The Christie NHS Foundation Trust is the largest single-site cancer centre in Europe, treating more than 44 000 patients a year. The first UK centre to be officially accredited as a comprehensive cancer centre, it serves a population of 3.2 million across Greater Manchester and Cheshire. In 2017, 66 447 systemic anticancer chemotherapy agents were administered in the UK's largest chemotherapy unit, across 14 other sites, a mobile chemotherapy unit and in patients' homes. Since 2005, when the first patients outside of a clinical trial were treated with trastuzumab (Herceptin), a nurse-led service has been developed to facilitate a supported and safe treatment pathway for patients. There has been a substantial rise in the number of patients treated with trastuzumab over the last 10 years (Figure 1) with additional developments in line with the Five Year Forward View vision for patient choice in relation to treatment venue and the overall goal of treatment administration closer to home (NHS England, 2014).
Significant inroads have been made in facilitating care closer to home or in the home for patients at The Christie, particularly for those receiving trastuzumab. Treatment is now available over 16 sites, with many patients taking advantage of a well-developed ‘Christie at Home’ service to receive their treatment. This in-house facility was preceded by the availability of other drugs, such as faslodex and denosumab, that lend themselves more easily to home administration. In addition, across Monday to Friday the mobile chemotherapy unit visits four locations: Bolton, Chadderton, Rochdale and Trafford. Numerous standard chemotherapy treatments are suitable for administration on the mobile unit, however, short-duration treatments, such as trastuzumab are particularly suited to this environment.
Intravenous administration
Until December 2013, trastuzumab, licensed for the treatment of patients with Her2-positive early or metastatic breast cancer, was available as a powder for reconstitution before intravenous administration. After an initial loading dose of 8 mg/kg, a maintenance dose of 6 mg/kg was administered every 3 weeks. In 2008, following a risk assessment across the Trust of medium/high-risk parenteral preparations using the National Patient Safety Agency (NPSA) (2007) Risk Assessment Tool, trastuzumab was identified as medium risk because of the need for dilution, a complex calculation, and the number of vials required.
It was also recognised that the time taken to prepare the doses within the chemotherapy suite posed a significant burden in terms of time, staffing and resources. The use of dose banding, as with many standard chemotherapy regimens, reduced the requirement for complex dose calculations as well as reducing preparation time. Thus, dose banding became standard practice with suggested doses being set within 5% of the actual calculated dose. At this time, Baxter Healthcare, who provided an in-house dispensing service, provided extended stability data (35 days at 2-8°C). This facilitated the opportunity for pre-ordered treatments to be available for immediate use and resulted in a significant reduction in drug wastage and reduced waiting times for patients. Recycling of unused doses was also possible using the previous guidelines. However, re-loading schedules were implemented if treatment was delayed beyond 7 days.
Administration of the drug was via a cannula, peripherally inserted central catheter (PICC), central venous catheter (CVC), or implantable venous access system (‘port’), each of which could give rise to local discomfort, increased costs related to insertion and management of the devices and increased risk of infection with subsequent sepsis requiring intravenous antibiotic treatment and hospital admission.
Insertion of an intravenous cannula is the most common invasive procedure in hospitals across the world (Ahlqvist et al, 2010) with the inherent risks of local complications including phlebitis, extravasation, occlusion and thrombosis (Kagel and Rayan, 2004). In England in 2011, 42.3% of bloodstream infections were attributed to central venous access devices (Department of Health, 2011).
Patients with early breast cancer received chemotherapy and cycles 1 and 2 of trastuzumab in the hospital setting, with most patients going on to receive the remaining trastuzumab cycles in their home or an outreach treatment setting. Accelerated intravenous infusion times of 30 minutes, rather than the recommended 90 minutes, became standard practice at the Trust following consultation with the specialist breast team consultants and unanimous approval for this protocol amendment. Not only did the Trust operate a 30-minute infusion time on site, approval was also given for continuation of the 30-minute infusion in the peripheral units and home setting. This improved the patient experience in terms of convenience and reduced the administration costs per cycle.
Change in administration
Since December 2013 a subcutaneous preparation of trastuzumab has been available as a result of the introduction of hyaluronidase, which facilitates the dispersion and absorption of the drug. Trastuzumab as a fixed dose of 600 mg with 10 000 u recombinant human hyaluronidase as an excipient can now be administered over 5 minutes. Noninferiority of the subcutaneous version has been demonstrated in the HannaH trial (Ismael et al, 2012). The subcutaneous preparation of trastuzumab has a similar pharmacokinetic and safety profile and is as effective as intravenous trastuzumab for patients with Her2-positive breast cancer (Pivot et al, 2013; Olofsson et al, 2016). The availability of subcutaneous trastuzumab marked significant progress towards treatment goals based on the preferences of patients informed by patient choice (Melichar et al, 2014) as it is considered more convenient, involves less time in hospital and fewer resources (Melichar, 2013).
In December 2013 the subcutaneous preparation of trastuzumab was made readily available and approved for administration. Although other centres have been relatively slow to change the main method of administration from intravenous to subcutaneous, the experienced nurse-led service at The Christie was able to facilitate an immediate change to this prescribed route. This was facilitated by a series of education sessions arranged by Roche to update the chemotherapy staff regarding the novel means of medication dispersal making the subcutaneous route possible. Nursing staff were all proficient in the subcutaneous administration technique and the transition to this administration method was without issue. There was now no need for dose banding or re-loading of trastuzumab if delays occurred in the treatment schedule.
Biosimilars and the need to consider the bigger picture
Trastuzumab and rituximab are the first two oncology biosimilar monoclonal antibodies to become available and acknowledged as suitable for switching from the originator drugs (British Oncology Pharmacy Association (BOPA), 2017). However, BOPA (2017) also acknowledged that the associated costs of changing to a biosimilar need to be accounted for, including pharmacy time in changing e-prescribing systems, facilitating clinician and patient engagement and acceptance and evidence of safe switching. The availability of biosimilar drugs, which will necessitate the use of the intravenous route in the absence of subcutaneous drugs with the patented hyaluronidase delivery system, will pose a significant challenge in terms of capacity to accommodate an influx of patients back into the hospital hub. The need for central venous access devices is also likely to rise as intravenous access over prolonged periods of time will make this a necessity.
To compare and determine the experience of patients receiving all of their trastuzumab treatment via the intravenous route versus the subcutaneous route, the team examined data from all patients referred to the nurse-led adjuvant Herceptin service between January and June 2013 (6 months) in order to determine the intravenous routes used, overall costs and need for hospital visits or admissions. A total of 116 patients commenced treatment with trastuzumab during the first 6 months of 2013, when all of this drug was administered via the intravenous route. Table 1 illustrates the relatively high number of peripherally inserted devices used during this 6-month period with 23 central venous access devices being required, affecting approximately 20% of patients, and 96 requiring peripheral cannulas (approximately 80%). Numbers shown are affected by the requirement for one patient to have a port, followed by a PICC, followed by a port again due to recurrent infections. In terms of location 69% of patients received their trastuzumab treatment at home, 15% in Oak Road Treatment Centre at The Christie and 16% via a peripheral clinic or district general hospital (DGH).
| Year | Number commenced treatment | Place of administration | Route of administration | |||||
|---|---|---|---|---|---|---|---|---|
| 2013 | Home | The Christie | Peripheral unit/DGH | PICC | CVC | Port | Cannula | |
| January | 27 | 22 | 3 | 2 | 0 | 1 | 8 | 18 |
| February | 13 | 10 | 3 | 0 | 0 | 2 | 1 | 10 |
| March | 10 | 6 | 2 | 2 | 0 | 0 | 1 | 9 |
| April | 30 | 20 | 4 | 6 | 1* | 1 | 5* | 26 |
| May | 23 | 16 | 1 | 6 | 0 | 0 | 2 | 21 |
| June | 13 | 6 | 4 | 3 | 0 | 0 | 1 | 12 |
| TOTAL | 116 | 80 | 17 | 19 | 1 | 4 | 18 | 96 |
CVC: central venous catheter DGH: district general hospital PICC: peripherally inserted central catheter
Longer-duration intravenous route administration led to a more frequent need for alternative methods of intravenous access. Not only does this include the cost of consumables such as PICCs, CVCs and ports but also additional ad hoc visits to the hospital procedure team and increased hospital admissions due to infections.
Costs for intravenous administration of trastuzumab include those associated with the method of administration: PICC, CVC, port or cannula. Table 2 shows estimated costs for a patient requiring intravenous administration through a port. Chair times allocated to the chemotherapy suite for administration of the intravenous preparation reflects the time required to either establish venous access or access a PICC, CVC or port and administer the drug. A 2-hour chair treatment time was allocated to administer intravenous trastuzumab, whereas a 30-minute chair time is required for administration via the subcutaneous route (Table 3).
| Trastuzumab drug cost* | £1500.00 |
| Dispensing cost | £78.00 |
| Nursing time—120 minutes | £105.00 |
| Total cost | £1683.00 |
| Insertion of port | £1946.00 |
| Potential total cost | £3629.00 |
| Trastuzumab drug cost* | £1223.00 |
| Dispensing cost | £14.00 |
| Nursing time—30 minutes | £26.00 |
| Total cost | £1263 |
During the first 6 months of 2014, 94 patients commenced trastuzumab treatment via the subcutaneous route (Table 4). For these patients, a total of 13 central venous access devices were required (affecting 14% of patients)—these devices had been inserted for the administration of chemotherapy or were in use before the subcutaneous preparation was available. In terms of location, 67% of patients received their trastuzumab treatment at home, 4% at The Christie, 26% at a peripheral unit or DGH and 3% via the mobile chemotherapy unit.
| Year | Number commenced treatment | Place of administration | Route of administration | ||||||
|---|---|---|---|---|---|---|---|---|---|
| 2014 | Home | The Christie | Peripheral unit/DGH | Mobile unit | PICC | CVC | Port | Cannula | |
| January | 20 | 10 | 1 | 9 | 0 | 1 | 0 | 1 | 18 |
| February | 15 | 10 | 1 | 4 | 0 | 0 | 1 | 1 | 13 |
| March | 13 | 9 | 0 | 2 | 2 | 1 | 1 | 0 | 11 |
| April | 18 | 13 | 2 | 3 | 0 | 0 | 2 | 0 | 16 |
| May | 13 | 9 | 0 | 3 | 1 | 0 | 1 | 0 | 12 |
| June | 15 | 12 | 0 | 3 | 0 | 0 | 3 | 1 | 11 |
| TOTAL | 94 | 63 | 4 | 24 | 3 | 2 | 8 | 3 | 81 |
CVC: central venous catheter DGH: district general hospital PICC: peripherally inserted central catheter
Patients' views of intravenous versus subcutaneous drug administration
The Government White Paper Equity and Excellence: Liberating the NHS (Department of Health, 2010) set out the government's vision for the NHS in which patients would have more say and choice over their care. This included the principle of shared decision making, ‘no decision about me without me’ (Department of Health, 2010: 13), and sought to strengthen the collective voice of patients encouraging them to become more active participants in their care. This has extended to the oncology environment to recognise that patients may prefer to receive chemotherapy and radiotherapy treatments closer to home. The NHS England (2014)Five Year Forward View also endorsed the call for care closer to home to become the norm; including providing chemotherapy in the community. This strategy proposed three main concepts:
These themes were continued by the NHS England developed ‘vanguard’ system (NHS Confederation, 2016), with the Greater Manchester Vanguard being committed to strengthening the patient voice in co-production of services. With this in mind, the views of patients with experience of receiving their breast cancer adjuvant therapy drugs via the intravenous or subcutaneous route was sought. Patient preferences for intravenous or subcutaneous administration of trastuzumab were previously explored by the PrefHer Study Group in 2013. Of the 236 patients included in the evaluable intention-to-treat population, who either received subcutaneous followed by intravenous treatment or vice versa, only 6.8% (16 patients) preferred intravenous administration and 4 had no preference (Pivot et al, 2013). The survey here differed in that patients were also able to comment on the benefits of home administration of the subcutaneous drug.
To assess patients' perceptions of the benefits or disadvantages of intravenous versus subcutaneous drug administration, 110 current Christie patients were sent a brief, 1-page questionnaire to elicit their preferences for intravenous or subcutaneous administration routes. Patients had experienced both forms of administration of their breast cancer treatment drugs; an additional aim was to determine patient's key concerns with either administration method. A total of 67 patients (61%) responded to the questionnaire.
Of the patients who responded to the survey, 46% received their trastuzumab treatment at home, 31% at a DGH, 12% at a mobile chemotherapy unit and only 11% received treatment at The Christie site (Figure 2). Of those patients who already received subcutaneous treatment via the home care service, 58% (n=31) stated they would be happy to receive intravenous treatment at home, 29% were not happy to and 13% did not answer.
Regarding their preferred route (Figure 3), 75% of patients preferred administration of their drugs via the subcutaneous route, 9% preferred intravenous administration, 7% would be happy with either method and 9% did not respond to this question. Of those 6 patients who preferred administration of trastuzumab intravenously, one patient already had a PICC and the another had a port in situ. Of the 67 patients who responded overall, only 5 patients had required a peripherally inserted device, suggesting that the use of subcutaneous trastuzumab following completion of standard chemotherapy regimens lessened the likelihood of a device being required.
Of the 67 patients who responded, 15 (22%) reported redness, 9 (13%) swelling, 12 (18%) pain and 13 (19%) bruising following subcutaneous injection. Only 4 people experienced all these effects together.
Comments from patients who have benefited from treatment in their own home or close to home are illustrated in Box 1 (page S20). The vast majority of patients cite the benefits of a quick administration time, short duration and tolerable local reactions to the subcutaneous route versus the problems associated with repeated intravenous access, including multiple cannulation attempts and the need for PICCs, CVCs and ports.
Conclusion
Analysis of this data poses significant questions for the future, as with the advent of a biosimilar trastuzumab, it will be necessary to re-evaluate subcutaneous trastuzumab and determine if the savings delivered by a subcutaneous formulation are sufficient to offset the savings offered by a biosimilar trastuzumab.
One of the visions of the Greater Manchester Cancer Vanguard (http://www.gmcancervanguardinnovation.org) is that patients and carers will be equal partners in the planning process and services will be modelled around their changing needs with patient experience valued as highly as other patient outcomes. The previously described data allows the patient's voice to be heard. The National Institute for Health and Care Excellence (NICE) (2015) has previously stated:
‘Shared decision-making is an essential part of evidence-based medicine, seeking to use the best available evidence to guide decisions about the care of the individual patient, taking into account their needs, preferences and values’
The availability of this patient experience data will provide a valuable source of information for those involved in prioritising patient services.