On 5 May 2022 Aesculap Academia (the educational arm of B. Braun Medical) held a third webinar to discuss the results of research into the use of closed system transfer devices and the wider issues concerning the risks for nurses of occupational exposure to hazardous drugs. The earlier webinars in this series, held in November 2020 and April 2021, were reported in previous BJN oncology supplements (Clark, 2021a; Clark, 2021b).
An audience of 162 participants from around the world attended an interactive webinar to learn more about cancer nurses' risks of exposure to hazardous drugs.
Opening the meeting Co-Chairs Mark Foulkes (President of the UK Oncology Nursing Society (UKONS) and Nurse Consultant and Lead Cancer Nurse, Royal Berkshire NHS Foundation Trust) and Naomi Clatworthy (Acute Oncology Nurse Consultant, Royal Devon University Healthcare NHS Foundation Trust) commented that the previous two meetings had been strong meetings with lots of audience participation.
Hazardous drug in oncology workers
Hazardous drugs deserve deep respect in their handling, due to their toxicity, but some concerns could be allayed by implementing a comprehensive set of exposure controls, according to Dr Melissa McDiarmid (Professor of Medicine and Director, University of Maryland School of Medicine Division of Occupational and Environmental Medicine).
Dr McDiarmid traced the history of alkylating agents from the use of mustard gas as a weapon during the First World War to their first use as treatments for leukaemia and lymphomas in the 1940s. By the 1960s they were in regular use and by 1970s the first reports of secondary malignancies started to emerge. ‘An epidemiologic signal was visible showing that second malignancies were occurring in these patients treated for a different cancer with alkylating agents’, she said.
If patients treated therapeutically were developing second malignancies, could oncology workers develop a first malignancy from handling the drugs? In 1979 a study showed that among oncology nurses the urine mutagenicity level rose steadily during the week and fell again at the weekend away from work – in other words, a clear demonstration of a dose-response (Falck et al, 1979). These findings underlined need for safer working conditions. ‘All the early handling guidance began [to appear] in the 1980s, triggered by the Falck report’, she said. Pharmacy and nursing professional bodies began to write about the issue and to recommend safe handling.
It might seem counter-intuitive that a number of the drugs that are used to treat cancer, are also human carcinogens. The International Agency for Research on Cancer (IARC) (the cancer arm of the World Health Organization) classifies drugs as human carcinogens according to the strength of available evidence. About 18 of the drugs that we use are Group I, ‘no holds barred’ human carcinogens. Another 11 out 58 are classified as ‘probable human carcinogens’ (Group 2A) and a further 13 of 249 are ‘possible human carcinogens’ (Group 2B). Many of these drugs have characteristics that give scientists and epidemiologists cause for concern. Other evidence for the hazardous nature of the drugs came from reproductive and developmental studies in animals and humans. Typically, these effects occurred in patients and some were male-mediated so the idea of keeping pregnant women out of the way was not sufficient to mitigate the risks, commented Dr McDiarmid.
Results from the European Biosafety Network provide a picture of the situation in Europe. Some 80 sites contribute data to the EBN and a recent survey showed that 55% of sites perform regular monitoring for hazardous medicinal product (HMP) surface contamination, although the frequency of monitoring varies widely. Typical percentages of positive wipe samples ranged from 1% to 42% in areas where drugs are administered. Drugs such as busulphan, cyclophosphamide, etoposide and ifosfamide were all 25% or more. ‘It's not negligible; it's pretty significant’, said Dr McDiarmid.
In the UK, isolators are frequently used for compounding of cytotoxic doses whereas biological safety cabinets (BSCs) are more commonly used in the USA. One publication (Crauste-Manciet et al, 2005) showed that contamination was routinely found inside the isolators but rarely on the outside. However, when products are removed from the isolator contamination remains on the surface of infusion bags, for example. Another study showed that using a closed system transfer device (CSTD) within the isolator resulted in markedly reduced surface contamination of products (Vyas et al, 2016).
Many studies worldwide have reported contamination of work surfaces and in pharmacy preparation areas commonly affected sites include the interior of the BSC, the air foil, counter tops, waste containers, drug trays and totes. ‘Every study has been positive for at least one drug’, said Dr McDiarmid.
The next important question is, ‘Are the drugs getting inside workers?’. A number of studies have shown positive urine samples in pharmacy staff, even in some individuals who do not compound but work nearby. In one study, ifosfamide, last prepared 3 weeks earlier, was still found in workers' urine (Wick et al, 2003). Furthermore, 18 of 48 samples were positive for cyclophosphamide and 10 of 48 samples were positive for ifosfamide. In another study (Suspiro and Prista, 2011) 17 of 20 studies showed positive results for biomarkers of exposure. Many of these studies have been done in the past 10-15 years – despite the fact that safe handling recommendations have been in place for the past 30 years, noted Dr McDiarmid.
Chromosomal changes
The key question here is: ‘If the drugs get inside the body, are they causing biologically important effects?’. Here, the number of positive studies using genotoxic biomarkers is impressive. Two markers of genotoxicity are particularly important – chromosomal aberrations and micronuclei – both of which have been shown to predict future cancer risk and are considered to be robust endpoints. A meta-analysis of chromosomal aberrations as a biomarker of exposure confirmed a significant association between occupational exposure to antineoplastics and increases in chromosomal aberrations (Roussel et al, 2019)
Dr McDiarmid and her team undertook a study to look for the specific lesions that occur in patients treated with alkylating agents – abnormalities of chromosomes 5 and 7 – in oncology personnel in three university hospitals in the USA (McDiarmid et al, 2010). In addition, participants were asked to complete a form that recorded how many drug (alkylating agents) handling events they had undertaken. The analyses also included chromosome 11, which is a target of topoisomerase inhibitors but is less affected by exposure to alkylating agents. The results showed that there was almost a three-fold greater risk of having an abnormality in chromosome 5, and a 2.3-fold risk of an abnormality in chromosome 7. There was a 2.6-fold increase in risk for damage to either chromosome 5 or 7. As expected, an incidence rate ratio (IRR) of about 1 was found for chromosome 11, ie no change. These results confirmed the specificity of the risk, said Dr McDiarmid.
There are very few epidemiological studies of cancer in oncology workers. Two Danish studies (Skov et al, 1990; Skov et al, 1992), found the relative risk for leukaemia seen with alkylating agents for nurses was 2.85 (not significant) and for physicians there was a significant (more than five-fold) increase in risk. At the time physicians routinely handled alkylating agents, Dr McDiarmid noted. These studies looked for lymphatic and haematopoietic cancers, which is important because the cell types are biologically plausible, she added.
Cancer mortality studies in healthcare workers in 24 states of the USA showed that nurses had a 30% increase in mortality due to liver cancer and myeloid leukaemia; pharmacy staff had two-fold increase in mortality for myeloid leukaemia (Petralia et al, 1999). In addition, increases in leukaemia among nursing staff and healthcare workers have been reported (Blair et al, 2001) and increases in the risk of non-melanoma skin cancer and non-Hodgkin lymphoma in Danish female pharmacy technicians (Hansen and Olsen, 1994).
Turning to reproductive risks, Dr McDiarmid noted that one study showed that after adjusting for age, parity and shift work there was a two-fold increase in the risk of spontaneous abortion, especially with early spontaneous abortion before the 12th week of pregnancy, and a 3.5-fold increase in nulliparous women (Lawson et al, 2012).
Immunomodulators
It had been hoped that immunomodulator drugs (including monoclonal antibodies) would turn out to be less problematic but ‘it's not true that the immune modulators are always and everywhere less toxic’, said Dr McDiarmid. It is now known that adalimumab and etanercept are associated with a three-fold increase in the risk of lymphoma. In addition, tacrolimus and ciclosporin increase the risk of lymphomas and other malignancies, particularly those affecting the skin. The risks are related to intensity and duration of immunosuppression. Ciclosporin is an IARC Group 1 carcinogen.
If the package carries a warning about cancer risk for patients, Dr McDiarmid says she worries about the risks for workers who handle the drug. The National Institute for Occupational Safety and Health (NIOSH) 2020 hazardous drug list has not yet been finalised but the draft version includes all ‘-mabs’ and ‘-nibs’ (monoclonal antibodies and kinase enzyme inhibitors) on the basis that the package inserts advise handling as if hazardous.
Moreover, a summary list of targeted therapies for cancer showed that most targeted anticancer therapies are toxic to reproduction. ‘A lot of these drugs – not just the immune modulators but the legacy antineoplastics make their way into human milk so … you need to be aware of that and make an informed decision …’ about work handling chemotherapy agents while breastfeeding, said Dr McDiarmid.
Managing the risks
The implementation of a comprehensive safe-handling programme using the hierarchy of controls can be used to manage the risks. The first step is always engineering controls. In practice, this means containment by means of biological safety cabinets, isolators or CSTDs, explained Dr McDiarmid.
Administrative controls are the next step and these include standard operating procedures and safe work practices. Training is also really important here. Medical surveillance, which involves keeping track of the people who are handling hazardous drugs and watching for ‘early warning signals’, is also essential.
Alternative duty is a measure to ‘get people who are highly at-risk out of handling those drugs, for example, those who are actively trying to conceive, pregnant or breast feeding’. They can still work but just not handling hazardous drugs, she added.
The final step is personal protective equipment (PPE) – typically gown, gloves and eye protection.
University of Maryland
In the USA it is not possible to look at the cancer risk through existing registries because there is no national registry. The University of Maryland is now setting up a national exposure registry of oncology personnel ‘so that we can comprehensively characterise the demographics and exposure circumstances of oncology workers exposed to these drugs and assess the burden of cancer and other health risks’, explained Dr McDiarmid. ‘We're also going to be a centre that advocates for and promotes adoption of safety practices nationally and we're engaging with a lot of partners and people that are … interested in safe handling’, she added. The registry will be web-based. Comprehensive health and exposure data will be recorded and this will enable analysts to link exposure to outcomes. Dr McDiarmid hopes that this will be the next step in determining an ongoing risk and any increased burden of cancer in oncology workers.
Reducing exposure to monoclonal antibodies
The introduction of closed system transfer devices for preparation and administration of monoclonal antibodies (mAbs) reduced drug wastage and improved the quality of care for patients, Kelli Shephard (Lead Systemic Anti-Cancer Treatment CNS) and Jemma Pincombe (Chemotherapy Clinical Practice Educator, Royal Devon University Hospital Foundation Trust) told the audience.
In contrast to cytotoxic drugs there is only limited research and guidance on the risks to healthcare workers posed by mAbs. There is uncertainty about the risks and a lack of consensus in the standards and guidelines available (Meade, 2015).
One case study has described sensitisation to bevacizumab in a nurse who was exposed when she prepared the drug using a needle and syringe (Barrott and Foreman, 2020). A further, unconfirmed case had occurred at the North Devon Hospital when a nurse preparing infliximab experienced a reaction (itchy hands and neck, tachycardia, dyspnoea).
The workforce at the hospital is predominantly young and female and so mitigating the risk has always been really important, Ms Pincombe and Ms Shephard explained. CSTDs were already in use but multiple spills had occurred due to a faulty batch of devices. This was regarded as a serious safety incident because patients and nurses were exposed to additional risk as a result. A different type of CSTD was trialled (Tevadaptor™) that uses a dry membrane-to-membrane connection rather than a closed, male Luer lock. The users felt that this was a safer, more robust system and as the cost difference was minimal, the change was made.
In addition to the new CSTDs extra PPE was also introduced. The ‘usual’ PPE comprises a surgical gown, gloves, apron and a surgical mask. When reconstituting dry powder drugs, such as infliximab injection, additional protection in the form of an FFP3 mask and eye protection is used. The combination of a CSTD and PPE is a measure that is supported by the (US) Oncology Nursing Society (2018) Safe Handling Toolkit.
All doses of chemotherapy, immunotherapy and mAbs are now administered using a CSTD. In addition, drugs prepared on the unit require a CSTD to prevent exposure of staff through vapours or skin contamination.
Ms Pincombe and Ms Shephard described how the suite of closed system devices is used and why they feel these are the gold standard for administration preventing exposure. They showed how closed system devices are available for each step – spiking of vials, reconstituting drug and removing the solution and adding drug to the IV bag. The administration system that they chose is the CytoSet, which is also a closed system that reduces the need for despiking and respiking of systemic anti-cancer therapy (SACT) bags and multiple flushes – a recognised source of cytotoxic contamination.
The same closed-system components are used for the preparation and administration of subcutaneous mAbs. A poster illustrating show how this is done step-by-step is displayed in the unit. ‘This prevents dermal contamination from the top of the vial but also prevents contamination of the syringe itself and exposure of the nurse’, commented Ms Shephard.
Given the increased demands in the unit and the shortage of staff in the pharmacy department it was necessary to find a way to meet the service need in a safe and timely manner. In discussion with the lead pharmacist for cancer services they agreed that some low risk level drugs would be suitable for preparation in the clinical area. Subcutaneous drugs were most suitable as they are fixed doses, require no calculations and take only 2-3 minutes to prepare. A suitable space for preparation work, with adequate ventilation, was found in a treatment room.
The introduction of the closed systems gave them the ability to prepare doses safely in the unit, explained Ms Shephard. Currently they are preparing only subcutaneous oncology/haematology mAbs within the unit, she added. This involves a growing list of drugs including Herceptin (trastuzumab), Phesgo (pertuzumab trastuzumab hyaluronidase), daratumumab, rituximab and denosumab.
Overall, this initiative has relieved some pressure on the pharmacy department and has provided benefits for patients. There is greater flexibility for patients as those on maintenance subcutaneous doses who feel well and continue to work have been able to arrange appointments to fit around their schedules. This has had a big impact on patients and enabled them to ‘take some control back’, said Ms Shephard. As a result, there has also been an improvement in patient satisfaction, she added.
Drug wastage has also been reduced because doses are prepared on the unit only after the patient has been assessed. Training is essential for this type of programme and annual revalidation plans have been put in place.
Nurse perceptions of exposure to cytotoxics
Cancer nurses will be dealing with growing volumes of cytotoxic therapy administration in the inpatient, outpatient and homecare settings and so it is important to measure the individual and collective experiences and perceptions on handling and administering cytotoxic drugs, according to Dr Karen Campbell (Macmillan Associate Professor in Cancer Nursing, Edinburgh Napier University).
A 2-year study, funded by UKONS, is examining nurse perceptions of potential occupational exposure to cytotoxic drugs. Worldwide, there have been other studies, Dr Campbell acknowledged, but it is important to determine the UK perspective because there are variations in practice across the globe. Other important factors are the ongoing uncertainty about how big a risk cytotoxic handling poses for nurses and the fact that anxiety about the perceived hazard may be contributing to poor recruitment and retention of staff in chemotherapy units.
The study comprises several stages. The first stage is a systematic review and this is currently in progress. Next there will be a UK survey to get a national perspective. The following stage will involve in-depth interviews with cancer nurses. Finally, the data will be triangulated to give a broad overview of the current landscape of experiences and perceptions of potential occupational exposure to cytotoxic drugs across the UK. Presentations at UKONS conferences in 2022 and 2023 will provide feedback to members and encourage discussion and debate, said Dr Campbell. It should then be possible to recommend evidence-based standards for practice, she added. Dr Campbell encouraged cancer nurses to make contact with her if they are interested in participating the in-depth interviews.
Click. Close. Protect
Denise Davis and Marius Nicola (Market Development Managers, B. Braun Medical) described how the B. Braun ‘Click. Close. Protect.’ system serves to protect nurses from cytotoxic exposure and also protects patients and the drug from microbial contamination.
Discussion
During the discussion a number of practical points were raised.
Asked about risk assessment when preparing mAbs with or without CSTDs, Ms Shephard and Ms Pincombe explained that they worked closely with their lead pharmacist for cancer services to assess the data for each drug. Where the risks were considered low level, the drug was deemed suitable for ward preparation using CSTDs and PPE.
Considering whether the same safe-handling protocol should be used for all SACT drugs regardless of classification, Dr McDiarmid suggested that if a product was hazardous, then safe handling was required and that manufacturers' advice on the need for safe handling should be followed.
Ms Shephard and Ms Pincombe felt that closed systems should be made mandatory for the administration of SACT. They also confirmed that they dispose of mAbs in the cytotoxic disposal bin.
Asked if the study of nurse perceptions could impact the current UKONS SACT safe handling guidance, Dr Campbell said this was part of the reason for the study and Mr Foulkes said that UKONS was hoping that the results would guide practice.
Conclusion
This meeting was the third meeting designed to examine the risks of exposure to hazardous drugs to cancer nurses. As such, it focused mainly on the evidence for adverse effects of exposure to hazardous drugs – both cytotoxic agents and immune modulators (monoclonal antibodies) – and the evidence for the effectiveness of protective measures. A number of conclusions can be drawn from the presentations. Evidence of harm is provided by dose-dependent increases in chromosomal aberrations and reproductive abnormalities. The long-term effects of exposure to monoclonal antibodies are as yet unknown and in view of the rapid growth in their use at least one centre has already decided to use CSTDs to prevent unnecessary exposure. UKONS is firmly focused on gathering evidence to ensure that nurses are able to practice safely and minimise exposure to hazardous drugs. As part of this drive it has now funded a 2-year study to examine nurse perceptions of the risks of exposure to cytotoxic drugs.