On 29 April 2021 Aesculap Academia (the educational arm of B. Braun Medical) held a second 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 first webinar was held on 25 November 2020 and was reported in a previous BJN oncology supplement (Clark, 2020). An audience of 180 participants from around the world attended an interactive webinar to learn more about cancer nurses' risks of exposure to hazardous drugs.
Introducing the meeting, Mark Foulkes (President Elect, UK Oncology Nursing Society (UKONS), Nurse Consultant and Lead Cancer Nurse, Royal Berkshire NHS Foundation Trust) said that the speakers represented a wide range of experience and opinions about protecting nurses from the risks of exposure to hazardous drugs and this should help to formulate some conclusions about what could now be done in practice.
Systemic anticancer therapy: where we are now
‘Systemic anticancer therapy (SACT) comprises a wide range of treatments, but in the context of occupational exposure and protection of nurses, the debate is firmly focused on cytotoxics and biological therapies administered by the intravenous route’, explained Lisa Barrott (Macmillan Nurse and AHP lead for cancer, palliative and end-of life care, University Hospitals Sussex NHS Foundation Trust and Lead for UKONS SACT MIG). SACT is associated with risks of genotoxicity, carcinogenicity, teratogenicity and fertility impairment. Health professionals are at risk of occupational exposure to SACT and could experience any of the toxicities that patients experience if adequate protection is not provided when handling the products. For patients, the risks are outweighed by the benefits—management or cure of cancer—but for health professionals there is no such benefit. Lack of adequate precautions and training could lead to inadvertent exposure to SACT as a result of skin contamination, inhalation or ingestion or workplace contamination that could affect others.
All organisations delivering SACT must undertake a risk assessment and have policies relating to safe management and handling specific to their organisation, according to the Control of Substances Hazardous to Health (COSHH) regulations. Risk assessments should be regularly reviewed.
The risk to staff handling cytotoxic agents has to be minimised as far as is reasonably practicable. The routes of exposure include dermal absorption, inhalation of aerosols or particles and needlestick injuries. Drug preparation, which is the riskiest stage of the process, is undertaken in a pharmacy aseptic unit rather than on wards. ‘I think we can all agree that this is the time when there is most potential for exposure’, said Ms Barrott. There are also risks of exposure during administration, handling of patient waste, and cleaning of spills.
Acute toxic effects of SACT include abdominal pain, hair loss, nasal sores, vomiting, liver damage and contact dermatitis. There is also risk to pregnancy so it is important to consider protecting all women of childbearing potential, not only those who are pregnant or planning to become pregnant.
In order to minimise exposure, COSHH recommends the use of totally enclosed systems ‘where reasonably practicable’. It also advises workplaces should ‘control exposure at the source by adequate extraction systems and appropriate organisational measures’. If these measures do not achieve adequate control then personal protective equipment (PPE) should be issued.
‘Much is down to local interpretation and implementation’, explained Ms Barrott. A guidance document published in 2018 draws on multidisciplinary expertise (Specialist Pharmacy Service, 2018). It highlights the importance of PPE, but also advises that closed systems should be used. Ms Barrott said, ‘the authors acknowledge the lack of empirical evidence to show that closed systems are actually required but their argument is that, in the absence of evidence, we should be utilising closed systems’. However, this has not been endorsed by the British Oncology Pharmacy Association (BOPA), UKONS or by the UK Chemotherapy Board, ‘because there is a lack of supporting evidence that closed systems reduce risk of exposure over PPE alone’, said Ms Barrott.
Additional guidance comes from a 2016 EU document that recommends the use of closed systems to protect staff (European Biosafety Network, 2016).
At present there is no nationally-agreed standardised equipment for staff to wear when administering SACT. ‘PPE is the mainstay, but there is variation in what this includes’, said Ms Barrott.
UKONS is pushing forward standardised training for nurses handling SACT by means of the SACT passport—a competency and assessment framework for SACT administration. This highlights the importance of PPE, ensuring that staff use it appropriately and adhere to local policies. UKONS has also offered a research grant for research into safe handling of SACT, she added.
The UK Chemotherapy Board issued a position statement on closed systems in 2018. It said that it was essential that handling risks to health professionals be minimised. However, it also noted that further research into closed systems was needed to ascertain whether they give additional protection above that provided by current practices.
Evidence-based practice
‘Evidence-based practice has been shown to be effective through rigorous scientific evaluation’, said Elaine Tomlins (Chemotherapy Nurse Consultant, Royal Marsden Hospital). ‘It relies on the hierarchy of evidence, usually represented as a pyramid, in which case studies and guidelines are the lowest level and randomised controlled trials and meta-analyses of RCTs are the highest level’, she continued.
In 2019, the European Oncology Nursing Society (EONS) published a safety manifesto in which it acknowledged that ‘closed system transfer devices (CTSDs) can protect spillage together with safe handling’, but also called for more evidence on the effectiveness of CSTDs.
A Cochrane review of CSTDs plus safe handling concluded that there is no evidence to support or refute the use of CSTDs in addition to safe-handling practices (Gurusamy et al, 2018). ‘It was really frustrating for everybody involved’, said Dr Tomlins. ‘In terms of the strength of the evidence, it is near the top of the pyramid, but it did not provide an answer for practice’, she added.
Summarising the current position Dr Tomlins noted that, at present, in terms of the evidence, best practice is good enough, especially if it becomes the standard of care, but evidence is clearly needed and all evidence (in the pyramid) is valid. ‘Surety requires further robust studies. In any case, most importantly, safety should drive innovation and not the pathways and capacity challenges that sometimes do’, concluded Dr Tomlins.
Effects of hazardous drugs in health workers
Melissa McDiarmid (Professor of Medicine and Director, University of Maryland School of Medicine Division of Occupational and Environmental Medicine) recalled how when she was a House Officer she mixed chemotherapy without the PPE and safety practices that are used now. Since then her career has involved extensive research into occupational exposure to SACT agents. Dr McDiarmid's research is mainly focused on alkylating agents.
Dr McDiarmid discussed the timeline of anticancer treatments, pointing out that alkylating agents were first widely used to treat lymphomas and leukaemias in the 1960s. Secondary malignancies were first reported in the 1970s and mutagenic chemicals were reported in the urine of nurses who handled cytotoxic drugs. Early SACT handling guidance started to appear in early 1980s, she said.
The anti-metabolites such as 5-fluorouracil interfere with DNA synthesis and are therefore undesirable when there are rapidly dividing cells (eg early in pregnancy). Both alkylating agents and intercalating agents, such as doxorubicin, can damage DNA. Mitotic inhibitors can cause copy number abnormalities (ie aneuploidy—unusual numbers of chromosomes) posing risks of cancer and reproductive abnormalities.
The International Agency for Research on Cancer (IARC, 2021) classifies some SACT drugs as:
- Group 1: definite human carcinogens
- Group 2A: probable human carcinogens
- Group 2B: possible human carcinogens.
Many of these drugs are also well-documented reproductive and developmental toxicants in men and women, noted Dr McDiarmid. In addition, they are ‘associated with biologically plausible health effects in studies of exposed populations’. Early on, patients who had received chemotherapy were the ‘exposed populations’ and they gave clues as to what to look for in exposed nurses and pharmacy staff, explained Dr McDiarmid. Typically, these were myelodysplastic syndromes and secondary malignancies as a result of chronic exposure.
Interventions and documentation of exposure
‘Characterising workplace exposure is a bona fide way that public health agencies use exposure assessment in the workplace as actionable documentation of exposures’, said Dr McDiarmid. It also allows them to establish approved workplace exposure limits and thresholds for action. ‘We think that skin exposure is one of the big issues with handling hazardous drugs and that's why there is [such] emphasis on wipe sampling and containment’, she added.
Measurement of surface contamination in the workplace before and after an intervention is one useful way to assess the impact of changes or ‘to see if you are getting somewhere regarding a clean workplace’, she said. According to a survey of aseptic compounding units by the European Biosafety Network in 2018, 55% said they undertook regular monitoring of surface contamination. Cyclophosphamide—a quintessential alkylating agent—was a frequent contaminant. In addition, 65% performed regular monitoring on surfaces in areas where dugs were administered. Again, alkylating agents, including busulfan and ifosfamide, featured prominently.
Numerous studies have shown surface contamination in areas where cytotoxic drugs are prepared or administered. Dr McDiarmid noted that contamination was routinely found inside isolators that are used for preparation of cytotoxic doses. ‘The problem is that the drug that you are containing in the isolator then hitches a ride on the surface of infusion bags and so, downstream, nurse colleagues and ward furniture get contaminated’, she said. One study showed that when a CSTD was introduced for dose preparation inside the isolator contamination was markedly reduced. (Vyas et al, 2014).
Studies have also detected traces of cytotoxic drugs in nurses and pharmacy staff. In 17/20 studies where healthcare workers' urine was analysed, positive biomarkers of exposure were found. ‘About 35% of people went home that night with carcinogens in their urine from workplace exposure’, said Dr McDiarmid.
Numerous studies have documented genotoxicity in healthcare workers. Two classes of abnormalities, chromosomal and micronuclei abnormalities, are of particular interest. These two endpoints have been found in other epidemiological studies of people who later develop cancers. A meta-analysis confirmed the association between occupational exposure and increases in chromosomal aberrations (Roussel et al, 2019). Dr McDiarmid's research group investigated healthcare workers who were routinely handling anticancer drugs (alkylating agents) to see whether they had increases in abnormalities on chromosomes 5 and 7. These are the specific markers for alkylating agents causing second malignancies. The results showed that those who had carried out 100 ‘handling events’ in a 6-week period had a three-fold increase in chromosome 5 abnormalities, and ‘almost significant’ increases in chromosome 7 abnormalities (McDiarmid et al, 2010).
Epidemiological studies have shown that the risk of cancers in oncology healthcare workers is increased. One 30-year-old study found that nurses had a three-fold risk of developing leukaemias, and doctors a five-fold risk of developing for lymphatic and haematopoietic cancers (Skov et al, 1990). Other studies had also reported a doubling of the risk of spontaneous abortions in those who handled cytotoxic drugs. In addition, targeted therapies cause reproductive toxicity and immunomodulators (eg ciclosporin) have now turned out to be carcinogenic, said Dr McDiarmid.
Managing risk
Comprehensive safe handling programmes are managed through a hierarchy of controls. ‘We always start with engineering controls—the word hierarchy means that the order in which we apply the controls matters so we don't start at the bottom with PPE, we start at the top with source control’, said Dr McDiarmid. Primary controls are Biological Safety Cabinets (BSCs) or isolators and secondary engineering controls are CSTDs. Administrative controls, such as safe work practices specifying where and how SACT is handled, come further down the hierarchy. Training is critical and medical surveillance is recommended because it can provide early warning to occupational health services. Alternative duties should be available for pregnant women and those trying to become pregnant. PPE is at the bottom and not at the top of the hierarchy ‘because it means that you are knowingly putting people in harm's way without the superior methodologies (such as engineering controls) for protection’, said Dr McDiarmid. Moreover, in the absence of good source control, PPE needs to work harder; it should be donned correctly, cannot tear or break and has to be available. ‘There's a lot of downsides to having a PPE-driven safety programme’, added Dr McDiarmid.
In summary:
- Hazardous drugs are contaminating oncology work areas resulting in biologically important exposure to genotoxic drugs
- Dose-dependent increases in chromosomal aberrations and reproductive abnormalities are occurring
- Risk management requires a comprehensive safe-handing programme using the exposure control hierarchy in this order—engineering controls, administrative controls, PPE.
Monoclonal antibodies
Reducing exposure when handling monoclonal antibodies offers an opportunity to improve the patient pathway and experience, according to Tom Marler-Hausen (Matron, Macmillan Cancer Centre, UCLH NHS Foundation Trust, London)
Monoclonal antibodies are produced by B cells and specifically target antigens on the outer surfaces of cells (eg CD20 or CD52 on cancer cells). Whereas with chemotherapy there is usually a limit to the number of treatment cycles that can be given, antibody treatment can often continue for years, explained Mr Marler-Hausen. The majority of monoclonal antibodies are used in cancer treatment and their numbers are growing rapidly.
‘There are minimal data on the long-term risks to healthcare workers when we are handling monoclonal antibodies’, said Mr Marler-Hausen. There has already been one case report of a nurse who was sensitised to bevacizumab (Barrott and Foreman, 2020). When the nurse came back to work she also had similar reactions to other drugs that were being administered nearby.
Monoclonal antibodies are said to be too large for dermal absorption to occur, but staff with skin conditions might be at risk suggested Mr Marler-Hausen. Furthermore, inhalation could be a route of exposure, he added.
A method for risk assessment of monoclonal antibodies has been published (Bauters and Vandenbroucke, 2019). In essence, it recommends that high-risk products should be prepared in the pharmacy and low-risk products may be prepared on wards, ideally using a CSTD.
It is important to choose an effective CSTD. A study published in 2018 compared the performance of four different CSTDs against the needle and syringe method. (Wilkinson et al, 2018). The results showed that one product was no better than a needle and syringe but others provided effective containment. ‘There are good published data to support decision-making about which CSTD you should use,’ he noted.
The rapid growth in the use of monoclonal antibodies combined with the fact that the pharmacy aseptic unit was already functioning at full capacity forced Mr Marler-Hausen to undertake a reappraisal of the way that doses were prepared. After reviewing the literature he concluded that CSTDs are effective and could protect nurses from unnecessary exposure. He conducted a brief pilot study, a cost analysis and a short audit to find out how long it took to prepare the monoclonal antibody doses using the CSTD. The results were favourable and now CSTDs are used for preparing most monoclonal antibody doses in the clinical area. He has also introduced a scheme to carry out a risk assessment of new monoclonal antibodies to determine whether they should be prepared in the pharmacy or in the clinical area.
He concluded that nurses deserve to work in an environment that has been made as safe as possible and that the precautionary approach is appropriate.
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 product from microbial contamination.
In 2018 the NHS Pharmaceutical Quality Assurance Committee (PQAC) published guidance to minimise the risks of occupational exposure to cytotoxic agents in clinical areas. This included two key recommendations—first that the practice of de-spiking empty bags of cytotoxic chemotherapy should be stopped (ie the chemotherapy bag should remain sealed after emptying and/or administration) and, second, that CSTDs should be used for syringes and bladder instillations containing cytotoxic drugs.
Approximately 2 ml remains in an infusion bag after administration and this is normally discarded in hazardous waste. Thus, for example, if 50 doses were infused in a day, a ward could dispose of 100 ml of hazardous drug in this way; there could also be spillages/leakages from ‘open’ syringes. Research has shown that cytotoxic drugs escape during preparation, administration and disposal as droplets, aerosols and vapours. However, all of these can be contained using closed systems.
Tevadaptor® CSTD - shown here for syringe preparation
There are several types of connecting device that offer varying levels of protection against leakage. The Luer lock syringes with needle-free (open) systems offer no protection and the closed male connector with a needle-free (leak-proof) connector offers only partial protection. The membrane-to-membrane (dry) devices offer the highest level of protection. When closed male connectors with needle-free ports are used there is still a risk of residual droplets remaining on the needle-free connector, but this does not happen with membrane-to-membrane devices.
A study by Wilkinson and colleagues showed differences in vapour release across different systems using 2-phenoxyethanol as a hazardous drug surrogate (Wilkinson et al, 2018). Drug vapour escaping from the Tevadaptor® was undetectable (below the limit of quantification). In a UK study in a chemotherapy unit comparing open and closed systems, 9 out of 10 open procedures resulted in contamination but only one in 10 when the Tevadaptor CSTD was used; investigators believed this was due to pre-existing contamination of the syringe surface. (Marler-Hausen T et al, 2020).
The B Braun Click. Close. Protect. system was developed to comply with the PQAC recommendations. It comprises the infusomat Cyto-Set® AirStop giving set and the Tevadaptor CSTD. It provides a fully closed system from syringe/bag to patient with capacity for up to four chemotherapy infusions without the need to de-spike or disconnect. The Tevadaptor dry membrane-to-membrane connectors and Cyto-Set AirStop ensure minimal risk for health professionals and the environment when hazardous drugs are administered. Time savings are also possible and fewer flush bags are used.
Discussion
During the discussion a number of points were raised. Mr Foulkes emphasised that UKONS is firmly focused on gathering evidence that might eventually support the use of closed systems.
Commenting on the Cochrane review of CSTDs, Dr McDiarmid said that the Cochrane methodology ‘straightjackets’ researchers and what the UKONS asked of the Cochrane review ‘was almost beyond what it was capable of’. In addition, there is a ‘boatload of literature’ showing that CSTDs protect the environment. ‘The reviewers identified 85 studies, but the final review was based on 24. The studies that were excluded were empirical studies of efficacy and of simulations and were all peer reviewed … People were straightjacketed by decisions about what was included and excluded and … it was wholly unsatisfactory to everybody involved’, she said.
Considering surveillance of healthcare workers handling cytotoxic agents Dr McDiarmid said that questionnaires are an important part of surveillance. For example, if there were a spontaneous abortion cluster, it would be revealed by a questionnaire survey. In the USA, routine biomonitoring is normally reserved for research and new staff, she explained.
Regarding handling of monoclonal antibodies Mr Marler-Hausen said that the ideal situation would be provision of ready-to-administer injections. ‘However, there is not the current capacity or pharmacy staff available to offer this solution to everyone. In the short term, preparing monoclonal antibodies safely with a CSTD in the clinical area can both improve the patient experience and waiting times, although each drug should be assessed for suitability’, he said.
Conclusion
This meeting was the second 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—predominantly SACT agents—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. However, a Cochrane review failed to provide evidence either for or against the use of CSTDs in protecting nurses. The long-term effects of exposure to monoclonal antibodies are as yet unknown and in view of the rapid growth in their use it may be wise to use CSTDs to prevent unnecessary exposure. Surveillance of healthcare workers who handle SACT through the use of questionnaires is an important way to monitor for emerging problems. The UKONS is firmly focused on gathering evidence to ensure that nurses are able to practice safely and minimise exposure to hazardous drugs.