The toxicity of antineoplastic drugs has been well known since they were introduced in the 1940s. Because most antineoplastic drugs are nonselective in their mechanism of action, they affect noncancerous as well as cancerous cells, resulting in well-documented side effects. During the 1970s, evidence came to light indicating health care workers may be at risk of harmful effects from antineoplastic drugs as a result of occupational exposure. Since that time, reports from several countries have documented drug contamination of the workplace, identified drugs in the urine of health care workers, and measured genotoxic responses in workers. Evidence also exists of teratogenic and adverse reproductive outcomes and increased cancers in health care workers. During the past 30 years, professional organizations and government agencies have developed guidelines to protect health care workers from adverse effects from occupational exposure to antineoplastic drugs. Although many safety provisions were advanced to reduce worker exposure in the 1980s, recent studies have shown that workers continue to be exposed to these drugs despite safety policy improvements. In 2004, the National Institute for Occupational Safety and Health (NIOSH) published an alert reviewing the most recent information available and promoting a program of safe handling during their use.

https://onlinelibrary.wiley.com/doi/pdf/10.3322/canjclin.56.6.354

Preventing Occupational Exposures to Antineoplastic Drugs in Health Care Settings

http://stacks.cdc.gov/view/cdc/34341/cdc_34341_DS1.pdf

Occupational exposures among nurses and risk of spontaneous abortion

Stability studies performed by the pharmaceutical industry are only designed to fulfill licensing requirements. Thus, post-dilution or -reconstitution stability data are frequently limited to 24h only for bacteriological reasons regardless of the true chemical stability which could, in many cases, be longer. In practice, the pharmacy-based centralized preparation may require infusions to be made several days in advance to provide, for example, the filling of ambulatory devices for continuous infusions or batch preparations for dose banding. Furthermore, a non-justified limited stability for expensive products is obviously very costly. Thus, there is a compelling need for additional stability data covering practical uses of anticancer drugs. A European conference consensus was held in France, May 2010, under the auspices of the French Society of Oncology Pharmacy (SFPO) to propose adapted rules on stability in practical situations and guidelines to perform corresponding stability studies. For each anticancer drug, considering their therapeutic index, the pharmacokinetics/pharmacodynamics (PK/PD) variability, specific clinical use and risks related to degradation products, the classical limit of 10% of degradation can be inappropriate. Therefore, acceptance limits must be clinically relevant and should be defined for each drug individually. Design of stability studies has to reflect the different needs of the clinical practice (preparation for the week-ends, outpatient transportations, implantable devices, dose banding…). It is essential to use validated stability-indicating methods, separating degradation products being formed in the practical use of the drug. Sequential temperature designs should be encouraged to replicate problems seen in daily practice such as rupture of the cold-chain or temperature-cycling between refrigerated storage and ambient in-use conditions. Stressed conditions are recommended to evaluate not only the role of classical variables (pH, temperature, light) but also the mechanical stress. Physical stability such as particles' formation should be systematically evaluated. The consensus conference focused on the need to perform more studies on the stability of biotherapies, including a minimum of three complementary separating methods and a careful evaluation of submicron aggregates. The determination of the biological activity of proteins could be also useful. A guideline on the practical stability of anticancer drugs is proposed to cover current clinical and pharmaceutical practice. It should contribute to improved security of use, optimization of centralized handling and reduced costs. Finally, we have attempted to establish a new drug stability paradigm based on practical clinical needs, to complement regulatory guidelines which are essentially orientated to the stability of manufactured drugs.

https://ejhp.bmj.com/content/ejhpharm/19/3/278.full.pdf

Guidelines for the practical stability studies of anticancer drugs: A European consensus conference

Objectives: Antineoplastic drugs are known reproductive and developmental toxicants. Our objective was to review the existing literature of reproductive health risks to workers who handle antineoplastic drugs. Methods: As tructured literature review of 18 peer-reviewed, English language publications of occupational exposure and reproductive outcomes was performed. Results: Although effect sizes varied with study size and population, occupational exposure to antineoplastic drugs seems to raise the risk of both congenital malformations and miscarriage. Studies of infertility and time to pregnancy also suggested an increased risk for subfertility.Conclusions: Antineoplastic drugs are highly toxic in patients receiving treatment, and adverse reproductive effects have been well documented in these patients. Health care workers with long-term, low-level occupational exposure to these drugs also seem to have an increased risk of adverse reproductive outcomes. Additional precautions to prevent exposure should be considered.

/pdf/reproductive-health-risks-associated-with-occupational-12lsyhuhfr.pdf

Reproductive Health Risks Associated with Occupational Exposures to Antineoplastic Drugs in Health Care Settings: A Review of the Evidence

Exposure to antineoplastic drugs should be avoided due to the risk of getting adverse health effects. Antineoplastic drugs such as cyclophosphamide (CP) and ifosfamide (IF) are commonly used in medical attendance. In this study the variability of surface contamination of CP and IF was investigated by repeated wipe sampling over time in four workplaces in a university hospital. The surface contamination levels were also evaluated and health care workers were biologically monitored. A hospital pharmacy, two oncology wards and one oncology outpatient department were selected. Between 10 and 13 different surface areas such as work areas, floors and handles were selected in each workplace and wiped between 7 and 8 times during 9 months. Pre- and post-shift urine samples were collected from the workers in the investigated workplaces. Analysis was performed by liquid chromatography combined with tandem mass spectrometry. Measurable amounts of CP and IF were detected on the majority of the sampled surfaces. The highest concentrations were found on the floors in the patient lavatories and utility rooms (up to 95 ng cm−2). In general, the surface contamination of CP and IF on floors did not vary much over time. Work areas and handles had larger variability. Neither CP nor IF were detected in any of the collected urine samples. The variability in surface contamination of CP and IF was rather low especially on floors. Higher concentrations of CP and IF were found on the floors compared with the work areas. The highest surface loads were found on floors (in patient lavatories and utility rooms) that were related to patient activities such as handling of patients’ urine. Although high contaminations were found, the biological monitoring showed no uptake. Wipe sampling is a good method to improve the work practices.

/pdf/environmental-and-biological-monitoring-of-antineoplastic-2dlqhulb1b.pdf

Environmental and biological monitoring of antineoplastic drugs in four workplaces in a Swedish hospital

Objective. A systematic review and meta-analysis was conducted to test the hypothesis that oncology health care workers are at an increased risk of cancer, reproductive complications and acute toxic events.Design. A structured literature search of Index Medicus/MEDLINE, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews and Healthstar was performed from 1966 to December 2004 for human epidemiological studies evaluating the risk of toxic events in health care workers exposed to cytotoxic drugs. Raw data and adjusted odds ratios (OR) reported in eligible studies were combined using a random effects model to calculate point estimates and 95% confidence intervals (CI) for each potential risk outcome.Main outcome measures. Adjusted OR for congenital malformations, stillbirths and spontaneous abortions among health care workers exposure to cytotoxic agents compared to a non-exposed control group.Results. The systematic review identified 14 studies evaluating the outcomes of interest, seven of which wer...

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature.

6082 Background: It has been well documented in the literature that cancer patients receiving certain chemotherapy drugs are at an increased risk for developing secondary malignancies. This concern...

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta analysis of the literature

Background : The bortezomib product monograph indicates that after reconstitution, the drug may be stored for up to 3 h in a syringe, and the total storage time for the reconstituted material must not exceed 8 h when exposed to normal indoor lighting. Given the product packaging and vial size, as well as the currently recommended dosage regimen (which, for a clinic treating between 1 and 10 patients daily, entails using about half a vial each day), there is potential for substantial wastage, about $13,000 for a 5-cycle course of bortezomib therapy for a single patient. The aim of this study was to evaluate the stability of bortezomib (3.5-mg vials) reconstituted with 3.5 mL of 0.9% sodium chloride (NS) to produce a 1 mg/mL solution. Methods: On study day 0, six 3.5-mg vials of bortezomib were reconstituted with 3.5 mL NS per vial, to prepare solutions of 1.0 mg/mL. Three of the vials were stored in the refrigerator, and 3 were stored at room temperature. Concentration was measured and physical inspection was completed for each vial on study days 0, 1, 4, 8, 11, 15, 18, 21, 28, 34, and 42. The intervals between study days were consistent with the recommended dosage regimen, as published in the product monograph. Bortezomib concentrations were determined by a validated, stability-indicating, liquid chromatographic method. Results : All solutions remained clear and colourless. During the study period, all solutions retained more than 98% of the initial concentration, and the amount remaining on day 42 was greater than 98% (with 95% confidence). During the study period, the absolute deviation from the known concentration for standards and quality control samples averaged less than 4%, and analytical reproducibility within a day (by coefficient of variation) was high, with error on replicate analysis averaging less than 2%. Conclusions : Bortezomib, supplied in 3.5-mg vials and reconstituted with 3.5 mL NS, is physically and chemically stable for up to 42 days at 4°C or at room temperature. RESUME Historique : La monographie du bortezomib mentionne qu'apres reconstitution, le medicament peut etre conserve jusqu'a trois heures dans une seringue, mais que la duree totale de conservation du medicament reconstitue ne doit pas depasser huit heures si le produit est expose a un eclairage interieur normal. Vu le conditionnement du produit, le format des fioles et la posologie recommandee actuellement (qui, dans une clinique qui traite de 1 a 10 patients par jour, signifie l'emploi d'environ une demi-fiole par jour), le potentiel de gaspillage est considerable, et peut etre evalue a environ 13 000 dollars pour cinq cycles de traitement par le bortezomib pour un seul patient. L'objectif de cette etude etait d'evaluer la stabilite du bortezomib (en fioles de 3,5 mg) reconstitue avec 3,5 mL de chlorure de sodium a 0,9 % (NS) pour obtenir une concentration de 1 mg/mL. Methodes : Au jour 0, on a reconstitue six fioles de 3,5 mg de bortezomib avec 3,5 mL de NS par fiole, pour obtenir des solutions a 1.0 mg/mL. Trois des fioles ont ete entreposees au refrigerateur et les trois autres, a la temperature ambiante. La concentration a ete mesuree et une inspection physique a ete effectuee pour chaque fiole aux jours 0, 1, 4, 8, 11, 15, 18, 21, 28, 34 et 42 de l'etude. Les intervalles entre les jours de l'etude correspondaient a l'intervalle posologique recommande conformement a la monographie du produit. Les concentrations de bortezomib ont ete determinees au moyen d'une epreuve de stabilite par chromatographie liquide validee. Resultats : Toutes les solutions sont demeurees limpides et incolores. Pendant la periode de l'etude, toutes les solutions ont conserve plus de 98 % de leur concentration initiale, et il en etait de meme au jour 42 (intervalle de confiance a 95 %). Pendant la periode de l'etude, l'ecart absolu par rapport a la concentration connue des echantillons de reference et de controle de la qualite etait en moyenne inferieur a 4 %, et la reproductibilite analytique au cours d'une journee (selon le coefficient de variation) etait elevee, avec une erreur moyenne entre les mesures inferieure a 2 %. Conclusions : Les solutions obtenues a partir de la reconstitution du contenu d'une fiole de 3,5 mg de bortezomib avec 3,5 mL de NS sont physiquement et chimiquement stables pendant une periode allant jusqu'a 42 jours a une temperature de 4 °C ou a la temperature ambiante.

/pdf/stability-of-bortezomib-reconstituted-with-0-9-sodium-30kcvn2h2a.pdf

Stability of Bortezomib Reconstituted with 0.9% Sodium Chloride at 4°C and Room Temperature (23°C)

Background Cancer Care Ontario’s (CCO) Program in Evidence-based Care has provided a credible basis for policy development and the funding of new and expensive anticancer drugs in the province of Ontario. In November 1997, vinorelbine was approved for the first-line treatment of advanced non-small cell lung cancer (NSCLC) on the basis of evidencebased practice guidelines generated by the Provincial Lung Disease Site Group. In June 1998, gemcitabine was approved as an alternative to vinorelbine for use in selected patients (e.g. significant venous access problems, peripheral neuropathy, severe toxicity to vinorelbine). A provincial drug database was used to determine the impact that these new policies had on the rate of vinorelbine and gemcitabine uptake within the CCO new drug funding programme. Methods Drug utilization data for vinorelbine and gemcitabine from October 1997 to June 1999 were obtained from the CCO drug database. Individual patient data consisted of age, gender, first-line agent used, number of treatments, duration of therapy, treatment location (regional cancer centre vs. other) and total cost. Demographic and drug utilization data were analysed descriptively as means, medians, or proportions. Multivariable logistic regression analysis was then used to identify factors associated with the selection of gemcitabine over vinorelbine, as a first-line therapy. Results Following the approval of the first policy in November 1997, there was a rapid adoption of vinorelbine use in new NSCLC patients. When the gemcitabine policy was approved in June 1998, there was a rapid uptake in its use reaching a stable plateau of approximately 15% of all NSCLC patients within 9 months. The logistic regression analysis identified patient age greater than 65 years [odds ratio (OR) = 1.90, P = 0.001] and treatment in a non-regional cancer setting (OR = 1.71, P = 0.008) as significant predictors of gemcitabine utilization. Overall, the mean drug cost per patient treated with first-line gemcitabine was significantly higher than vinorelbine ($Can2590 vs. $Can1030, P < 0.001). Conclusions The new funding policies were associated with a rapid increase in drug utilization reaching a stable plateau within 9 months. Factors contributing to the usage of these new drugs for NSCLC included patient characteristics, such as age and treatment location.

The impact of practice guidelines and funding policies on the use of new drugs in advanced non-small cell lung cancer.

Background: At the Royal Marsden Hospital (RMH) many high-risk patients undergo complex major surgery. An integrated perioperative medicine service has been developed to optimise these patients and minimise perioperative risks. We describe our patients’ perioperative journey using Perioperative Quality Improvement Programme (PQIP) data. Methods: All patients having surgery at RMH are screened for PQIP by research specialist nurses. We extracted PQIP data for patients who were recruited and had surgery between 1 January 2020 and 31 December 2022. These data have been used to demonstrate the perioperative patient journey at the RMH looking specifically at risk assessments, preoperative anaemia, postoperative destination, and complications. Results: We identified 373 patients in the time period (Table 1).Tabled 1Table 1 Patient characteristicsPatients recruited373SpecialityAge (yr)60Urology58(15.5)Male, n (%)172(53.7)Upper gastrointestinal64(17.2)Female, n (%)201(46.0)Lower gastrointestinal45(12.1)ASA 1, n (%)7(1.9)Hepatobiliary79(21.2)ASA 2, n (%)225(60.3)Thoracics4(1.1)ASA 3, n (%)139(37.3)Abdominal - Other39(10.5)ASA 4, n (%)1(0.3)Burns & Plastics10(2.7)Gynaecology73(19.6) Open table in a new tab The RMH has a daily consultant-led pre-assessment clinic. Cardiopulmonary exercise testing (CPET) was undertaken in 45% (168) of patients: anaerobic threshold mean was 10.7 ml min−1 kg−1 (7–18 ml min−1 kg−1), VO2 peak mean was 19.1 ml min−1 kg−1 (10.6–36 ml min−1 kg−1). Documented perioperative risk discussion occurred in 68.0% (256/372 ) cases: qualitative in 69.1% cases (177/256), quantitative 14% (36/256), and both in 16.8% (36/256). A perioperative anaemia service screens and treats patients: 115 (30.8%) patients were anaemic (50 female, 65 male) in whom ferritin was checked in 48.7% (56). Twenty patients received iron infusions within 3 months of surgery. Postoperatively, 174 (46.9%) patients received level three care, 181 (48.8%) level two care, nine (2.4%) level one, and seven patients (1.9%) ward-based care. Two hundred and twelve (56.8%) patients remained in hospital at 7 days. One hundred and sixty patients (41.7%) had no complications (Clavien–Dindo classification1). The most frequently occurring complications were grade one 79/224 (35.3%) or two 114/224 (50.9%). Twenty-nine patients experienced grade three complications (12.9%) and two patients (0.89%) experienced grade four complications. Conclusion: The low serious complication rate at RMH is reflective of the high-quality care delivered by the integrated perioperative medicine service. 1.PQIP Standard Operating Procedures Ver 2.2 Aug 2020. Available from https://pqip.org.uk/FilesUploaded/PQIP_SOP_v2.2%202020-Aug-12.pdf (accessed 15 February 2023) 

http://www.bjaopen.org/article/S2772609623000473/pdf

Debbie Milliken

Papers

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature.

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta analysis of the literature

Stability of Bortezomib Reconstituted with 0.9% Sodium Chloride at 4°C and Room Temperature (23°C)

The impact of practice guidelines and funding policies on the use of new drugs in advanced non-small cell lung cancer.

Using PQIP to demonstrate the perioperative patient journey at the Royal Marsden Hospital