Sacituzumab govitecan in metastatic triple-negative breast cancer patients treated at Institut Curie Hospitals: efficacy, safety, and impact of brain metastases.

BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.

[Overwiew of compounding oncology pharmacy in France in 2021]. / États des lieux de la pharmacotechnie oncologique en France en 2021.

The pharmacotechnical expert group of the French Society of Oncological Pharmacy presents the results of its national survey carried out in 2021 in the form of an inventory of pharmaceutical compounding units dedicated to oncology. Premises, equipment, controls, production flows and trends are described in this article, providing an overview of the sector at a time when the new Good Manufacturing Practices (GMP) are applicable. This overview will allow us to better address the needs and expectations of production pharmacists regarding the application of GMP and the development of their units.

Advanced prescription of injectable anticancer drugs: Safety assessment in a European Comprehensive Cancer Centre using the risk matrix approach.

AIMS: The purpose of this work was to assess failures in the advanced prescription of parenteral anticancer agents in an adult day oncology care unit with more than 100 patients per day. METHODS: An a priori descriptive analysis was carried out by using the risk matrix approach. After defining the scope in a multidisciplinary meeting, we determined at each step the failure modes (FMs), their effects (E) and their associated causes (C). A severity score (S) was assigned to all effects and a probability of occurrence (O) to all causes. These S and O indicators, were used to obtain a criticality index (CI) matrix. We assessed the risk control (RC) of each failure in order to define a residual criticality index (rCI) matrix. RESULTS: During risk analysis, 14 FMs were detected, and 61 scenarios were identified considering all possible effects and causes. Nine situations (15%) were highlighted with the maximum CI, 18 (30%) with a medium CI, and 34 (55%) with a negligible CI. Nevertheless, among all these critical situations, only three (5%) had an rCI to process (i.e., missed dose adjustment, multiple prescriptions and abnormal biology data); the others required monitoring only. Clinicians' and pharmacists' knowledge of these critical situations enables them to manage the associated risks. CONCLUSIONS: Advanced prescription of injectable anticancer drugs appears to be a safe practice for patients when combined with risk management. The major risks identified concerned missed dose adjustment, prescription duplication and lack of consideration for abnormal biology data.

Errors in prescribing injectable anticancer drugs: benefits of a pharmaceutical long-term monitoring to improve patient safety in a European comprehensive cancer centre.

OBJECTIVES: We aimed to assess the impact of pharmacist interventions on injectable chemotherapy prescription and the safety of early prescription practice in an adult daily care unit. METHODS: Prescription errors were recorded before and after implementing corrective measures. Errors identified from the pre-intervention period (i) were analysed to identify areas for improvement. During the post-intervention period (ii) we compared the errors in anticipated prescription (AP) with those in real-time prescriptions (RTP). We performed Chi-square statistical tests (α=0.05). RESULTS: Before implementing corrective measures (i), 377 errors were recorded (ie, 3.02% of prescriptions). After the implementation of corrective measures (ii), there was a significant decrease in errors, with 94 errors recorded (ie, 1.20% of prescriptions). The error rate in AP and RTP groups was 1.34% and 1.02%, respectively, without a significant difference between the two groups. CONCLUSIONS: This study highlights the importance of prescription review, as well as collaboration between pharmacists and physicians, in reducing prescription errors, whether these prescriptions were anticipated or not.

[Robotic production of injectable anticancer drugs in hospital pharmacies]. / Production robotisée des préparations d'anticancéreux injectables en pharmacie hospitalière.

INTRODUCTION: Following the 2005 decree on securing the medicine supply chain, the production of "chemotherapies", anticancer drugs (cytotoxic, cytostatic, immunotherapy), was centralised within hospital pharmacies. To cope with increasingly growing activities, pharmacies are moving towards robotisation. This work offers feedback from four French sites pioneers in robotic production. MATERIAL AND METHOD: A review of the literature was carried out on the PubMed and Google Scholar scientific databases and GERPAC publications relating to the robotic production of chemotherapy preparations. This review allowed to select 25 articles. RESULTS: The robotisation of the production of "chemotherapies" requires infrastructural prerequisites, a reengineering of the manufacturing process and the patient journey. This impacts all the parties involved in this complex process. The "cobotisation" concept or collaborative robotics must be anticipated by the teams. Robotisation is an institutional decision, which must be owned by the pharmaceutical team and endorsed by the medical team and management. DISCUSSION/CONCLUSION: For reasons of optimisation, safeguarding and management of human resources, a large number of centres get equipped with robotic systems. Robotic preparation should extend to other non-hazardous preparation, as it is already the case in other countries. This strategic view should be carried out today to anticipate problems, ensure safety and improve the healthcare quality.

Attenuated cytarabine, etoposide, dexamethasone plus rituximab (R-Mini-CYVE) regimen for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma not eligible for intensive chemotherapy.

OBJECTIVES: To evaluate the efficacy and tolerability of an attenuated immunochemotherapy regimen based on cytarabine, etoposide and dexamethasone plus rituximab (R-mini-CYVE) in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). METHODS: We included pretreated adult patients with B-cell NHL who were ineligible for high-dose immunochemotherapy (HDT). Cytarabine and etoposide were given at four different dose levels, depending on the patient's frailty. Up to 8 cycles were administered. RESULTS: Between 2013 and 2019, 56 patients with diffuse large B-cell lymphoma (n = 45, 80%) and indolent B-cell lymphoma (n = 11, 20%) were included. Median age was 75 (range: 36-88). Nineteen patients (35%) had a performance status ≥2. Patients received a median of 4 cycles of R-mini-CYVE. The objective response and the complete response rates were 50% and 33%, respectively. Median progression-free survival and overall survival times were 5.7 (95% CI: 0.5-10.9) and 14.7 (95% CI: 3.5-25.9) months, respectively. Grade ≥3 anaemia, thrombocytopenia and neutropenia occurred in 44%, 55% and 60% of the patients, respectively. The most frequent non-haematological grade ≥3 adverse events were sepsis (21%), fatigue (13%) and cytarabine-related neurotoxicity (5%). CONCLUSION: R-mini-CYVE demonstrated a meaningful antitumour efficacy and an acceptable safety profile in patients with relapsed/refractory B-cell NHL who were ineligible for HDT.

Organization of chemotherapeutic preparations in advance: Do we save or waste money?

OBJECTIVE: The development of oncology day-hospital activities contributes to increase quality of life of patients and consequently have changed their perception about waiting. The extemporaneous preparation of antineoplastic has become difficult to achieve given the increasing activity, and hospital pharmacists have taken up the challenge by the implementation of the antineoplastic preparation in anticipation. Because anticipation can lead to an important number of preparations to be discarded, we also develop a recycled process for other patients to limit these waste extra costs. We aim to demonstrate the positive balance of anticipated preparation in this 4-year study report.Data sources: This prospective study was conducted in a major European oncology day-hospital from January, 2012 to December, 2015. The data were extracted from our software WinSimbad™ and updated as needed. The number and cost-associated of preparation ungiven chemotherapy doses (recycled or discarded) were compared to the global drug budget of our hospital in order to not exceed 2%.Data summary: 303,100 antineoplastic have been prepared. Approximately 35% of them were anticipated with an average of 5,431±984 that were finally ungiven. Two-third was recycled and the cost of the ungiven preparations finally discarded represents 1.7±0.15% of the global drug budget. CONCLUSIONS: This study assesses the drug wastage and its associated cost of this concept through a prospective study and discusses the cost of ungiven antineoplastic preparations. With prior consideration of the need to define the acceptable rate of discarded ungiven preparation, the hospitals with an high oncology day-hospital activity should implement this approach.

High incidence of cetuximab-related infusion reactions in head and neck patients.

BACKGROUND: Cetuximab is crucial in the management of squamous cell carcinoma of the head and neck of patients. Grade 3-4 cetuximab-induced infusion reactions (CI-IRs) occur in 2% of patients with colorectal cancer. Despite the 2.7% CI-IR rate in the EXTREME trial, higher rates were reported in small series of patients with head and neck squamous cell carcinoma (HNSCC) (6%-18%). There is an urgent need to better appraise the natural history and the predictive factors for CI-IRs in patients with HNSCC exposed to cetuximab. METHODS: The medical records from patients with HNSCC (n=428) treated by cetuximab at Gustave Roussy from January 2013 to December 2015 were reviewed. The impact of potential risk factors was analysed. RESULTS: Out of 428 patients, 24 patients (5.4%) presented CI-IR, including grade 3-4 (95.7%); about 21% (5/24) requiring intensive care unit referral and quasi all occurred within the first cycle (21/24). In a multivariate analysis, the occurrence of grade 3-4 CI-IR was associated with tobacco and alcohol history (p=8.5e-3) and with prior allergy history (p=2.9e-3). CI-IRs tended to be associated with poor overall survival in patients with recurrent and metastatic HNSCC and with a higher number of further lines of chemotherapy. CONCLUSION: In real life, CI-IRs appear far more common in patients with HNSCC (5.4%) than reported in prospective trials. This is the largest series of patients ever focusing on the risk of CI-IR in patients with HNSCC. Prior allergy history and tobacco history are associated with CI-IR and could be used to better allocate treatment. Further prospective data are required to confirm these findings.

Computerized pediatric oncology prescriptions review by pharmacist: A descriptive analysis and associated risk factors.

BACKGROUND: Systematic prescription analyses by clinical pharmacists result in pharmacist interventions (PIs) to reduce prescription errors and improve medication safety. PIs are particularly critical in oncology, because antineoplastic drugs are highly toxic with low therapeutic indexes especially in a pediatric population. The aim of this study is to describe PIs in a pediatric oncology department and to identify potential risk factors associated with prescription errors. PROCEDURE: We conducted a 20-month observational study in a pediatric oncology department concerning electronic prescription of injectable chemotherapies was conducted. PIs were analyzed for drug-related problems (DRPs), type of intervention, population characteristics, involved drugs, and the potential risk factors. RESULTS: Clinical pharmacists made 90 PIs for 10,214 antineoplastic prescriptions for a rate of 88 PIs per 10,000 prescriptions. The majority of DRPs were dosage errors (61.8%), imputable to measurements (weight and/or height) in 47.4% or unreported dose reduction. The most common patient ages were in the range 1-10 years and the most common time for medical double checks was 2-9 pm. There were statistically more prescription errors in standardized protocols (P < 0.001). CONCLUSIONS: Not surprisingly, PIs were predominantly to correct dose errors, half of which related to height and weight measurements that were not updated. No significant risk factors for errors were identified for errors except in the standardized status of prescription, which appears to be linked in part to our software that did not automatically reflect dose reduction from one course to the next. Medical double-checking followed by a clinical pharmacist's double check were effective in order to prevent prescription errors.

Stability of Melphalan in 0.9% Sodium Chloride Solutions Prepared in Polyvinyl Chloride Bags for Intravenous Injection.

Melphalan is an alkylating agent frequently used in an intravenous formulation to treat hematologic malignancies and solid tumors in both adults and children. According to the manufacturer, melphalan is stable in sterile 0.9% sodium chloride for 90 min at room temperature (RT). Several authors have studied the stability of different concentrations of melphalan; however, most were not adapted to the current manufacturing process applied in pharmaceutical centralized units. This study was conducted to determine the stability of melphalan in 0.9% sodium chloride solutions at concentrations used for intravenous injection in practice. Melphalan is commonly prepared in diluted solutions ranging from 2 to 4 mg/ml for the treatment of adult patients and at lower concentrations (down to 0.5 mg/ml) for pediatric use. Accordingly, these were the three concentrations chosen for this study. Melphalan concentrations were measured with high-performance thin-layer chromatography (HPTLC). At RT, admixtures prepared at 4 mg/ml were stable for up to 8 h without protection from light; however, at lower concentrations, such as 0.5 and 2 mg/ml, stability did not exceed 2 h. When refrigerated, melphalan was stable for 24 h at 2 mg/ml; however, at 0.5 and 4 mg/ml, the drug was not stable. Melphalan solutions present with limited stability at 0.5, 2, and 4 mg/ml and are not adapted for delayed administration in pharmaceutical centralized units. However, at 4 mg/ml and at RT, a stability of 8 h is very interesting in practice and allows sufficient time for preparation, pharmaceutical control, transport, and administration.

Stability of etoposide solutions in disposable infusion devices for day hospital cancer practices.

In a context of day hospital care of cancer patients, a protocol combining etoposide and carboplatin is used in paediatrics. Disposable infusion devices can be used to improve patient quality of life and to optimize nursing time. Stability data are available for carboplatin in these devices but not for etoposide. The aim of this study was to determine the stability of etoposide solutions in these devices by monitoring the changing etoposide concentration. To study the changing etoposide concentration, we investigated three different concentrations, each in two different solvents: sodium chloride (NaCl) 0.9 % and dextrose 5 %, in Intermate(®) disposable infusion devices. Quantitative analyses were performed by high-performance liquid chromatography coupled with ultraviolet (UV) detection on samples collected over a 24-h study period. The results showed that 100 mg/L etoposide solutions were stable for 24 h in NaCl 0.9 % and for 12 h in dextrose 5 %, whatever the temperature. The 400-mg/L solutions were stable for 24 h in both diluents, whatever the temperature, whereas the 600-mg/L solutions when diluted in NaCl 0.9 % and dextrose 5 % in water were stable for 8 and 6 h, respectively. We found that precipitation was the main phenomenon responsible for decreased etoposide concentrations. This study allowed us to conclude that etoposide solutions prepared in Intermate(®) infusion devices are stable for day hospital administration in paediatrics. It will also allow us to conduct a future clinical study that will focus on the medico-economic feasibility of this protocol and on the evaluation of patient and nurse satisfaction.

Physico-chemical stability of busulfan in injectable solutions in various administration packages.

BACKGROUND AND OBJECTIVES: Busulfan is used as part of a conditioning regimen prior to hematopoietic stem cell transplantation for the treatment of certain cancers and immune deficiency syndromes. Due to its instability in aqueous preparations, busulfan for infusion is prepared from a concentrate and has a relatively short shelf life once prepared. The purpose of this study was to identify the most suitable storage container and temperature to maximize the shelf life of busulfan therapeutic infusions prepared from Busilvex(®). METHODS: Busilvex(®) 6 mg/mL was diluted to 0.55 mg/mL with 0.9 % NaCl and aliquots dispensed into polypropylene syringes, polyvinyl chloride bags, and glass bottles. Three storage temperatures were evaluated: 2-8 °C, 13-15 °C (thermostatically controlled chamber), and room temperature (20 ± 5 °C). At set time points, samples were analysed for busulfan content, using a high-performance liquid chromatography (HPLC) system with ultraviolet detection. The change in pH and osmolarity on storage was also determined, and solutions were inspected visually for formation of a precipitate or colour change. To determine the contribution of precipitation to loss of busulfan content on storage, samples from one time series were treated with the solvent dimethylacetamide prior to HPLC separation and quantitation of busulfan. RESULTS: The results of the active substance content monitoring study over a 48-h period demonstrate that busulfan solution is stable at a 5 % threshold, at 2-8 °C for 16 h in syringes, 14 h in glass bottles, and 6 h in bags. In addition, the period of stability decreases as the temperature increases (4 h at 20 ± 5 °C). The solution is considered to be stable, subject to precipitation liable to be observed regardless of the temperature. CONCLUSION: The best stability was observed for busulfan solutions placed at 2-8 °C in syringes. This study demonstrated that precipitation, in addition to hydrolysis, has a significant influence on the busulfan content.

Application of an acceptance sampling plan for post-production quality control of chemotherapeutic batches in an hospital pharmacy.

BACKGROUND: About 26,000 chemotherapeutic batches were produced in 2003 in the Institute Gustave Roussy and 83% were qualitatively and quantitatively assessed in post-production controls via an analytical platform. The rate of non-conformity (outside the specification limits of the target concentration +/-10%) decreased from 8.9% to 2.2% between years 2001 and 2003. A cost- and time-saving acceptance sampling plan was applied to assay fewer batches whilst maintaining an accurate estimate of the quality level. METHODS: The opportunity to apply a single sampling plan by attributes with an acceptance quality level of 2.2% was evaluated. A prognostic study using a logistic regression model was performed for some drugs to identify risk factors associated with the non-conformity rate of preparations. RESULTS: Out of 26 drugs, 17 have not been sampled, since they were prepared less than 400 times per year. For six drugs, a reduction of about 50% in the number of assays was estimated. Three drugs were "at risk" of being non-conform: for these drugs, all batches were analysed. CONCLUSIONS: The sampling plan allowed a reduction of almost 8000 analyses with respect to the number of batches analysed for 6 drugs. For the 3 drugs with the higher risk to be non-conform, associated risk factors were identified to set up corrective actions.