV clinical trial where the relationships between compliance, efficacy and tolerability will be assessed.

Comparative toxicities of 3 platinum-containing chemotherapy regimens in relapsed/refractory lymphoma patients.

Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non‐Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone‐High dose aracytine (cis)platin (DHAP), dexamethasone‐High dose aracytine carboplatin (DHAC), or dexamethasone‐High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin‐based regimen (50.0% versus 12.0%, P < .05) and female (44.6% versus 29.7%, P < .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P < .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I‐II and 15 grade III‐IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I‐II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens.