Cancer, immune suppression and Coronavirus Disease-19 (COVID-19): Need to manage drug safety (French Society for Oncology Pharmacy [SFPO] guidelines).

The Coronavirus disease (COVID-19) pandemic is disrupting our health environment. As expected, studies highlighted the great susceptibility of cancer patients to COVID-19 and more severe complications, leading oncologists to deeply rethink patient cancer care. This review is dedicated to the optimization of care pathways and therapeutics in cancer patients during the pandemic and aims to discuss successive issues. First we focused on the international guidelines proposing adjustments and alternative options to cancer care in order to limit hospital admission and cytopenic treatment in cancer patients, most of whom are immunocompromised. In addition cancer patients are prone to polypharmacy, enhancing the risk of drug-related problems as adverse events and drug-drug interactions. Due to increased risk in case of COVID-19, we reported a comprehensive review of all the drug-related problems between COVID-19 and antineoplastics. Moreover, in the absence of approved drug against COVID-19, infected patients may be included in clinical trials evaluating new drugs with a lack of knowledge, particularly in cancer patients. Focusing on the several experimental drugs currently being evaluated, we set up an original data board helping oncologists and pharmacists to identify promptly drug-related problems between antineoplastics and experimental drugs. Finally additional and concrete recommendations are provided, supporting oncologists and pharmacists in their efforts to manage cancer patients and to optimize their treatments in this new era related to COVID-19.

Providing Oncology Pharmacy Services During the Coronavirus Pandemic: French Society for Oncology Pharmacy (Société Francaise de Pharmacie Oncologique [SFPO]) Guidelines.

PURPOSE: Patients with cancer are at higher risk for contracting the COVID-19 infection and are more likely to have higher morbidity and mortality. This is a big challenge for oncology teams that have to treat patients to avoid contamination by SARS-CoV-2. The aim of the current work is to present oncology pharmacy practice guidelines during the COVID-19 pandemic to secure the pharmaceutical care of patients with cancer. METHODS: The bureau of the French Society for Oncology Pharmacy proposed these recommendations according to the French High Authority of Health following the Guidelines of Good Practice, slightly modified according to the pandemic crisis situation. These guidelines were developed by a working group of 7 experts in oncology pharmacy practice. Furthermore, the guidelines were assessed by 31 independent reviewers. RESULTS: One hundred percent of reviewers approved the guidelines and 90% of them suggested some improvements. The final version incorporates the best comments and consists of 26 recommendations organized in 8 different sections. CONCLUSION: These guidelines allow secure pharmaceutical management of patients with cancer during the COVID-19 pandemic.

Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: A real-life evaluation in France.

AIMS: Despite fluoropyrimidines (FPs) constituting the main component of the chemotherapy combination protocols in 50% of chemotherapies for solid tumour treatments, incidence data for FP-related toxicity are poorly documented in real life. This study evaluated the number of patients receiving FP-based chemotherapies in France, along with the true incidence of FP-related serious adverse effects (SAEs) before the recent mandatory dihydropyrimidine dehydrogenase (DPD)-screening was introduced by French health authorities, DPD being the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. METHODS: Exhaustive data on the number of patients treated with FP-based chemotherapy in 2013-2014 were collected in the Centre-Val de Loire region of France. True incidence of SAEs was extracted from a cohort of 513 patients with incident solid tumours receiving first-line FP-based chemotherapy. RESULTS: After extrapolation at national level, we estimated that 76,200 patients are currently treated annually with 5FU (53,100 patients, 62% digestive system-related versus 26% breast cancers versus 12% head and neck cancers) or capecitabine (23,100 patients, 45% digestive system-related versus 37% breast cancers versus 18% non-documented). Earlier (in the first two cycles) the SAE incidence rate was 19.3% (95% confidence interval (CI) 16-23%) including one toxic death (0.2%, 95%CI 0-1%). SAE incidence rate was 32.2% (95%CI 28-36%) over the first 6 months of treatment. Incidence of death, life-threatening prognosis or incapacity/disability was 1.4% (95%CI 0.4-2.4%) and 1.6% (95%CI 0.5-2.6%) during first two cycles and first 6 months, respectively. CONCLUSION: These data highlight the significant public health issue related to FP toxicity, with around 1200 patients developing FP-related life-threatening prognosis or incapacity/disability annually in France, including 150 toxic deaths. It is hoped that DPD-deficiency screening will reduce such iatrogenic events and eradicate toxic deaths.

SMABcare study: subcutaneous monoclonal antibody in cancer care: cost-consequence analysis of subcutaneous rituximab in patients with follicular lymphoma.

Rituximab is used as a standard of care for follicular lymphoma and is usually administered intravenously. A novel subcutaneous formulation recently showed non-inferior efficacy with similar pharmacokinetic and safety profiles compared to intravenous rituximab in patients with follicular lymphoma. This new approach is promising in terms of comfort for patients and time-saving for hospital staff. To evaluate the real-life economic impact of subcutaneous rituximab as maintenance therapy in patients with follicular lymphoma in real life, we conducted a cost-consequence analysis from the hospital's point of view in three French teaching hospitals. Health-related quality of life (EQ-5D-3L) was investigated as well as patients' and nurses' perception. Compared to intravenous rituximab, subcutaneous administration showed an estimated cost-saving of €109.20 per patient per cycle (p < 0.001), 78.6% of which could be attributed to the rituximab cost. Health-related quality of life showed no significant difference between the two groups despite tendencies for greater pain in the subcutaneous group and greater anxiety in the intravenous group. Thus, subcutaneous rituximab had a favorable pharmacoeconomic profile, with clinical efficacy similar to that of intravenous rituximab. The subcutaneous form was preferred by almost all patients, but further consideration should be given to improve the patients' experience: a dedicated day unit with trained medical, nursing, and pharmaceutical staff could be helpful.

Effect of formulation on the stability and aerosol performance of a nebulized antibody.

Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together.

Computer-assisted management of unconsumed drugs as a cost-containment strategy in oncology.

BACKGROUND: Cost-containment strategies are required to deal with rising drug expenditure, also in oncology. Drug wastage related to the preparation of chemotherapy drugs for patients is costly, but solutions exist for optimizing the use of unconsumed anticancer drugs. OBJECTIVE: Our pharmacy department makes use of a computerized drug storage bank, which records stability data and the amounts of unconsumed drugs available, and is connected to prescription software via an interface. We aimed to evaluate the real cost savings generated by this system. METHOD: We assessed the cost savings achieved with this system, for 37 different anticancer drugs, over a 1-year period. French drug pricing and the amounts of drugs from the storage bank potentially re-used were assessed. RESULTS: The re-use of unconsumed anticancer drugs generated substantial cost savings, for nine drugs in particular: azacitidine, bevacizumab, bortezomib, cetuximab, docetaxel, liposomal doxorubicin, rituximab, topotecan and trastuzumab. Overall cost savings accounted for about 5 % of total anticancer drug expenditure at our hospital (8.5 M). CONCLUSION: In medical hematology-oncology, drug wastage reduction and a computerized physician order entry system could be applied in routine practice at centralized drug-processing units, with significant financial benefits.

Development of an ion-pairing reversed-phase liquid chromatography method using a double detection analysis (UV and evaporative light scattering detection) to monitor the stability of Alimta(®)-pemetrexed preparations: identification and quantification of L-glutamic acid as a potential degradation product.

A new method based on high-performance liquid chromatography coupled to ultraviolet and evaporative light scattering detection (HPLC-UV-ELSD) was developed for the determination of L-glutamic acid, a potential degradation product of pemetrexed, and for the quantification of pemetrexed itself. This is an ion-pairing, reversed-phase method. The column was a Synergi MAX-RP C12 4 µm (150 mm x 4.6 mm). The mobile phase was 1 mM tridecafluoroheptanoic acid in aqueous solution and acetonitrile under gradient elution mode. L-Glutamic acid was detected by ELSD, and pemetrexed by UV at 254 nm. Good resolution was achieved between pemetrexed and L-glutamic acid. The HPLC method was validated according to SFSTP and ICH guidelines, and applied the accuracy profile procedure with a five-level validation experimental design. For pemetrexed, the decision criteria selected consisted of the acceptability limits (±3%) and the proportion of results within the calculated tolerance intervals (95%). In conclusion, the proposed analytical procedures were validated over the selected validation domains for L-glutamic acid (0.005-0.025 mg/mL) and pemetrexed (0.4-0.6 mg/mL) and shown to provide a very effective method.

[The need for a better definition of therapeutic indications of carboxypeptidase in delayed elimination of methotrexate]. / Les critères d'utilisation de la carboxypeptidase dans les surexpositions au méthotrexate doivent être mieux définis.

OBJECTIVES: High dose methotrexate (HD-MTX) may cause nonhaematological and haematological toxicities. MTX overexposure may be subsequent to administration errors or to delayed renal elimination resulting from MTX nephrotoxicity. The rescue agent carboxypeptidase rapidly hydrolyses MTX to inactive metabolites. However, current criteria for carboxypeptidase use are not well defined. We retrospectively evaluated the number of patients how should have received the drug if the criteria were applied, but who didn't receive it, and analysed their toxicities. METHODS: Patients treated at our institution in 2004 and 2005 and presenting the following criteria: concentrations of MTX at H48 >or= 3 microM, or impaired renal function, were considered. Post-course tolerance was recorded and graded. Recovery of renal function was followed-up periodically up to the 3rd month following the end of treatment. RESULTS: Twenty courses over 301 (7%) and 18 patients over 120 exhibited at least one criterion. Grade 3-4 toxicity was observed in 30% of the courses, including 2 severe acute renal impairment. Renal function decreased in most patients but had recovered upon the 3rd month in all but 2 patients. CONCLUSION: Despite a higher rate of toxicity than in general population, most of the patients recovered from it. Considering the cost of this treatment, the criteria for its therapeutic use could be restricted to concentration of MTX at H48 superior at 10 microM, associated with renal impairment.

[Not Available]. / Les critères d'utilisation de la carboxypeptidase dans les surexpositions au méthotrexate doivent être mieux définis.

OBJECTIVES: High dose methotrexate (HD-MTX) may cause nonhaematological and haematological toxicities. MTX overexposure may be subsequent to administration errors or to delayed renal elimination resulting from MTX nephrotoxicity. The rescue agent carboxypeptidase rapidly hydrolyses MTX to inactive metabolites. However, current criteria for carboxypeptidase use are not well defined. We retrospectively evaluated the number of patients how should have received the drug if the criteria were applied, but who didn't receive it, and analysed their toxicities. METHODS: Patients treated at our institution in 2004 and 2005 and presenting the following criteria: concentrations of MTX at H48 ≥ 3 µM, or impaired renal function, were considered. Post-course tolerance was recorded and graded. Recovery of renal function was followed-up periodically up to the 3rd month following the end of treatment. RESULTS: Twenty courses over 301 (7%) and 18 patients over 120 exhibited at least one criterion. Grade 3-4 toxicity was observed in 30% of the courses, including 2 severe acute renal impairment. Renal function decreased in most patients but had recovered upon the 3rd month in all but 2 patients. CONCLUSION: Despite a higher rate of toxicity than in general population, most of the patients recovered from it. Considering the cost of this treatment, the criteria for its therapeutic use could be restricted to concentration of MTX at H48 superior at 10| M, associated with renal impairment.

[Cardiac effects of cytokines produced after rituximab infusion]. / Effets cardiaques des cytokines relarguées lors de l'administration de rituximab.

Rituximab (Mabthera) is used in the treatment of refractory low-grade non-Hodgkin's lymphoma or in case of relapse after chemotherapy. Among the different adverse reactions with this drug, the most common is a constellation of symptoms (fever, rigors and chills) that occur more frequently during administration of the first dose of drug. These symptoms could be related to a cytokine-release syndrome. We report the case of a 46 year-old patient, presenting a familial cardiomyopathy, deceased a few minutes after having developed this syndrome, at the time of the 2nd infusion of rituximab. Several hypothesis have been suggested to explain this sudden death: a cardiac failure following deterioration of the systolic function, potentially related to the negative inotropic effects of TNFalpha, and/or an impairment of the diastolic function following the volemic overload. The impact of the reflex "administration of monoclonal antibody/cytokine-release syndrome" was only little investigated under physiologic or pathologic conditions. In spite of a risk of adverse reactions apparently moderated compared to the other drugs used in this context, this case report underlines the need for a special attention when using rituximab among patients with cardiac risk factors (reassessment of the benefit-risk ratio, specific monitoring, pre medication). More generally, it underlines the need for a systematic and continuous identification and reporting of adverse drug reactions to the French network of regional pharmacovigilance centres.