Open Access
21.12.2023 | Original Research Article
The PHASTER Study: Economic and Organizational Impact of Subcutaneous (SC) Pertuzumab and Trastuzumab Fixed-Dose Combination (PH FDC SC) for Treatment of HER2+ Breast Cancer Patients
verfasst von:
Elisabetta Munzone, Alessandra Fabi, Giuseppe Buono, Roberta Caputo, Emilia Montagna, Mara Negri, Francesco Nuzzo, Antonella Palazzo, Ida Paris, Luca Conti, Anna Baggi, Jean Marie Franzini, Michelino De Laurentiis
This study evaluated the impact of using the subcutaneous fixed-dose combination of pertuzumab + trastuzumab (PH FDC SC) compared with intravenous pertuzumab followed by intravenous trastuzumab (P+T IV) in HER2+ breast cancer patients.
Methods
Data from three Italian hospitals were collected to assess the organizational and economic benefits of PH FDC SC versus P+T IV on (i) patient pathway time, (ii) personnel time, (iii) direct costs and (iv) recoverable efficiency for the hospital, and (v) social impact for patient and caregivers. Data from hospitals were averaged when calculating results.
Results
PH FDC SC induced a reduction in patients' pathway time (ΔIV→SC: −59 min), driven by the administration phase (ΔIV→SC: −89 min); personnel time (ΔIV→SC: −17 min /patient), and direct costs for hospitals (ΔIV→SC: −125.95€/patient). A complete switch to PH FDC SC would also induce potential productivity gains in terms of additional oncological therapies administered by the hospital (ΔIV→SC: +532/year), together with decreased yearly social indirect costs for patients (−13.3%) and caregivers (−13.5%).
Conclusion
Overall, PH FDC SC demonstrated potential economic and organizational advantages for hospitals and patients compared with P+T IV, even though patients treated subcutaneously experienced longer waits between activities, indicating the need for optimized organizational choices.
Key Points For Decision Makers
Use of the subcutaneous formulation by hospitals in treating HER2+ breast cancer can save costs and optimize productivity by reducing administration time, healthcare personnel involvement, and resources utilization.
The subcutaneous formulation improves patients’ and caregivers’ experience by reducing hospital stays and administration time.
Potential benefits of the subcutaneous formulation could be exploited more in the future thanks to personnel expertise and optimized organizational choices.
Introduction and Research Question
Over the past few years, the increase in the number of cancer patients [1], the chronicity of oncological pathologies [2], and the decrease in resources have led to overloaded hospital systems, especially oncological day hospitals (DHs) [3]. Several studies have therefore begun to emphasize the need to rethink the logistics of oncological treatment to optimize available resources, proposing solutions such as (i) switching to more manageable routes of administration compared with intravenous (IV) therapies, (ii) considering treatment regimens with lower frequencies of infusion [4], and (iii) delivering and administering the treatments in different settings with respect to the DH [5]. Furthermore, rethinking the patient pathways has become even more important in the context of the COVID-19 pandemic, where the minimization of time spent in hospital by patients at risk took on an additional dimension of importance [5].
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Breast cancer (BC) is among the most diagnosed cancers in women worldwide, including in Italy, with over 55,700 new diagnoses in 2022 [6]. Among BC types, HER2-positive BC (HER2+ BC) accounts for approximately 20% [7] of all BC cases and is associated with a more aggressive disease course. Pertuzumab and trastuzumab are monoclonal antibodies targeting the HER2 protein and are, in association with chemotherapy, the standard of care for HER2+ BC both in curative early BC (eBC) (as neoadjuvant-adjuvant and adjuvant treatment for patients at high risk of recurrence) and metastatic settings [8, 9]. However, until recently, the combination therapy of pertuzumab + trastuzumab, either alone or in addition to chemotherapy, was available only through IV administration (hereafter termed P+T IV) [10, 11].
In 2021, a new fixed-dose drug combining pertuzumab and trastuzumab for subcutaneous (SC) injection with the commercial name ‘Phesgo’ (PH FDC SC) was approved by the European Medicines Agency for HER2-positive early and metastatic breast cancer [12]. On March 1, 2021, PH FDC SC received Marketing Authorization (MA) from the Agenzia Italiana del Farmaco (AIFA; Italian drug agency), and since September 9, 2022, this treatment has been reimbursed by the Italian NHS [13]. PH FDC SC is the first oncology therapy to combine two monoclonal antibodies (i.e., pertuzumab + trastuzumab) in one ready-to-use vial for SC administration and represents an alternative mode of administration to IV infusion. While doses of trastuzumab IV formulation vary based on the patient’s weight, the PH FDC SC formulation has a fixed dose. Furthermore, PH FDC SC allows for much shorter administration and observation times than P+T IV (excluding the first dose, 90 min for P+T IV vs 5 for PH FDC SC, and 180 min for P+T IV vs approximately 15 for PH FDC SC, respectively) [10‐12].
Two studies on trastuzumab SC were conducted in Italy in 2018 and 2020 [14, 15]; they provided evidence that SC administration has a lower economic and organizational impact on both hospitals and patients than IV administration. Indeed, studies have shown that SC formulations of trastuzumab might offer, with the same efficacy and safety profile, several benefits [14, 15]:
reduced time of administration, thus enabling a capacity increase in terms of patients managed on the same DH treatment chair;
reduced total time spent by the patient in DH;
lower hospital costs (considering consumables, personnel time, overheads, and minor use or a less invasive choice of catheter for drug administration) [14];
no drug waste and reduced risk of dosing errors that arise due to weight-based calculations [14, 16].
Given the already demonstrated non-inferiority of PH FDC SC with respect to P+T IV [17], in 2022 we designed and carried out a cross-sectional observational study named PHASTER, with the aim of confirming that similar advantages in terms of time and cost savings are also likely to be found for PH FDC SC compared with P+T IV in the real-world setting (even more so as PH FDC SC effectively replaces two IV administrations instead of one). To this end, the PHASTER study quantifies the impact of the new formulation considering multiple points of view: organizational and economic implications for hospitals and society, and benefits experienced by patients. In this paper, the findings of the PHASTER study are presented.
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Methods
Centers Involved and Ethical Approval
PHASTER is a cross-sectional observational study that involved three Italian hospitals selected by convenience sampling [18] based on each hospital’s willingness to participate and their expertise in BC:
European Institute of Oncology (IEO), (Milan); ethical committee (EC) approval: February 23, 2022 (Protocol ID R1625/22-1733);
Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome); EC approval: February 17, 2022 (Protocol ID 4764);
Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale” (Naples), which was the pilot center supporting the research protocol design (study number SL44004) (Naples); EC approval: January 25, 2022, (Executive Notice n.90).
Hereafter, the hospitals will be referred to, without a specified order, as ‘Hospital 1’, ‘Hospital 2’, and ‘Hospital 3’.
Treatment Regimen and Patient Sample
The analysis of the PHASTER study was performed considering HER2+ BC patients treated with pertuzumab + trastuzumab, both in early and advanced settings, as clinical practice, under treatment in the three hospitals participating in the study.
Regardless of the administration route, the treatment cycle of the aforementioned therapeutic options is divided into two phases: a first combination phase (P+T + chemotherapy) followed by a monotherapy phase. In the former phase, the administration of P+T is associated with chemotherapy drugs (i.e., docetaxel, carboplatin, paclitaxel or vinorelbine). In the latter, pertuzumab + trastuzumab is delivered as monotherapy (not combined with other treatments).
Treatment duration differs based on disease staging and treatment phase: patients in the adjuvant setting receive four cycles in the combination phase and 14 cycles of monotherapy [19]; patients in the metastatic setting receive six cycles in the combination phase and a continuation of monotherapy until disease progression is envisaged (up to 24 cycles from the CLEOPATRA study [20]). In the monotherapy phase, regardless of the disease staging, treatments are delivered every 3 weeks.
In the PHASTER study, patients were divided into two groups: (i) patients receiving P+T IV (hereafter referred to as ‘IV patients’) and (ii) patients on PH FDC SC therapy (hereafter referred to as ‘SC patients’). Both formulations were administered in the hospital setting. PH FDC SC, which at the start of the study was approved but not yet reimbursed by the Italian NHS, was administered free of charge from Roche S.p.A. to the centers involved.
The three hospitals enrolled the patients according to the following eligibility criteria: appropriateness of the treatment (i.e., the patient was indicated for the treatment and at least 18 years old), clinical evaluation (i.e., if the patient was naïve to the therapy or if a route of administration switch was the best option for the patient), and willingness to participate. The patients’ treatment was not determined or assigned by the study procedures but was based on standard clinical practice.
The sample of the IV branch of patients was decided considering the limited number of SC doses available. The IV patients were selected to match SC patients by age (older/equal or younger than 65 years) and clinical status (adjuvant and metastatic). Patients in these two settings differ for two variables included in the study: the use of catheters and the number of cycles in the monotherapy phase (14 for adjuvant and up to 24 for metastatic setting). Considering that data about catheters declared by nurses were the same between the two settings, we addressed the second difference by conservatively assuming that each patient receives, on average, 14 cycles of therapy in the course of a year, regardless of the treatment setting. This approach is conservative, as patients in the metastatic setting can receive up to 18 administrations assuming that the therapy starts on the 1st of January.
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Data Sources
Data used for the analysis of the PHASTER study were collected from four different sources over the period between January 27 and November 31, 2022.
Interviews with health care professionals to map the processes and procedures involved in managing a typical HER2+ BC patient treated with P+T IV or PH FDC SC. Specifically, one oncologist, one nurse, and one pharmacist from each hospital were interviewed.
Questionnaires administered to the patients during patients' visits for their respective treatments. All patients provided written informed consent prior to participating in the study.
On-site observations, through a ‘time-motion’ study, of patients’ duration of stay within the DH, to compare it against the same information declared by patients in the questionnaires and eventually integrated.
Literature, to complete the data collection on personnel and overhead costs.
Identification of the Patients’ Pathway
The first step carried out during the PHASTER study was mapping the BC patients’ pathway within the DH, using the information shared by the health care personnel during interviews. Patients treated with P+T, either with PH FDC SC or P+T IV, undergo six activities during each administration cycle: (i) acceptance of the patient, performed generally by administrative staff; (ii) blood collection and analysis, managed by nurses and laboratory technicians; (iii) visit and drug prescription by the oncologist; (iv) drug preparation, performed either by a pharmacist or a nurse within the pharmacy unit; (v) administration of the therapy and observation, performed by nurses; and finally (vi) discharge. Notably, phase (ii) can be either performed inside the hospital on the same day as the whole patient pathway (hospital 3) or in an external laboratory the day before the administration to avoid waiting for blood test results (hospitals 1 and 2).
The Average Center
After collecting and analyzing the data from the three hospitals, we aggregated the results to create a hypothetical ‘average center’. This approach allowed us to assess the potential benefits of SC therapy in a more general context beyond the specific characteristics of each hospital. Patient volume, and patient and caregiver characteristics were extrapolated from the questionnaires and compounded for the build-up of the average center. Furthermore, we assumed that patients in the average center go through all the phases of the patient pathway within the hospital, the same day of administration.
Outcomes
By comparing the activities of patients and health care professionals within the DH, this study measured the economic and organizational impact, together with benefits experienced by patients, generated by the use of PH FDC SC compared to P+T IV. The outcomes focus on the following dimensions:
(i)
Patient pathway times as benefits experienced by patients in terms of length of stay within the DH;
(ii)
Personnel time as organizational impact for the hospital, in terms of time spent by health care professionals in managing the patients;
(iii)
Direct costs for the hospital in terms of economic impact, accounting for personnel costs, consumables, and other organizational costs of the structure;
(iv)
Recoverable efficiency for the hospital, as organizational impact for the hospital, in terms of the number of additional therapies that can be provided with the same resources;
(v)
Social impact (indirect costs) for patients and caregivers, measured in economic terms.
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As a secondary outcome, we also considered the patient perspective, specifically their level of satisfaction with the service provided.
To compare the IV and SC routes of administration, all results are reported as a difference between the use of P+T IV and PH FDC SC formulations (hereafter referred to as ΔIV→SC).
As detailed in Table 1, all the outcomes mentioned above are presented considering either a single DH access, 14 cycles of treatment for a single patient, or the annual number of BC HER2+ patients managed by the hospitals where more appropriate.
Table 1
Key parameters of comparison for each primary outcome
Outcomes
One patient
All centers’ patients
Single access
14 cycles of treatment
14 cycles of treatment
(i) Patients’ pathway time
✔
(ii) Personnel time
✔
(iii) Direct costs for the hospital
✔
✔
(iv) Recoverable efficiency
✔
✔
(v) Social impact
✔
✔
Patient Pathway Times
Once the phases of the patient’s pathway were defined, the time required for each phase of the administration process was measured. For some SC patients, it should be noted that questionnaires were administered more than once, during different treatment cycles. In the time analysis, two leading indicators helped determine the status of the DH: (i) the total length of stay (i.e., the total time spent by the patient in the hospital, from arrival to discharge), and (ii) the proportion of activity time versus waiting time. Activity time is considered when health care professionals actively manage the patient (e.g., during the visit). In contrast, waiting time is the time spent between activities with no added value to the process.
Personnel Time
The time spent by health care personnel was measured by looking at the time required for every phase of the path within the DH and measuring the differences deriving from the route of administration. This dimension also considers the time required by the pharmacist to prepare the drug. Drug preparation and administration times were reported by the hospitals’ personnel during the interviews, while questionnaires and on-site recordings registered time for other phases. In particular, time absorption during drug administration was declared by the nurse as IV therapies do not require total commitment during the whole stay on the treatment chair.
Direct Costs for the Hospital: Mean Cost of the Subcutaneous (SC) and Intravenous (IV) Routes of Administration
Direct costs for the hospital were measured considering the resources involved in the activities in the DH. The following variables were taken into consideration: cost of health care personnel, consumables used during administration (e.g., infusion bags, syringes, gloves, medication), implantation of venous catheters, and overhead costs (e.g., administrative costs, services, and utilities).
The personnel cost was calculated using the average time absorbed during the different activities by each professional involved and their average annual gross salary. Salaries (taken from the literature) were as follows: Oncologist: 91,597€, Pharmacist: 68,540€, Laboratory Technician: 37,026€, Nurse: 36,909€ [14], Administrative staff: 34,084€ [21].
The costs of consumables employed for drug preparation and administration included the following items: Luer-lock syringes, Luer-lock connectors, physiological solution, sterile clothes (gloves, masks, suits), infusion and washing bags, IV lines, medications (bandages and patches), and sanitizers. Unit costs (including institutional discounts and value-added tax [VAT]) were obtained from purchase orders, reflecting the actual costs sustained by the hospitals.
For catheter costs, we considered the frequency of use of the different types of catheters declared by HC professionals and relative costs from national tariff registries for implantation, maintenance, and removal. Frequencies of utilization of catheters for P+T IV and PH FDC SC were declared by the nurses in the interviews. Table 2 shows the utilization rates of the port-a-cath (PORT) and the peripherally inserted central catheter (PICC) declared for each hospital (1, 2, and 3) and the averaged results.
Table 2
Utilization rate of catheters in the three hospitals and in the average center
Catheter types
Hospital 1
Hospital 2
Hospital 3
Avg Center
P+T IV
PH FDC SC
P+T IV
PH FDC SC
P+T IV
PH FDC SC
P+T IV
PH FDC SC
PORT
95%
60%
20%
70%
68%
7%
PICC
5%
40%
30%
32%
None
100%
80%
100%
93%
Avg average, IV intravenous, P+T pertuzumab + trastuzumab, PH FDC SC Perjeta Herceptin fixed-dose combination subcutaneous, PICC peripherally inserted central catheter, PORT port-a-cath catheter
Data in Table 2 are partially in line with similar studies on trastuzumab SC, which assumed frequencies of utilization for IV patients to be 30% for PORT, 16% for PICC, and 54% for none, while the frequencies of utilization for SC patients were assumed to be 10% for PORT, 7% for PICC, and 83% for none [14].
To estimate the average cost for implantation, maintenance, and removal of catheters, the following data were used:
Number of installations and removals necessary throughout the administration cycle (PORT: 1, PICC: 3)
Frequency of maintenance (PORT: once every 6 weeks, PICC: every week)
Time required for the nurse to install the catheter (PORT: 0—it is a surgical procedure, PICC: 40 min)
Time required for the nurse to maintain the catheter (PORT: 7 min, PICC: 9 min)
Time required for the nurse to remove the catheter (PORT: 0—it is a surgical procedure, PICC: 12 min)
Along with data from interviews, diagnosis-related costs (DRGs) of the devices were considered:
Implantation of PORT (included the device): 279.2€, code 38.94 [22]
The overhead costs, comprising intermediate health services, pharmacy costs, reversal, general, managerial, and indirect costs, depreciation, and nonmedical goods and services were allocated considering the length of stay on the treatment chair as a driver. Total overhead costs [15] were divided by the estimated yearly capacity time of treatment chairs to obtain the hourly overhead cost associated with its occupation.
Recoverable Efficiency: Impact of the SC Formulation on the Center Activity
The recoverable efficiency was calculated as the number of additional general oncological therapies that could be provided with the same resources (treatment chairs, staff, and regular DH opening hours). The input of the analysis was the difference in the average time spent in the treatment chair for IV compared with SC patients. The added capacity for additional yearly therapies the hospital could supply was calculated considering the total time saved in a hypothetical scenario where all patients were treated with PH FDC SC instead of P+T IV. The total time saved was then divided by the average administration time of a generic oncological therapy (124 min) [14].
Social Impact (Indirect Costs) for Patients and Caregivers
The indirect costs associated with the loss of work activity by the patient and the caregiver were estimated for the PH FDC SC and P+T IV groups. To calculate the social impact on patients and caregivers, we used the length of stay in the DH, also adding the average transportation time of the patient’s round trip to the hospital (113, 121, 90, and 112 min for Hospitals 1, 2, 3, and the average center, respectively), averaged from time declared by patients in questionnaires. Only employed patients and caregivers accompanying them in the DH were considered in this analysis. Notably, the percentage of working patients and caregivers were considered equal between IV and SC patients, so the differences were only based on the total length of stay in the DH. The results are expressed in economic terms and consider an average hourly cost of 15.67€ (for the patients) and 17.53€ (for the caregivers); these figures were obtained by dividing the respective gross annual average salaries of 31,335€ (for female patients) and 35,062€ (for male or female caregivers) [20] for 250 working days of 8 h.
Patient Perspective
In the questionnaires, patients were asked to evaluate their experience in the DH to assess potential differences in perceptions between SC and IV patients. Specifically, patients were asked to consider their stay in the DH and evaluate the appropriateness of
1.
Waiting times between activities (“During your stay in the DH, did you have adequate waiting times?")
2.
Total time spent in the DH (“During your stay in the DH, did you consider the total length of stay to be adequate?")
3.
Level of organization perceived (“During your stay in the DH, did you consider the level of organization to be adequate?")
4.
Support of the health care personnel (“During your stay in the DH, did you consider the level of support given by the health care personnel to be adequate?")
Patients rated these dimensions on a scale from 1 (inadequate) to 5 (very adequate). The results were averaged separately for SC and IV patients to capture differences in perception. A further question was explicitly directed to SC patients who were administered intravenously prior to the study and therefore experienced both administration routes. These patients were asked to rate their preference for PH FDC SC over IV administration on a scale from 1 (not at all) to 5 (very much).
Results
The results section is structured as follows: (i) sample size, (ii) the average center, (iii) patient pathway times, (iv) personnel time, (v) direct costs for the hospital, (vi) recoverable efficiency, (vii) social impact, and (viii) patient perspective.
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Sample Size
A total of 42 patients were treated with PH FDC SC (17, 18, and 7 patients for Hospital 1, 2, and 3, respectively). Out of these patients, 33 responded to the questionnaires administered for the study, with 5 and 28 patients being in the combination phase and monotherapy phase of the treatment, respectively. Given the meagre number (n = 5) and heterogeneity of the combination phase subgroup, data from these patients were collected only for exploratory purposes and are not included in this paper. Overall, 21 IV patients in the monotherapy phase responded to the questionnaires.
The percentage of patients aged between 18 and 65 years was 79% and 81%, respectively, for SC and IV patients, while the remaining patients were over 65 years old. Considering the treatment setting, 33% were in the adjuvant and 53% in the metastatic setting for IV administration, against 89% in the metastatic setting for SC administration. Furthermore, 11% of SC patients and 14% of IV patients did not provide information regarding the treatment setting.
The Average Center
Table 3 outlines the characteristics of patients in Hospitals 1, 2, and 3 and the average result for the average center.
Table 3
Characteristics of patients in the three hospitals and in the hypothetical average center
Characteristic
Hospital 1
Hospital 2
Hospital 3
Avg Center
No. of HER2+ BC patients/year treated with P+T
45
85
28
53
% Working patients
63%
28%
57%
43%
% Patients accompanied by a caregiver
63%
64%
57%
61%
% Working caregivers
50%
69%
50%
60%
Avg average, BC breast cancer, P+T pertuzumab + trastuzumab
Patient Pathway Times
A total of 51 time measurements were gathered for SC patients, coming from eight on-site observations and 43 questionnaire responses. As for IV patients, a total of 21 measurements were gathered, coming from both on-site observations (5) and questionnaires (16).
Figure 1 shows the times recorded for each activity in each hospital involved in the study; the results of the average center are represented in Fig 2.
Fig. 1
Activities and waiting times in hours for single DH access (1 patient) in the three hospitals involved in the study and the resulting average center. The number of respondents is composed of recordings coming from same patients, during different therapeutic cycles. DH day hospital, IV intravenous, SC subcutaneous
Fig. 2
A Time dedicated by the patient to each activity per single access (ΔIV→SC). (B) Effect of waiting time on the total length of stay (ΔIV→SC). IV intravenous, SC subcutaneous
×
×
The results in Fig. 1 show that the PH FDC SC approach reduces patients’ length of stay across all hospitals. Indeed, the reported time saved in length of stay was 1 h 20 min, 35 min, and 1 h 25 min in Hospital 1, 2, and 3, respectively; corresponding to ΔIV→SC of −32%, −10%, and −27%, respectively.
In more detail, Fig. 1 shows that the times required for the activities of acceptance, blood testing, and visit only slightly differ considering the route of administration, as expected due to the equivalence of these steps among the two formulations. On the other hand, the time registered for administration and observation sharply decreases when PH FDC SC is used over P+T IV.
Interestingly, in all three hospitals, the waiting times in absolute terms for SC patients (133 min per Hospital 1, 269 min per Hospital 2, 181 min per Hospital 3) were higher than those for IV patients (124, 222, 162 min, respectively). Waiting time on the SC and IV pathways is even more noticeable when examining its relative impact: 77%, 81%, and 88%, respectively, for Hospital 1, 2, and 3 for SC patients compared with 49%, 53%, and 65%, respectively, for IV patients.
Focusing on the average center, the data show that ΔIV→SC is associated with an average reduction in the length of stay (59 min, − 18%), as shown in Fig. 2A.
In line with what is seen for the three hospitals separately, time required for acceptance, blood testing, and visit does not show relevant differences (36 min on average for both IV and SC patients), while the time for administration and observation is much lower for the PH FDC SC group, with a reported time saved of 1 h and 29 min (ΔIV→SC: − 87%). Considering that the total length of stay for SC patients is 59 min lower than that for IV patients, waiting times between activities have a large impact on the benefits related to the use of PH FDC SC, as illustrated in Fig. 2B.
In conclusion, the results underline that the time reduction is driven mainly by the administration phase and that variability in waiting time attenuates the benefits of PH FDC SC.
Personnel Time
Applying PH FDC SC rather than IV reduced the personnel time for each patient in all three hospitals. In Hospitals 1 and 2, where blood testing was held the day before administration outside the structure, time savings for the HC personnel in the transition ΔIV→SC were 11 min (– 21%) and 28 min (− 42%), respectively. In Hospital 3, SC patients required 22 min less to be managed (− 34%). Fig. 3 shows the personnel time required to manage each step of the patient pathway (for single access in the DH) in the average center.
Fig. 3
Personnel time absorbed by each activity of the patient pathway for one access in the day hospital. IV intravenous, SC subcutaneous
×
The time dedicated to acceptance (administrative personnel), blood testing (nurse), and visit (oncologist) for both P+T IV and PH FDC SC was approximately 37 min. On the other hand, PH FDC SC preparation by the pharmacist lasted 5 min less than P+T IV preparation. For the therapy administration time, SC treatment almost halved the time directly dedicated to the patient by the nurse.
Considering all the phases, the PH FDC SC formulation takes 17 min (ΔIV→SC: − 25%) less than P+T IV for the HC professionals (specifically to the pharmacist and the nurse) involved in the patient pathway.
Direct Costs for the Hospital
Costs of the consumables declared during the interviews were 11.14€, 15.82€, and 24.56€ for P+T IV in hospitals 1, 2, and 3, respectively, and 3.08€, 1.85€, and 12.68€ for PH FDC SC. As a result, the average costs of consumables among the three hospitals amount to 17.17€ in the case of P+T IV and 5.87€ in the case of PH FDC SC.
In the average center, PORT and PICC catheters are estimated to cost 18.70€ and 32.41€ per administration, respectively. Therefore, considering frequency of usage (presented in the Method section), an IV patient costs 23.04€ per administration, compared with 1.25€ for an SC patient, with a ΔIV→SC of − 21.79€.
As for overheads, 57.6€ is the estimated cost associated with the occupation for 1 h of a treatment chair.
For Hospitals 1, 2, and 3, savings in the transition ΔIV→SC for single access sum up to 118.6€, 123.9€, and 139.8€, respectively. With a yearly volume of 45, 85, and 28 patients, the annual savings for 14 treatments would amount to 74,718€, 147,441€, and 54,802€ for Hospital 1, 2, and 3, respectively.
Fig. 4 shows the savings for a single access derived from the use of PH FDC SC versus P+T IV in the average center.
Fig. 4
Hospital cost savings in the transition ΔIV→SC per single day hospital access. IV intravenous, SC subcutaneous
×
The average total cost estimated for a single PH FDC SC administration was lower than that estimated for a P+T IV administration (41.6€ and 167.6€, respectively), resulting in savings of 125.95€ for a single access. Based on the yearly volume of 53 patients treated, switching all patients to PH FDC SC would amount to an annual savings of 93,455€.
Recoverable Efficiency
SC patients registered lower administration and observation times than IV patients (ΔIV→SC: − 1 h and 31 min, − 1 h and 23 min, and − 1 h and 37 min for Hospitals 1, 2, and 3, respectively). Therefore, considering all the BC HER2+ patients treated (see Table 3) in the hospitals and their access to the DH (14), the amount of time saved amounted to 956, 1646, and 634 h in Hospitals 1, 2, and 3, respectively, and resulted in a potential increase of 422, 837, and 307 delivered therapies, respectively.
Taking into account the average time savings of 1 h and 29 min yielded by the application of PH FDC SC rather than P+T IV, the average center would save a total of 1100 h in a year if 53 patients were treated per year, thus allowing the administration of 532 additional generic oncologic therapies.
Social Impact (Indirect Costs)
The time dedicated to receiving therapy in the average center amounted to 7 h and 17 min (5 h and 25 min in hospital and 1 h and 52 min for transportation) for IV patients and 6 h and 18 min (4 h and 26 min in hospital and 1 h and 52 min for transportation) for IV and SC patients, respectively. Assuming a total of 14 administrations, for a working patient treated in the average center, the social cost would be 1601€ for a patient treated with P+T IV and 1388€ for a PH FDC SC patient, thus indicating that the latter approach yielded savings of 213€ (ΔIV→SC: − 13.3%). Considering then the percentage of working patients (43%) on the total volume of patients managed yearly by the average center (53), total indirect costs savings in the transition ΔIV→SC would be 4854€ per year (total indirect costs: 36,487€ for IV and 31,633€ for SC patients).
For working caregivers, the annual indirect costs amounted to 1784€ and 1544€ for patients in the P+T IV and PH FDC SC groups, respectively, thus indicating that the latter approach yielded savings of 240€ (ΔIV→SC: − 13,5%). In this case, along with the percentage of employment (60%) among caregivers, we considered the percentage of patients accompanied by a caregiver in the DH (61%). As a result, using PH FDC SC rather than P+T IV would reduce indirect costs for caregivers by 4656€ per year (total indirect costs: 34,606€ for P+T IV and 29,950€ for PH FDC SC).
Overall, considering all patients and caregivers, the social impact in the average center would decrease by 9510€/year thanks to the shorter length of stay related to PH FDC SC over P+T IV. More specifically, for Hospital 1, 2, and 3, the yearly total savings amounted to 12,942€, 8414€, and 7749€, respectively.
Patient Perspective
Fig. 5 shows the average results for the four variables considered: waiting time, total length of stay, organizational level, and support received by the personnel. The patient experience within the DH differed slightly between the two cohorts (SC vs IV patients).
Fig. 5
Patients’ perspective of their stay in the DH. DH day hospital, IV intravenous, SC subcutaneous
×
While both SC and IV patients perceive waiting times and total length of stay as moderately appropriate, with slightly better ratings for the latter group, the organizational level of the DH is consistently rated higher by IV patients than by SC patients. Finally, the support given by the personnel is rated as very adequate by both IV and SC patients. These results, in line with what was observed in Hospitals 1, 2, and 3 separately, show that even though SC patients spend less time in the hospital thanks to the faster administration of the therapy, the average perceived quality is lower than that of IV patients, especially when looking at the organizational level variable. Nevertheless, when SC patients who, before the study, were treated with P+T IV (27 patients) were asked to rate their preference for PH FDC SC or P+T IV, a strong preference in favor of PH FDC SC was observed, with an average score of 4.6 out of 5.
Overall, these results suggest that the high proportion of waiting time and the organization of the DH negatively impact the perception of SC patients.
Discussion
This study aimed to compare the economic and organizational impacts of PH FDC SC versus P+T IV on the treatment of HER2+ BC patients. For this purpose, data were collected from three Italian centers that treated patients with both routes of administration. The characteristics of these hospitals were pooled together to create the average center.
Since most recent studies on PH FDC SC have demonstrated its noninferiority regarding pharmacokinetic properties, efficacy, and safety compared with P+T IV [17], our analysis focused only on its organizational and economic impact on oncological DHs and HER2+ BC patients. The results of the PHASTER study outlined the advantages linked to the adoption of the SC formulation. From the hospital perspective, the analysis included the following dimensions: personnel time, cost of resources, and productivity gains. Drug cost and waste were not included in the analysis, as the PH FDC SC was not yet reimbursed, and its price was still under negotiation with the NHS [13]. From the patients’ point of view, time saved and indirect costs were taken into consideration to measure social impact.
PH FDC SC induced a reduction in the length of stay of patients in all participating hospitals, resulting in an average time decrease of 59 min in the hypothetical average center. Moreover, the administration phase is confirmed to be the primary driver of time reduction, as PH FDC SC takes on average 1 h and 29 min less (ΔIV→SC: − 87%) than P+T IV. However, the results also show that patients treated with PH FDC SC have longer waits between activities (acceptance, blood testing, visit, administration). Even though waiting time is a physiological component of the process, it can vary greatly depending on the organizational choices managing the patient pathway and on how efficient and ‘well oiled’ the overall process is. While it is likely possible to reduce waiting times and create efficient pathways for both IV and SC routes of administration, it is important to acknowledge that organizational choices can play a particularly significant role for SC patients. Indeed, in situations where there are no separate pathways for the two types of administration, there may be a tendency to prioritize the management of IV patients (who require more complex organizational support) over SC patients, potentially resulting in longer wait times for the latter group. Notably, an Italian study involving 66 DHs shed light on several key organizational factors that significantly impacted patient experiences within hospitals [23]. In this study, multidisciplinary onco-hematological teams were asked to define organizational solutions able to optimize the patients’ pathway through a Lean approach. The study’s key organizational strategies encompassed (i) punctual scheduling of patients’ arrival in the DH based on the length of their administration (−35% in the average length of stay of patients); (ii) splitting the phases over 2 days, with the blood testing and the visit made the day before administration, therefore creating ‘ready-to-go’ patients who only have to undergo the administration phase when coming to the DH (−35% of average waiting times and − 15% of average length of stay); (iii) anticipating (when possible) the preparation of therapies the day before administration (−15% of average length of stay); (iv) and the creation of ambulatory nursing for managing noncomplex cases (average waiting time for visits dropping from 30 to 3 min) [23].
To the best of the authors’ knowledge, no previous time-motion studies have been conducted on the use of PH FDC SC in hospital settings and the organizational benefits derived from it. A time-motion study of PH FDC SC is currently ongoing in Spain (EudraCT Number: 2020-004241-36) and is expected to provide further data. Therefore, to compare the results of the PHASTER study, we searched for similar studies conducted both in Italy and in other European countries, focusing on the organizational impact of SC versus IV trastuzumab for treating BC [14, 15, 23‐32]. In a study conducted in an Italian oncology DH in 2016, SC administration of trastuzumab reduced patients’ average length of stay by 50%. In comparison, for the administration phase alone, the time reduction was 52% [15]. In another study published in 2018 involving 69 Italian DHs, a consistent time reduction related to the use of SC formulation was measured both in total length of stay (−37%) and in administration time (−85%) [14]. Evidence that SC administration induces time savings for patients compared with IV was also gained in several European observational studies [25, 28‐32]. Overall, these results support the findings of the PHASTER study.
Additional evidence in the PHASTER study is strictly related to the time savings induced by the use of PH FDC SC over P+T IV. The employment of PH FDC SC reduces the time dedicated by the HC professionals to each patient, which drops on average by 25%. This reduction is driven by the phases of administration and drug preparation. In line with our results, other European [24‐27, 31] and Italian [14, 15] studies observed time savings for HC professionals. Interestingly, in the PrefHer study, the main driver of time reduction was patient preparation (e.g., no installation or disconnection of peripheral catheters, no permanent line flushing) rather than the administration phase [25]. This difference can be explained by the fact that in PHASTER, the time required for the patients’ preparation tasks was included in the administration phase.
Furthermore, the use of PH FDC SC reduces direct costs for the hospital, on average 125.95€ for each administration and up to 93,455€ per year in the hypothetical average center. Evidence that the use of SC trastuzumab over IV reduces non-drug-related costs can be found both in the Italian [14, 15] and international literature [26‐28, 31]. Considering that PH FDC SC is a combination of two antineoplastic drugs (P+T), our results are aligned with others in the Italian context, which estimated savings associated with the use of trastuzumab SC of 111€/administration [14] and 80€/administration [15]. At the international level, although no time-motion studies have been conducted on PH FDC SC, a recent model-based cost-minimization analysis used data from the PrefHer trial to estimate the potential non-drug-related cost differences between PH FDC SC and P+T IV in Europe [33]. In this analysis, savings per patient were estimated to be in a range between 152.6€ and 498.6€ for each administration [33]. These findings are also in line with the PHASTER study, considering the heterogeneity across countries and the fact that the three hospitals involved were not experienced in managing the new SC drug.
Moreover, alongside economic benefits, time freed on the treatment chairs during the administration phase generates potential productivity gains. Considering 1 h and 29 min of time freed for each PH FDC SC therapy over P+T IV, a switch to the SC route of administration for all patients would allow the average center to provide up to 532 additional generic oncological therapies (124 min long) [14] on a yearly basis. Time freed on therapy chairs has been considered an important outcome in previous Italian [14, 15] and European studies [25, 26, 28‐30] on trastuzumab SC. In particular, within a study in the Italian context, productivity gains were also expressed as potential generic oncological therapies delivered per year (+194) transitioning from IV to SC trastuzumab [14].
Finally, from the patients’ and caregivers’ perspectives, PH FDC SC decreases social indirect costs by 4854€ (−13.3%) for patients and by 4656€ (−13.5%) for their caregivers in the hypothetical average center. Among the literature on indirect costs saved by patients and caregivers when using SC rather than IV trastuzumab [26, 30, 31], studies conducted in the Italian context estimated a 28% [14] and 11% [15] cost reduction thanks to the switch of all eligible patients to the SC formulation. In these studies [14, 15], percentages of working patients and caregivers were defined separately for the SC and IV cohorts rather than equally (as in the PHASTER study). With the same assumption, the results could be even more consistent with those of the PHASTER study.
As a secondary outcome, responses to the questionnaires showed that patients undergoing PH FDC SC perceived their stay in DH to be worse than that of IV patients (in terms of waiting times between activities, overall length of stay, level of organization, and support given by the health care personnel). This might be because the proportion of waiting time compared with the total length of stay in the DH was 81% for SC patients compared with 53% among IV patients. In more detail, this intriguing result can potentially be attributed to differing expectations between SC and IV patients. In the case of IV patients, where the administration phase typically constitutes approximately 30% of their total hospital stay, an average wait time of 3 h and 4 min may appear reasonable. Conversely, for SC patients, the administration phase represents only around 5% of their overall stay in the DH. Consequently, for these patients, having to wait an average of 3 h and 34 min, despite their shorter overall stay compared with IV patients, might be viewed more negatively than expected. Nevertheless, patients who switched from IV to PH FDC SC therapy preferred the latter approach, in line with the results of the PHranceSCa study, a randomized, open-label, phase II study [34].
It should be noted that there are some limitations to this study. First, the data were collected from only three hospitals, and therefore, the results of the hypothetical average center may not be completely generalizable to other oncological DHs. Factors such as personnel, patient and caregiver wages, cost of consumables, structural overhead costs, and volumes of patients treated are likely to vary among different hospitals. Considering the absence of prior time-motion studies on PH FDC SC in hospital settings in Italy, the lack of external validation through specific external data or research studies might also limit the generalizability of our study. However, when considering the general applicability of our findings, it is important to note that the patient pathway time within the DH is composed of two key components: (i) activity time and (ii) waiting time. Notably, our results consistently demonstrate that, across all three hospitals, the primary source of benefits are generated mainly by the shorter administration time associated with the SC formulation. While the waiting times are significantly influenced by each hospital’s organization and its ability to streamline the patient pathway, the administration time, categorized as ‘activity time’, is a fixed time dependent on product characteristics (EPAR) [10‐12]. Therefore, these results are reasonably expected to be applicable to other centers. Furthermore, it is important to emphasize that the results of the PHASTER study may be underestimated. Indeed, thanks to the learning curve of the healthcare personnel and the potential introduction of organizational measures to optimize the SC patient pathway, even greater benefits for hospitals, patients, and society are reasonably expected in the future. Second, given that the new PH FDC SC was supplied to the hospitals before the commercial launch, the number of patients involved in the study was limited, and it was not possible to include the drug cost in the analysis. Consequently, drug waste was not included in the direct costs analysis, although this could be a further variable in favor of PH FDC SC, as it used a fixed dose, while the dose of P+T IV depends on weight. Third, the results refer only to patients in the monotherapy phase of the treatment. Patients in the P+T + chemotherapy phase were not considered because of the low number of patients and the heterogeneity of the patient subgroup.
To address these limitations, future studies should strive to include a more extensive and diverse array of centers and patients, to obtain more precise estimations of organizational impact factors and ensure the broader applicability of the conclusions presented in the manuscript. Additionally, future research may consider a deeper investigation of patient perception in a real-world setting. Finally, more precise measurement of organizational benefits is expected in the future, when PH FDC SC will have been available for all hospitals.
Conclusions
The PHASTER study demonstrated, as have other national and international studies, that the application of SC oncological therapies rather than IV formulations represents a valuable option in reducing resource overload and health care expenditure for hospital systems while improving patients’ quality of life. Indeed, the transition from P+T IV to PH FDC SC is expected to result in reduced time spent by patients and caregivers in hospital settings, allowing an important social cost reduction. For the hospitals, this transition (P+T IV PH FDC SC) could lead to a reduction in the time and resources required by health care professionals in managing patient care, resulting in potential significant economic savings for health care facilities, and opportunity to deliver additional treatments to more patients, thereby enhancing the hospitals’ productivity and efficiency.
Acknowledgments
The authors thank Gabriella Luzi, Alessia D’Eugenio, and Simona Antro from Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome), Chiara Pari, Claudia Sangalli, and Davide Merli from European Institute of Oncology (IEO) (Milan), Valeria Pesce, Brigida Salvati, and Monica Capozzi from Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale” (Naples) for their fruitful support in data collection and questionnaires distribution during the study.
Declarations
Funding
No funding (grants) was received for conducting the study. The study was sponsored by Roche S.p.A and conducted by BIP S.p.A. The SC formulation pertuzumab + trastuzumab (PH FDC SC), which at the start of the study was approved but not yet reimbursed by the Italian NHS, was given out freely from Roche S.p.A. to the centers involved, for a total of 42 patients.
Conflicts of interest
Elisabetta Munzone: Consulting or advisory role: Exact Sciences, MSD Oncology, Daiichi Sankyo/Astra Zeneca, Pfizer, Seagen, Ipsen. Travel, accommodation, expenses: Roche, Pfizer, Lilly, Novartis, Gilead Sciences, AstraZeneca, Pierre Fabre. Alessandra Fabi: Consulting or advisory role, travel accommodation or funding for scientific meetings from Roche, Novartis, Lilly, Pfizer, MSD, Dompè, Pierre Fabre, Eisai, Sophos, Epionpharma, Gilead, Seagen, Astra Zeneca, Exact Science. Giuseppe Buono: Received honoraria or speakers’ fee from Novartis, GSK, Eli-Lilly, Pfizer, AstraZeneca, Roche, Daiichi Sankyo, Exact Science, Genetic.Spa. Roberta Caputo: Ely Lilly, Novartis, Pfizer, Roche, Gilead, Seagen, Daichii Sankyo, Veracyte, MSD, Astra Zeneca, Exact Science. Emilia Montagna: Consulting and Advisory role for Pfizer and Novartis. Mara Negri: There are no competing interests to declare. Francesco Nuzzo: There are no competing interests to declare. Antonella Palazzo: MSD, Novartis, Pfizer, AZ/Daiichi Sankyo, Gilead (speakers’ invitation or grant travel). Ida Paris: Consulting or participation in advisory boards: Seagen, Novartis, Lilly, AstraZeneca, Gilead, MSD, Pfizer, Roche, Gentili. Travel accommodation, registration for international congresses: Novartis, Lilly, Roche, Gilead. Funding for organization of scientific events: Novartis, Lilly, Roche, Gentili. Luca Conti: There are no competing interests to declare. Anna Baggi: There are no competing interests to declare. Jean Marie Franzini: There are no competing interests to declare. Michelino De Laurentiis: Speaker’s honoraria, consulting honoraria, and advisory board honoraria from Novartis, Eli Lilly, Pfizer, Roche, Sophos, Genetic, Menarini, Daiichi-Sankyo, Seagen, Pierre Fabre, GSK, Takeda.
Availability of Data and Materials
The data supporting the conclusions of this study are in the possession of the corresponding author but are subject to limitations in terms of public availability, as they are proprietary to Roche S.p.a. Therefore, these data are not openly accessible. However, they can be obtained from the corresponding author upon reasonable request and with the necessary permissions from Roche S.p.a.
Ethics Approval
The PHASTER study was conducted in three Italian hospitals. Each hospital underwent the process of ethical committee approval: European Institute of Oncology (IEO), (Milan); ethical committee (EC) approval: February 23rd, 2022 (Protocol ID R1625/22-1733). Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome); EC approval: February 17th, 2022 (Protocol ID 4764). Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale” (Naples), which was the pilot center supporting the research protocol design (study number SL44004) (Naples); EC approval: January 25th, 2022, (Executive Notice n.90).
Consent to Participate
Data used for the analysis came from questionnaires administered onsite during patients' visits for their respective treatments. All patients provided written informed consent prior to participating in the study.
Consent for Publication
No identifying details of the participants were disclosed in the manuscript. All information is anonymous, and the manuscript does not include images that may identify the participants.
Author Contributions
EM: Writing—review & editing, methodology. AF: Writing – review & editing, methodology. GB: Data curation, validation. RC: Data curation, validation. EM: Data curation, validation. MN: Data curation, validation. FN: Data curation, validation. AP: Data curation, validation. IP: Data curation, validation. LC: Writing—original draft, formal analysis, conceptualization, methodology. AB: Writing—original draft, formal analysis, conceptualization, methodology. JMF: Supervision. ML: Writing – review & editing, conceptualization, methodology.
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The PHASTER Study: Economic and Organizational Impact of Subcutaneous (SC) Pertuzumab and Trastuzumab Fixed-Dose Combination (PH FDC SC) for Treatment of HER2+ Breast Cancer Patients
verfasst von
Elisabetta Munzone Alessandra Fabi Giuseppe Buono Roberta Caputo Emilia Montagna Mara Negri Francesco Nuzzo Antonella Palazzo Ida Paris Luca Conti Anna Baggi Jean Marie Franzini Michelino De Laurentiis
