Introduction

In Sweden, breast cancer (BC) is the most common cancer among women, and is responsible for one-third of all female cancer cases. In Stockholm County alone, approximately 1,700 women are diagnosed with early BC (eBC) annually, of which approximately 15% will overexpress the Human Epidermal growth factor Receptor (HER2) [1].

The HER2 positivity is associated with higher tumor aggressiveness and metastasis risk, and has therefore become an important target in the development of targeted therapies [2–4]. Trastuzumab (Herceptin) is one such therapy that binds to the HER2 receptor on the tumor surface and prevents tumor cell proliferation. It has become the standard of care in HER2-positive eBC and metastatic BC and has increased survival [5,6].

From its first European Union regulatory approval in the year 2000, trastuzumab has been administered intravenously (IV). However, since September 2013 a subcutaneous (SC) formulation of trastuzumab (Herceptin SC) is available which enables the delivery of trastuzumab via hand-held syringe or single-use injection device, thus obviating the need for intravenous infusion [7]. By way of direct comparison, a trastuzumab IV infusion requires 90-minute loading followed, if well tolerated, by subsequent doses over 30 minutes; while a 600 mg fixed SC dose of trastuzumab, is administered by manual injection/hand-held syringe in less than 10 minutes [7,8].

There is no significant difference concerning the severe adverse events defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE grade ≥3) version 3.0 between the two formulations [8]. Importantly, controlled clinical studies have demonstrated that trastuzumab SC is an effective treatment that is as well tolerated as trastuzumab IV, and preferred by patients most commonly because of the time saving as well as the reduction in pain and discomfort typically associated with IV infusions [8,9]. In addition to patient convenience benefits, the SC formulation has also been claimed to unlock economic efficiency gains for hospitals–and hence the health system as such–as a result of health care professional time savings and drug wastage reduction [10–12].

The objective of this study was to quantify the actual realized economic benefits associated with SC trastuzumab usage compared to trastuzumab IV. We analyzed trastuzumab SC usage within the Department of Oncology at the Karolinska University Hospital, which during 2015 handled 2,769 SC administrations.

Methods

This paper synthesizes a single institutional study designed to estimate the actual annual economic benefits associated with switching from IV infusion to SC administration of trastuzumab for the department. The study was developed in two steps: first, a series of interviews with treating physicians and nurses was used to identify SC-induced changes in trastuzumab practice along the patient pathway (e.g. patient scheduling) and; second, realized benefits were quantified where possible on the basis of cost and revenue information for the calendar year 2015, obtained from the hospital's financial controlling department.

Dosing of trastuzumab IV is weight-based (8 mg/kg loading dose, 6 mg/kg maintenance doses every three weeks). The cost of trastuzumab IV is 609.92 EUR per vial containing 150 mg of trastuzumab and the cost of 600 mg fixed SC dose of trastuzumab is 1,792.39 EUR per administration [13]. We are not able to calculate the drug cost of trastuzumab IV, since no patient data including the weight of the patients was accessed.

Results

Direct monetary cost savings

Comparison of costs per IV and SC administration showed that the use of SC allowed the hospital to save 603,000 EUR on direct monetary costs. This consisted of a) savings from avoided surgeries to implant port-a-caths (419,000 EUR), b) avoided fees the hospital has to pay the pharmacy for the reconstitution of IV doses (167,000 EUR), and c) the use of less expensive consumables in a SC setting (17,000 EUR). The cost for nurses’ time is not included since there is no time difference for nurses’ preparation of IV vs. SC administration. Underlying calculations are laid out in Table 1.

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Table 1. Direct monetary cost savings.

https://doi.org/10.1371/journal.pone.0211783.t001

1. Patients receiving SC therapy did not receive a port-a-cath implantation, which are otherwise required for IV infusions. Estimated all-inclusive costs per implantation are 2,782 EUR and the cost of a PICC line that is used instead of the port-a-cath in an SC setting is estimated to be 428 EUR. Hence, the SC-driven saving per newly diagnosed patient is 2,354 EUR. Given the number of 178 newly diagnosed patients with HER2-positive eBC, incremental savings on port-a-cath implantations amounted to 419,000 EUR.
2. While IV administrations are reconstituted at the hospital pharmacy, SC doses are prepared by nurses at the ward. Since the hospital pays the pharmacy a flat fee per reconstituted IV dose, every SC administration comes with an implicit saving in pharmacy fees. With a total of 2,769 SC administrations and a base flat fee per IV reconstitution of 60 EUR, the hospital saved 167,000 EUR in 2015.
3. Finally, SC administrations require a different, less expensive set of consumables than IV (e.g., syringe) infusions. Given the consumable cost difference of 6.27 EUR per administration and the total number of SC administration (2,769), this led to total cost savings of 17,400 EUR.

In summary, the total direct monetary cost savings amounted to 603,000 EUR with the greatest proportion attributable to avoided port-a-cath surgeries (69%), then avoided fees for reconstitution at pharmacy (28%), and finally materials for reconstitution and administration (3%).

Implied incremental revenue potential through capacity gain

From the perspective of the hospital, the ability to treat additional patients represents an incremental revenue potential of an estimated 1.5 million to 3.0 million EUR, depending on the patient mix. This calculation is based on the 2,441 SC mono administrations that create the potential for 1–2 additional patients per day to be treated, and average revenue per administration of 634 EUR (Fig 1).

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Fig 1. Summary of overall economic benefits encompassing cost savings as well as potential revenue gains through released capacity (thousands Euros; 2015).

https://doi.org/10.1371/journal.pone.0211783.g001

Discussion

This study of SC trastuzumab usage, compared to trastuzumab IV, documents quantifiable economic benefits of up to 3.6 million EUR in 2015 at the Karolinska University Hospital; of which 603,000 EUR represents actual direct monetary cost savings and the remainder corresponds to the maximum value of an implicit revenue gain. In addition, the hospital was able to save roughly 1,100 hours (4.6 per workday) on trastuzumab administration and nurse time, due to the shorter duration of an SC injection compared to an IV infusion. These time savings not only represent the time nurses can use to pursue other activities leading to an increased oncological day clinic capacity and shortening of the waiting list for other cancer patients, but also the time that patients treated with trastuzumab spent less at the hospital, contributing to their own quality of life.

In addition to direct monetary cost savings such as pharmacy fees and consumables, the introduction of SC unlocked capacity for additional administrations at the hospital without any additional infrastructural investment. In practice, this meant an SC-induced change in patient scheduling practice allowed the hospital to treat 1–2 additional patients for every trastuzumab mono administration given subcutaneously instead of intravenously. With the increase of the maximum daily chair capacity, the hospital managed to increase the total ward capacity and reduce the waiting list for all oncological day-care treatment without any infrastructural investment (e.g., additional chairs or rooms).

Costs for BC treatments are both resource-intensive and tend to increase due to the increasing number of diagnosed patients. This constitutes a major burden for the society. Any attempt to increase the efficiency of cancer care that aims to rationalize and reduce costs without compromising quality is a priority within healthcare. The purpose of this study was primarily to estimate economic benefits due to transition from IV infusion to SC administration of trastuzumab in a hospital setting. In the PrefHer study the patients and nurses preferred the SC administration above IV with reduced patient chair time and health care professional time [9]. Our results showed similarly a shorter patient chair time with SC administration through reduced nurse time. Today Sweden has a shortage of oncology nurses while the number of cancer patients is increasing and demands for oncological day-care treatments are rising. Our results showed 1,101 hours saved nurse time per year that is equivalent to 0.5 of a full-time nurse per year. This time saving was beneficial for both the oncological day clinic and the cancer patients since the waiting list for other cancer patients was reduced. Our results showed that SC administration resulted in a incremental revenue potential through time savings and financial savings, these results are similar to other studies analyzing SC formulation over IV infusions of trastuzumab [14,15].

Our analysis is based partially on interviews identifying SC-induced changes in trastuzumab practice along the patient pathway. It could be more precise with a prospective observational study such as other time and motion studies. However, the economic benefits due to practice changes were possible to be documented from the interviews and hospital's financial controlling department. Critically, indirect costs related to the time lost to receive treatment, including both time off work (production loss) and lost leisure time were not calculated in this study as the intent was to purely look at the financial impact from the perspective of the provider, namely Karolinska University Hospital.

In conclusion, this study tangibly demonstrates that the inherent efficiency benefits of the SC formulation over IV infusions can be translated into actual economic benefits for the providing center or hospital. It describes how one particular university hospital adapted its processes to cater to the specifics of the SC formulation and then logically deduces the causal impact of these process changes on hospital economics. Therefore, our study addresses the key shortfall of previous publications which tried to convert time savings into monetary gains without assessing if hospital operations had been adapted at all–the key criteria to realize economic benefits. These results are based on a single institutional study and should therefore be applied with caution in generalizing the results, particularly as every hospital operates in its own context. For the future, SC trastuzumab could be self-administered at home by the patient in order to improve the patients care including increase in patients satisfaction.

Supporting information