Abstract
Background
The introduction of human epidermal growth factor receptor 2 (HER2)-targeted treatment options, including dual HER2 blockade, has improved the prognosis for patients with HER2-positive breast cancer (BC) substantially. However, most of these treatments are administered via the intravenous (IV) route, which can present many challenges, such as long infusion and observation times, issues associated with repeated IV access, and increased strain on time and resources of medical centers and healthcare professionals. A fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd, Basel, Switzerland; PH FDC SC)) has been approved for use alongside chemotherapy for early-stage and metastatic HER2-positive BC.
Objectives
This systematic literature review was performed to identify evidence relating to time/resource use and resulting cost differences between SC and IV administration of oncology biologics in a hospital setting, and, ultimately, to inform economic modeling and associated health technology assessment of PH FDC SC.
Methods
Electronic databases (Embase, MEDLINE, and EconLit) were searched on 9 April 2020. Additional hand searches were performed to identify publications not captured in the electronic database search. Publication screening and data extraction (study characteristics, participants, interventions, costs, and time/resource use) were carried out per the standard Cochrane review methodology. The quality of economic evidence of cost analyses was assessed using the 36-item checklist of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for submission of evidence (January 2015).
Results
The database search identified 2,740 records, of which 237 underwent full text screening. Full text screening, prioritization of publications about patients with a cancer diagnosis, and the addition of four citations identified during the hand search resulted in 72 final included publications, relating to 71 unique studies. This included 40 publications that described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of HER2-positive BC, and 28 publications that described time/resource use and/or costs associated with rituximab SC versus IV administration for the treatment of non-Hodgkin’s lymphoma/follicular lymphoma and diffuse large B-cell lymphoma. The majority of publications showed substantial time savings for preparation and administration of SC versus IV therapy, and cost savings associated with reductions in healthcare professional time and resource use for SC administration.
Limitations
There was a lack of consensus between publications regarding time and cost measurements. In addition, the search was limited to publications related to anticancer drugs; the majority of the studies included were performed in European countries.
Conclusions and implications
This review indicated a substantial body of evidence showing time/resource and cost savings of SC versus IV administration of oncology biologics in a hospital setting, which can be used to inform economic evaluations of PH FDC SC.
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Most of the publications identified in this systematic review showed time/resource and cost savings associated with subcutaneous versus intravenous administration of anticancer biologics in a hospital setting. |
This evidence can provide relevant inputs for economic evaluations of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd; PH FDC SC)). |
1 Introduction
Breast cancer (BC) is the most prevalent form of invasive cancer among women, with over 2.2 million cases and almost 700,000 deaths worldwide in 2020 [1, 2]. Approximately 20% of BC cases are human epidermal growth factor receptor 2 (HER2)-positive, a subtype defined by amplification of the HER2 oncogene and overexpression of the HER2 transmembrane receptor protein on the surface of tumor cells. HER2 interacts with other HER family proteins as part of signal transduction pathways, mediating cell growth, survival, and differentiation [3]. HER2-positive BC is associated with poor prognosis, arising from increased tumor aggressiveness, higher rates of recurrence, and increased mortality [3, 4].
Trastuzumab (Herceptin®, F. Hoffmann-La Roche Ltd, Basel, Switzerland), the first approved HER2-targeted monoclonal antibody, transformed the treatment and prognosis of patients with HER2-positive BC in both the early and the metastatic settings [5,6,7,8,9,10,11,12,13,14,15]. This has led to the development of dual anti-HER2 blockade with pertuzumab plus trastuzumab (PERJETA® and Herceptin®, F. Hoffmann-La Roche Ltd; standard of care in first-line HER2-positive metastatic BC (MBC) and high-risk early BC (EBC)) [13,14,15,16,17,18,19,20,21] and the anti-HER2 antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla®, F. Hoffmann-La Roche Ltd; used in second-line HER2-positive MBC and in EBC for the treatment of residual invasive disease following neoadjuvant therapy and surgery) [13,14,15,16, 22,23,24]. These treatment options have improved the prognosis for patients with HER2-positive BC substantially.
However, intravenous (IV) administration of anticancer biologics can present multiple challenges for many patients, including long infusion and observation times, the need for repeated, invasive IV access (sometimes over long periods of time in cases where there is evidence of a treatment response), and the potential risks associated with indwelling venous access (e.g., catheter-associated pain/discomfort, thrombosis, or risk of systemic infections) [25,26,27,28]. Moreover, the increasing use of IV administered agents in oncology has placed a strain on medical centers and healthcare professionals (HCPs) with respect to the time and resources required to prepare and administer infusions [25, 29].
A subcutaneous (SC) formulation has previously been developed for trastuzumab (Herceptin® SC or Herceptin HylectaTM, F. Hoffmann-La Roche Ltd) [11, 30]. The HannaH study (NCT00950300) compared the pharmacokinetics, efficacy, and safety of SC trastuzumab with IV trastuzumab. SC trastuzumab was shown to be non-inferior to IV, for both co-primary endpoints (serum trough concentration at pre-dose cycle 8 and pathologic complete response rates), demonstrating that the SC formulation is a valid treatment alternative to IV [31,32,33,34]. Further to this, the safety and efficacy profiles for SC trastuzumab in combination with IV pertuzumab and docetaxel as a first-line treatment for patients with HER2-positive MBC in the MetaPHER study (NCT02402712) was found to be consistent with those observed for IV trastuzumab in combination with IV pertuzumab and docetaxel in the CLEOPATRA study (NCT00567190) [21, 35,36,37,38].
The PrefHer study (NCT01401166), in which patients with EBC were randomized to receive four cycles of SC trastuzumab followed by four cycles of IV trastuzumab, or vice versa, demonstrated a strong patient preference and increased HCP satisfaction with SC over IV administration [39, 40]. These results were also confirmed in the metastatic setting in the MetaspHer study (NCT01810393) [41]. The approval of a fixed-dose combination of pertuzumab and trastuzumab for SC injection (pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO®, F. Hoffmann-La Roche Ltd; PH FDC SC)) [42] presents an opportunity for an option that is preferred by patients and can potentially provide time-saving benefits to patients and HCPs versus IV administration, according to patient and HCP questionnaires in the PHranceSCa study (NCT03674112) [43].
This systematic literature review (SLR) was performed to identify evidence relating to differences in time/resource use and the resulting cost differences between SC and IV administration (but not differences in the drug costs themselves). The rationale for performing the SLR was as preliminary work that will ultimately inform economic modeling and associated health technology assessment of PH FDC SC. The most analogous evidence was likely to be data relating to the time/resource use and cost differences for SC versus IV administration of trastuzumab for the treatment of BC, or of rituximab (Rituxan® or MabThera®, F. Hoffmann-La Roche Ltd) for treatment of non-Hodgkin’s lymphoma (NHL)/follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Thus, the SLR initially sought to identify cost analyses as well as time-and-motion analyses for any indication where patients’ treatment requires IV or SC administration in a hospital setting, and was then restricted to oncology biologics.
2 Methods
A systematic search was conducted via the Ovid platform (Wolters Kluwer, Alphen aan den Rijn, Netherlands) on 9 April 2020 using a predefined search strategy within the Embase (1980–present), MEDLINE (1946–present), and EconLit (1961–present) electronic databases. The database search strings identified all relevant studies (full papers or abstracts from any conferences) indexed in Embase, and were modified for performing searches in MEDLINE and EconLit to account for differences in syntax and thesaurus headings. Searches included terms for free text and Medical Subject Heading (MeSH) terms. The search strategies used and details of any additional hand searches that were carried out to identify publications not captured in the electronic database search are provided in the Online Supplemental Material, Resource 1. Details on the study eligibility criteria are presented in Table 1.
The SLR followed the standard Cochrane review methodology [44] and included double screenings by two independent reviewers. Relevant data from included publications were extracted by a reviewer and verified by a second independent reviewer; any disputes were resolved through discussion. The types of data to be collected were predefined and included: study country, study design, industry sponsor, inclusion/exclusion criteria, target population, study aims, data source, intervention, study limitations, and conclusions. Cost and time/resource use outcomes were also captured and stratified by disease and route of administration. Quality assessments of the studies in the included publications were conducted by a single analyst and verified by a second analyst or project lead. The quality of economic evidence reported in the included cost analysis publications were assessed using the 36-item checklist of the National Institute for Health and Care Excellence Single Technology Appraisal Specification for manufacturer/sponsor submission of evidence (January 2015), adapted from Drummond and Jefferson [45]. The methodologic limitations of publications reporting on time/resource use and costs were assessed based on a model described by Drummond et al. [46] and adapted to cost of illness by Molinier et al. [47].
3 Results
This search identified 2,740 records, of which 237 underwent full-text screening. Ninety-five publications were excluded during full-text screening, leaving 142 potentially eligible publications, a higher number than anticipated due to broad eligibility criteria. Prioritization was therefore given to publications of patients with a cancer diagnosis, as noted in Table 1, given the target population for PH FDC SC, resulting in exclusion of 74 non-oncology publications. Hand searching identified a further four citations that met the revised eligibility criteria, resulting in 72 final included publications, relating to 71 unique studies. The PRISMA diagram is presented in Fig. 1.
3.1 Characteristics of Included Studies
Table 2 summarizes the characteristics of all included studies. In total, 40 publications were identified that described the time/resource use and/or costs associated with SC versus IV trastuzumab administration for the treatment of HER2-positive BC. Of these, 22 publications [25, 48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] (13 full papers [25, 51,52,53,54,55, 59, 62,63,64,65,66,67] and nine abstracts [48,49,50, 56,57,58, 61, 68]) reported time/resource use for administration of SC versus IV trastuzumab (Fig. 2). This included two publications related to PrefHer, a multinational study conducted in eight countries (Canada, France, Switzerland, Denmark, Italy, Russia, Spain, and Turkey), 18 publications that reported studies that were conducted in at least 12 individual European countries (the country was not stated in one of the publications) [48,49,50,51,52,53,54, 57,58,59,60,61, 63,64,65,66,67,68], one publication that reported a study in Hong Kong [56], and one that reported a study in New Zealand [62]. A total of 24 publications reported on the costs of SC versus IV trastuzumab administration. Of these, 19 reported data for at least 13 individual European countries (the country was not stated in one of the publications) [48,49,50,51, 53, 54, 57, 59,60,61, 63,64,65, 67]. The other five were in Canada, Chile, Singapore, Hong Kong, and New Zealand [56, 62, 69,70,71]. Budget impacts of introducing SC trastuzumab were reported by five publications (Arabia, Ecuador, Canada, Brazil, Spain) [69, 72,73,74,75]. Six other publications described costs related to SC trastuzumab: three compared SC trastuzumab with an IV trastuzumab biosimilar [76,77,78], two described cost minimization analyses for SC versus IV administration [79, 80], and one reported on cost savings for the administration of the SC route over 18 months compared with a combination of SC and IV [81].
A total of 28 publications were identified that described time/resource use and/or costs associated with rituximab SC versus IV administration for the treatment of NHL/FL or DLBCL. Nineteen of these publications reported on time/resource use, 11 of which also described related costs. There were an additional seven publications that reported only on costs, to give 18 publications with cost-related analyses. The remaining three publications described the likely budget impact of introducing the rituximab SC formulation for the treatment of NHL or DLBCL, and provided limited evidence relating to the comparative costs of rituximab SC and administrations.
3.2 Quality Assessment Results
A quality assessment of all full publications was conducted. Overall, the studies were considered to be of adequate quality. However, due to the wide range of study designs and the paucity of studies reporting individual outcomes, it was not feasible to categorize the studies according to risk. Although the study designs of the economic evaluations were generally well described, reporting of data collection methods and of analysis and interpretation of the results was inconsistent between studies. For example, time horizons of costs and benefits, discount rates, and sensitivity analyses were only discussed in a small proportion of the publications.
3.3 Time/Resource Use With IV Versus SC Administration of Trastuzumab
Of the 22 publications reporting data regarding time required, or the difference in time required, for administration of SC versus IV trastuzumab for the treatment of BC, 16 reported data either from time-and-motion studies or studies where the time for each specific procedure was directly measured. Some reported single-center studies, while others reported studies involving up to 16 centers. Two publications reported studies that estimated time based on information provided by drug preparation/administration software [51, 68]; one publication reported a study that estimated time from a survey of HCPs [66], and three publications did not report the manner in which time was estimated [52, 56, 58].
HCP time includes drug preparation and administration times, and may be reported according to specific roles (e.g., pharmacists, nurses, nursing assistants), or as an average of the HCP times. Variation in the description of the elements involved in preparation and administration of trastuzumab may limit comparison between publications. For example, one time-and-motion study publication [63] described the measured time for each step involved in preparation and administration, including involvement of the pharmacist, staff nurse, and clinical nurse specialist, and then provided the average HCP time required for administration based on this. Another publication [53] only reported active HCP times for preparation and administration, obtained from detailed case reports and stopwatch time measurements for all nurse activities for a subgroup of observed cases.
3.3.1 Preparation Time
Preparation time for trastuzumab was reported in seven publications, including two where only the difference in preparation time between SC and IV was reported. Within these, preparation time was directly measured [25, 49, 53, 62] or estimated from software records [51, 68] or HCP questionnaires [66]. HCP estimates were consistent with publications from studies in which time was measured directly. Preparation of IV trastuzumab for administration was reported to require 14–21 min, compared with 0–11 min for SC trastuzumab. The time difference between SC and IV was 3–14 min per preparation [25, 49, 51, 53, 62, 66, 68]. An additional publication reported preparation time for the loading dose to be 8 versus 2 min, for IV and SC trastuzumab, respectively. Nursing time was reported as 16 versus 7 min, and was deemed likely to relate to preparation rather than administration of the dose, giving a total time of 24 versus 9 min [61].
3.3.2 Administration Time
Administration time for trastuzumab was reported in five publications, of which four directly measured time [49, 53, 54, 62]; one publication reported estimated time from drug delivery software [51], which was found to be consistent with the other four publications. Administration times of 90 and 30 min were reported for IV trastuzumab loading and subsequent doses, respectively, in two of the publications [51, 54]. A further two publications reported times of 38 and 97 min for IV trastuzumab administration [53, 62]. In contrast, the reported times for SC trastuzumab administration ranged from 5 to 10 min, with no difference between loading and subsequent doses. The differences in administration time between IV and SC were 80–85 (loading dose) and 20–25 min (subsequent doses) [51, 54], and 32–107 min in the three publications in which loading/subsequent doses were not specified [49, 53, 62]. Additionally, two publications reported time savings of 47 min [60] and 61 min [48] with SC trastuzumab, for combined preparation and administration times.
3.3.3 Active Healthcare Professional (HCP) Time
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Active HCP time, and time savings with SC versus IV trastuzumab, were reported in nine publications and are shown in Fig. 3. Based on direct measurements, active HCP time was 13–92 min (IV) versus 7–30 min (SC); a difference of 6–62 min [50, 53, 59, 62,63,64,65, 67]. Two publications reported a longer administration time for the loading dose of IV trastuzumab (92 and 44 min); here, the time differences between the loading dose of IV and SC were 62 and 18 min [64, 65]. One publication reported only on the time difference (15 min) between IV and SC [57]. One other publication reported only the difference in HCP time (7 min), which was estimated based on drug preparation software [68]. One report of active HCP time included a range of 7–12 min (IV) versus 4–7 min (SC) [55]; however, it is unclear what was included within the time, and why the HCP times in this report were shorter than those of other publications. Active time differences were also reported for different HCPs and were all in favor of SC versus IV administration: differences in nursing times were 6.1 min [62] and 10.6 min [59]; pharmacist and nursing assistant time differences were 3.0 min and 0.3 min, respectively [59]; and one publication reported time savings of 0.18 full-time equivalents (FTE) and 0.14 FTE with SC for nurses and pharmacists, respectively [56].
3.3.4 Patient Chair/Infusion Time
Chair time, where defined, was described consistently as the period between entry and exit from the infusion chair; however, how the time was determined varied between publications, with some reporting studies that measured the time directly [25, 59, 62, 67] and others reporting studies that estimated time from chemotherapy prescription software and HCP interviews [57, 68]. Differences in chair time for trastuzumab administration were reported in 10 publications [25, 50, 52, 55, 57,58,59, 62, 67, 68], of which seven reported actual chair times and differences obtained through direct measurement; one publication estimated the chair time based on drug delivery software [68] and was consistent with the other seven publications. Chair time was 47–180 min (IV) versus 8–120 min (SC); the difference in time was 33–126 min (Fig. 4). One publication reported a sixfold decrease in chair time with SC administration [58], with another describing a 56% reduction [52]. The PrefHer time-and-motion study reported chair time differences from nine countries (Fig. 5), ranging from a difference of 47.1 min (Denmark) to 85.5 min (Spain) for administration with the single-use injection device and 40.3 min (Italy) to 80.6 min (Spain) for administration with a hand-held syringe [25]. Total time spent at the hospital was also reported, ranging from 3–7 h (IV) to 1–5 h (SC), with a difference of 1.5–2 h [59, 64, 67]. One publication reported the difference for subsequent doses (following the loading dose) to be lower (23-min difference: 90 min IV vs. 67 min SC) [64].
3.4 Costs Associated with IV Versus SC Administration of Trastuzumab
Costs for IV versus SC administration of trastuzumab were gathered from 24 publications with sufficient level of detail to show how the costs were defined. Costs were reported per administration, per treatment course, per patient per year, or for a particular cohort. Of these 24 publications, 18 reported costs based on data from time-and-motion studies or studies in which the time for specific procedures was directly measured; one based estimates on information provided by drug preparation/administration software [51], one estimated time from a survey of HCPs [70], and four did not report how time was estimated [56, 69, 82, 83]. Twelve of the publications were full publications, with the other 12 being congress abstracts with limited detail (Fig. 2).
Thirteen publications covering ten countries reported total direct medical costs for IV versus SC administration [51, 53, 54, 59, 60, 63, 64, 69, 82,83,84,85,86], which included non-drug costs for preparation, administration, HCP time and consumables, and savings related to reduced drug wastage or administered dose. All but four publications [51, 69, 82, 83] indicated that time assessments were made directly. Cost savings for SC compared with IV administration were reported in all but one publication, which reported data from a study conducted in Italy that used time estimates from drug delivery software rather than direct time assessments [51]. In this publication, total costs were numerically greater for SC administration; however, the difference was not statistically significant and was likely related to differences in drug acquisition costs as preparation and day hospital costs were shown to be significantly lower for SC administration [51].
In seven of the publications, direct costs for SC administration were approximately 1.3–6% lower than those for IV administration. One publication from a Russian study reported a 12.6% decrease [83] and one from the UK reported a 2.8-fold decrease [85] in direct costs with SC versus IV administration. Twelve publications provided information on costs directly related to active HCP time, preparation and/or administration time, patients’ time, or chair time [50, 53, 54, 56, 59, 62,63,64,65, 67, 84, 85]. All reported reduced time-related costs with SC versus IV administration.
In the five publications reporting total costs including indirect costs, indirect costs were lower for patients who received SC versus IV trastuzumab [51, 59, 63, 64, 71]. SC administration costs were also lower for consumables [49, 53, 54, 57, 59, 61,62,63,64, 67], drug wastage [67], use of central venous access devices [86], overheads [87], nursing and pharmacy supplies [84], and avoiding catheter implantation surgeries [54] compared with administration costs for IV in all publications that reported such information. One publication reported non-drug costs for the first and for subsequent cycles of therapy; reported costs were higher for the first cycle of therapy for both SC and IV administration [65]. One publication reported the costs for management of adverse events, which were slightly higher for SC versus IV delivery (US$1574 vs. US$1715 for 18 cycles) [71].
In addition to the 24 publications reporting cost-related data, five further publications were identified that reported on the budget impact of introducing SC trastuzumab; all reported cost savings across varying time periods [69, 72,73,74,75].
3.5 Time/Resource Use with IV Versus SC Administration of Rituximab
Nineteen publications (seven full publications [52, 66, 88,89,90,91,92] and 12 abstracts [93,94,95,96,97,98,99,100,101,102,103,104]) reported data on time required, or differences in time required, for IV versus SC rituximab for the treatment of lymphoma (NHL/FL or DLBCL in most publications) (Fig. 2). Of these, 12 reported data from time-and-motion studies or studies in which the time for specific procedures was directly measured, two estimated time from a survey of HCPs [66, 93], and five did not report how time was estimated [52, 89, 101].
3.5.1 Preparation Time
Preparation time or pharmacist time per infusion of rituximab was reported in five publications and ranged from 4–40 min (IV) to 2–20 min (SC) [66, 88, 90, 91, 104]. One of these publications reported a study that collected relevant data using a survey [66]; however, data were consistent with those estimated from direct measurement. In all publications, preparation/pharmacist time was shorter for SC administration, with time savings of 5.6–21 min (in one publication there was a marginal difference of 0.3 min (4.0 vs. 3.7 min) [90]).
3.5.2 Active HCP Time
Differences in HCP time per infusion of rituximab were reported in five publications and directly measured [88, 90,91,92, 104]. HCP times were 17–35 min (IV) compared with 12–24 min (SC) in three publications, whereas two publications reported longer times of 144 and 223 min (IV) versus 111 and 49 min (SC). All five publications found that SC administration was associated with a time saving. A further publication reported annual savings of nurse time to be 22 days for a single center in Tunisia [93] and one reported a time saving of 3 h in the day-care unit per infusion [95].
3.5.3 Patient Chair/Infusion Time
Chair time/infusion time for rituximab was reported in ten publications [88, 89, 92, 94, 96, 98, 100,101,102,103] and one further publication reported the time for IV administration [97]. For four of these publications, the method of time assessment was not reported; the remaining publications used direct time measurements. Chair time/infusion time was considerably shorter for SC versus IV administration in all publications, ranging from 150–262 min (IV; one publication reported a time of 6 h and 12 min (372 min)) to 6–11 min (46 and 135 min in two publications) for SC administration. Time saved with SC administration ranged from 1 h 45 min to 3 h 26 min (a saving of 6 h in one publication with a particularly long time for IV administration). A 74% reduction in chair time with SC administration was reported in another publication [52], and annual time savings per center of 101 h [99] and 193.5 days (administration time estimated using a survey) [93] were also reported. Time spent in the treatment room was directly measured and ranged from 264–321 min (IV) to 70–105 min (SC). Time savings with SC administration were ~200 min [66, 88, 92, 97]. One publication reported a time saving of 17.5 h per eight-cycle course of treatment [104].
3.6 Costs Associated with IV Versus SC Administration of Rituximab
Costs for management of patients with NHL/FL or DLBCL receiving IV versus SC administration of rituximab were gathered from 18 publications. Of these, 11 reported costs based on direct assessment of HCP time, one estimated time from a survey of HCPs [93], and six did not report how time was estimated [100,101,102, 105,106,107]. Only three of the publications were full papers; the rest were congress abstracts (Fig. 2). Three simulation analysis study publications conducted in the USA report cost savings for SC versus IV administration incrementally according to patient body surface area [100,101,102], which is used to calculate the IV dose (the SC dose is fixed). One publication reporting costs for rituximab maintenance therapy for FL over 2 years [101] and one publication reporting costs of rituximab as part of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy (R-CHOP) for patients with NHL [102] reported higher cost savings for patients with higher body surface area (BSA). The other publication, which also reported costs of rituximab as part of R-CHOP therapy for NHL, reported the highest cost savings for patients in the highest and lowest BSA categories, respectively [100]. However, the reason for this discrepancy is unclear. Reductions in direct medical costs for SC versus IV administration were reported in all nine of the publications reporting European studies, all but one [107] of which estimated time savings based on direct measurements, and in four additional publications of studies from Tunisia (time savings estimated by HCP survey) [93], Thailand [94, 106], and Brazil [108]. In the European publications, non-drug-related cost savings included savings related to HCP time [53, 91, 92, 103], consumables [53, 91], and day-care unit costs [53, 95]. One of the publications from Thailand, which reported societal costs, reported a reduction in productivity loss with SC versus IV administration [94]. A further three congress abstracts describing the budget impact of introducing SC rituximab in Brazil, Saudi Arabia, and Canada were identified, all of which reported cost savings at 1, 2, 3, or 5 years [109,110,111].
3.7 Other Publications
In addition to the publications regarding trastuzumab and rituximab, eight other publications were identified that report relative time or cost information for IV versus SC administration (Table 2) [112,113,114,115,116,117,118,119]:
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Three of four cost analysis publications were considered less relevant as they reported time and cost of supportive therapies (SC-administered denosumab vs. IV-administered zoledronic acid) rather than treatment with a targeted oncology drug [112, 114, 115]. The remaining cost analysis publication reported higher administration costs for the regimens containing SC bortezomib, daratumumab, and dexamethasone than for those containing daratumumab, lenalidomide, and dexamethasone (all IV) in patients with relapsed/refractory multiple myeloma from two Phase III clinical trials [116].
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One publication from a randomized controlled trial at a single Chinese hospital reported significantly (p < 0.0001) lower direct costs per patient for high-dose SC interferon-alpha compared with continuous IV interleukin-2 administration in patients with malignant myeloma [113].
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Three publications reported directly measured time assessments for various oncology therapies; all of these publications demonstrated reduced administration time for therapies administered by the SC route versus the IV route [117,118,119].
4 Discussion
4.1 Interpretation of Results
Global increases in yearly cancer rates have resulted in increased numbers of IV infusions of chemotherapies and anticancer biologics. This represents a growing burden for medical centers and HCPs, and has led to a shortage of chair time for patients with cancer. The substantially shorter administration times of therapies administered subcutaneously has the potential to offer several advantages over IV administration, including shorter treatment times, a reduction in healthcare resource use, increased convenience for patients, and greater patient preference [25, 39, 40, 120].
In this SLR, we identified 72 publications reporting on the time/resource use and/or costs associated with IV versus SC administration of oncology biologics in a hospital setting or on the budget impact of introducing an SC formulation. The majority of reported publications were of studies conducted in single countries or even single centers; all studies were published between 2012 and 2020.
Overall, the results were largely consistent in demonstrating the time savings associated with preparation and administration of SC therapies, across both oncology biologics and other supportive therapies. Moreover, reductions were seen in the HCP time and resource use (including non-drug consumables and drug wastage) required for SC versus IV therapy administration. Patient hospital time was also shorter with SC versus IV administration, and additional cost savings may be achieved at the society level due to a reduction in the loss of productivity and leisure time associated with patients attending the hospital for treatment. However, these improvements in patient productivity are likely to be greater in patients receiving maintenance therapy than those receiving SC-administered oncology biologics in combination with chemotherapy, due to the increased patient chair time required for chemotherapy administration. Cost savings due to reduced production and leisure time loss for SC versus IV trastuzumab across five Swedish oncology clinics were €78 and €62, respectively, for first-time patients and €10 and €6, respectively, for subsequent patients [64]. Similarly, a study conducted in six hospitals in the Netherlands reported lower societal costs (travel expenses and costs related to informal care and loss of productivity) for SC versus IV administration for both trastuzumab (cost saving of €22) and rituximab (cost saving of €28) [53].
There was some variation in times reported for IV and SC preparation and administration of trastuzumab, which may reflect differences in time estimate methodologies, definitions of time periods, and clinical practice/hospital setup between the different participating centers. Notably, the multinational PrefHer time-and-motion study reported time differences between countries [25], despite presumably using similar definitions for each time period across the different centers involved in the study. Similar variations were also seen with studies of rituximab [88]; however, a consistent trend in favor of SC administration was observed across all publications. During the COVID-19 pandemic, urgent cancer referrals and chemotherapy attendances declined by up to 84.3% and 63.4%, respectively, which might have resulted in increased mortality rates in patients with cancer and multimorbidity [121]. The time savings of SC administration have the potential to help increase throughput of patients now that cancer services have resumed. In addition to this, decreased hospital time for patients with cancer may help to reduce the risk of COVID-19 infection and the associated high probability of mortality in these patients [122].
As expected, there were also variations in costs for IV and SC administration between publications that could be compared based on use of the same currency. However, six European publications reported similar percentage savings in direct costs and most publications showed a trend for cost saving with SC versus IV administration of trastuzumab. Two of the rituximab publications that showed cost differences for the SC and IV formulations incrementally based on BSA reported that the largest cost savings occurred for patients with higher BSA.
The findings of this SLR are consistent with other published SLRs that have reported on the time, resource, and cost savings associated with SC administration versus IV, for both oncology and non-oncology biologics [123,124,125]. However, cost reductions associated with time savings for HCPs may be difficult to measure and achieve in clinical practice [126]. Therefore, methods of improving the transferability of time-related cost savings to the clinic should be investigated.
The purpose of this SLR was to ultimately inform economic modeling and associated health technology assessment of PH FDC SC. Recommendations for durations of post-administration surveillance for SC and IV trastuzumab are identical, with 6 h of observation recommended after the first dose and 2 h of observation for all subsequent doses [42, 127,128,129]. Within the context of this SLR, observation times for SC and IV cancel out (as they are the same). The efficacy and safety profiles of SC and IV trastuzumab were also assumed to be comparable in this study. However, real-world evidence suggests that target levels of trastuzumab may not be reached with the first SC administration in patients with a high body weight and, although cardiotoxicity risk does not appear to be increased in patients with low body weight, Phase III trials have reported higher rates of adverse events with SC vs. IV administration [130].
It is important to note that the focus of this SLR was on administration in the hospital setting only. However, similar to the benefits provided by other SC-administered oncology biologics [131,132,133], PH FDC SC is expected to offer advantages with regard to reduced time/resource utilization, improved patient quality of life, and the potential to be used in the future in a flexible care setting [43]. There is considerable evidence demonstrating that PH FDC SC is well suited to at-home administration by a HCP [134]. Providing at-home treatment requires planning, training, careful patient selection and technology to link patients, caregivers, and specialists in oncology clinics, as well as innovative methods for treatment delivery (e.g., mobile care units) [134]. A US expanded access study (NCT04395508) investigating at-home administration of PH FDC SC by a home health nursing provider is ongoing. This study focuses on patients with HER2-positive breast cancer previously treated with IV pertuzumab plus trastuzumab and chemotherapy and currently receiving or due to receive maintenance therapy with pertuzumab plus trastuzumab alone.
4.2 Strengths and Limitations
One strength of this SLR is that it identified studies with a range of designs, although some were described only as economic analyses with no additional clearly defined design details included. The inclusion of both clinical trials and studies conducted in the real-world setting suggests that the reported time and cost savings may be translated to SC versus IV oncology biologics administered during standard clinical practice. The publications included in this SLR also reported several different methodologies for time assessments; however, results from the two studies that reported time estimates from drug delivery software or based on HCP surveys were largely consistent with those from studies that used direct measurements from time-and-motion-type methodologies.
Although the majority of the trastuzumab and rituximab studies identified were performed in European countries, full-text publications were identified for studies conducted in Canada, Chile, China, New Zealand, and the USA, and abstracts identified for studies conducted in Ecuador, Hong Kong, Japan, Mexico, Panama, Singapore, Thailand, Tunisia, and Saudi Arabia. Despite the potentially limited generalizability of the conclusions due to country-specific differences in approaches to healthcare, the consistency of the evidence supporting SC-related time and cost savings compared with IV administration presented in this SLR suggest that the findings are likely to be applicable across different healthcare systems and countries.
Due to the large number of potentially relevant publications comparing SC with IV administration, the decision was made to focus the literature search on anticancer drugs. Although this pragmatic approach could lead to relevant data/insights being missed, the oncology publications included in this SLR can offer a chance of providing valuable insights into the impact of the route of administration on treatment costs.
The focus of this SLR was to identify potential time differences associated with SC versus IV administration, as well as differences in non-time-related cost elements such as non-drug consumables. As a result, the drug costs of the treatments being administered were not considered. However, it is important to acknowledge the need for decision makers to take a holistic approach to healthcare resource utilization, which accounts for both drug and non-drug costs, in order to ensure optimal management of resources.
In the future, more studies should address the economic benefits for different institutions of patients switching from IV to SC oncology biologics [54], rather than simply comparing different patient populations treated via either IV or SC administration. Furthermore, as the current economic assessments have mainly been performed in developed countries and there are concerns about the transferability of SC versus IV benefits to less developed countries [126], more studies should be conducted in regions such as Eastern Europe or Latin America to assess the applicability of our findings there.
5 Conclusion
This SLR indicates that there is a substantial body of evidence demonstrating oncology biologics administered by the SC route in a hospital setting to be associated with important time and resource use savings versus IV administration. The identified evidence provides valuable inputs for economic evaluations of PH FDC SC, or for other SC oncology treatments.
References
Ruiz-Fernández MD, Hernández-Padilla JM, Ortiz-Amo R, Fernández-Sola C, Fernández-Medina IM, Granero-Molina J. Predictor factors of perceived health in family caregivers of people diagnosed with mild or moderate Alzheimer’s disease. Int J Environ Res Public Health. 2019;16(19):3762.
Global Cancer Observatory. Estimated number of deaths in 2020, worldwide, females, all ages. 2021. https://gco.iarc.fr/today/online-analysis-pie?v=2020&mode=cancer&mode_population=continents&population=900&populations=900&key=total&sex=2&cancer=39&type=1&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&nb_items=7&group_cancer=1&include_nmsc=1&include_nmsc_other=1&half_pie=0&donut=0. Accessed Dec 2021.
Patel A, Unni N, Peng Y. The changing paradigm for the treatment of HER2-positive breast cancer. Cancers (Basel). 2020;12(8):2081.
Ménard S, Fortis S, Castiglioni F, Agresti R, Balsari A. HER2 as a prognostic factor in breast cancer. Oncology. 2001;61(Suppl 2):67–72.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84.
Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol. 2005;23(19):4265–74.
Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet (London, England). 2010;375(9712):377–84.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273–83.
Roche Registration Ltd. Herceptin® (trastuzumab). Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/herceptin-epar-product-information_en.pdf. Accessed 1 June 2022.
Genentech Inc. HERCEPTIN® (trastuzumab). Prescribing Information. 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103792s5345lbl.pdf. Accessed 1 June 2022.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Dec 2021.
Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group A. Guidelines of the AGO Breast Committee. 2022. https://www.ago-online.de/en/leitlinien-empfehlungen/leitlinien-empfehlungen/kommission-mamma. Accessed June 2022.
Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, André F, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020;31(12):1623–49.
Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194–220.
Roche Registration Ltd. PERJETA® (pertuzumab). Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/perjeta-epar-product-information_en.pdf. Accessed 1 June 2022.
Genentech Inc. PERJETA® (pertuzumab). Prescribing Information. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125409s124lbl.pdf. Accessed 1 June 2022.
Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016;17(6):791–800.
von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122–31.
Swain SM, Miles D, Kim SB, Im YH, Im SA, Semiglazov V, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519–30.
Roche Registration Ltd. Kadcyla® (trastuzumab emtansine). Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/kadcyla-epar-product-information_en.pdf. Accessed June 2022.
Genentech Inc. KADCYLA® (ado-trastuzumab emtansine). Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125427s108lbl.pdf. Accessed June 2022.
von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617–28.
De Cock E, Pivot X, Hauser N, Verma S, Kritikou P, Millar D, et al. A time and motion study of subcutaneous versus intravenous trastuzumab in patients with HER2-positive early breast cancer. Cancer Med. 2016;5(3):389–97.
Fallowfield L, Osborne S, Langridge C, Monson K, Kilkerr J, Jenkins V. Implications of subcutaneous or intravenous delivery of trastuzumab; further insight from patient interviews in the PrefHer study. Breast. 2015;24(2):166–70.
Jackisch C, Müller V, Maintz C, Hell S, Ataseven B. Subcutaneous administration of monoclonal antibodies in oncology. Geburtshilfe Frauenheilkd. 2014;74(4):343–9.
Shivakumar SP, Anderson DR, Couban S. Catheter-associated thrombosis in patients with malignancy. J Clin Oncol. 2009;27(29):4858–64.
De Cock E, Semiglazov V, Lopez-Vivanco G, Verma S, Pivot X, Gligorov J, et al. Time savings with trastuzumab subcutaneous vs. intravenous administration: a time and motion study. In: Poster presentation at the 13th St Gallen International Breast Cancer Conference; 13–16 March 2013. Abstract XXX; St Gallen.
Genentech Inc. Herceptin Hylecta™ (trastuzumab and hyaluronidase-oysk). Prescribing Information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761106s000lbl.pdf. Accessed Dec 2021.
Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre randomised trial. Lancet Oncol. 2012;13(9):869–78.
Jackisch C, Kim SB, Semiglazov V, Melichar B, Pivot X, Hillenbach C, et al. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Ann Oncol. 2015;26(2):320–5.
Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, et al. Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years’ treatment-free follow-up: final analysis from the phase III, open-label, randomized HannaH study. Cancer Res. 2017;78(4 Suppl):Abstract PD3-11 (and associated poster presentation).
Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen S-C, et al. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: Final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019;5(5): e190339.
Kümmel S, Tondini CA, Abraham J, Nowecki Z, Itrych B, Hitre E, et al. Subcutaneous trastuzumab with pertuzumab and docetaxel in HER2-positive metastatic breast cancer: Final analysis of MetaPHER, a phase IIIb single-arm safety study. Breast Can Res Treat. 2021;187(2):467–76.
Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–19.
Swain SM, Kim S-B, Cortés J, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461–71.
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34.
Pivot X, Gligorov J, Müller V, Barrett-Lee P, Verma S, Knoop A, et al. Preference for subcutaneous or intravenous administration of trastuzumab in patients with HER2-positive early breast cancer (PrefHer): an open-label randomised study. Lancet Oncol. 2013;14(10):962–70.
Pivot X, Gligorov J, Müller V, Curigliano G, Knoop A, Verma S, et al. Patients’ preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study. Ann Oncol. 2014;25(10):1979–87.
Pivot X, Spano JP, Espie M, Cottu P, Jouannaud C, Pottier V, et al. Patients’ preference of trastuzumab administration (subcutaneous versus intravenous) in HER2-positive metastatic breast cancer: results of the randomised MetaspHer study. Eur J Cancer. 2017;82:230–6.
Genentech Inc. PHESGO (pertuzumab, trastuzumab, and hyaluronidase-zzxf). Prescribing Information. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761170s000lbl.pdf. Accessed 1 June 2022.
O’Shaughnessy J, Sousa S, Cruz J, Fallowfield L, Auvinen P, Pulido C, et al. Preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer (PHranceSCa): a randomised, open-label phase II study. Eur J Cancer. 2021;152:223–32.
Higgins J, Thomas J. Cochrane handbook for systematic reviews of interventions. Version 6.2. 2021. https://training.cochrane.org/handbook/current. Accessed Dec 2021.
Drummond MF, Jefferson TO. Guidelines for authors and peer reviewers of economic submissions to the BMJ. The BMJ Economic Evaluation Working Party. BMJ. 1996;313(7052):275–83.
Drummond MF, Sculpher MJ, Torrance GW, O’Brien BJ, Stoddart GL. Methods for the exonomic evaluation of health care programmes. 3rd ed. Oxford: Oxford University Press; 2005.
Molinier L, Bauvin E, Combescure C, Castelli C, Rebillard X, Soulié M, et al. Methodological considerations in cost of prostate cancer studies: a systematic review. Value Health. 2008;11(5):878–85.
Andrade S, Santos A. Hospital resources consumption associated with trastuzumab treatment in breast cancer in Portugal. Value Health. 2013;16(7):Abstract PCN147.
Blein C, bernard Marty C, Priou V, Borg MC, mouret-Reynier M, Lebozec G, et al. A multicentric evaluation of consumables and transports cost of breast cancer patient’s treated by trastuzumab according to the administration form (IV versus SC). Value Health. 2018;21(Suppl 3):Abstract PCN95.
De Cock E, Pan YI, Tao S, Baidin P. Time savings with transtuzumab subcutaneous (SC) injection verse trastuzumab intravenous (IV) infusion: A time and motion study in 3 Russian centers. Value Health. 2014;17(7):Abstract PCN221.
Farolfi A, Silimbani P, Gallegati D, Petracci E, Schirone A, Altini M, et al. Resource utilization and cost saving analysis of subcutaneous versus intravenous trastuzumab in early breast cancer patients. Oncotarget. 2017;8(46):81343–9.
Favier M, Le Goc-Sager F, Vincent-Cantini I, Launay V, Giroux EA, Lievremont K, et al. Medico-economic benefits of subcutaneous formulations of trastuzumab and rituximab in day hospitalisation (SCuBA Study). Bull Cancer. 2018;105(10):862–72.
Franken MG, Kanters TA, Coenen JL, de Jong P, Koene HR, Lugtenburg PJ, et al. Potential cost savings owing to the route of administration of oncology drugs: a microcosting study of intravenous and subcutaneous administration of trastuzumab and rituximab in the Netherlands. Anticancer Drugs. 2018;29(8):791–801.
Hedayati E, Fracheboud L, Srikant V, Greber D, Wallberg S, Linder SC. Economic benefits of subcutaneous trastuzumab administration: a single institutional study from Karolinska University Hospital in Sweden. PLoS ONE. 2019;14(2): e0211783.
Jackisch C, Müller V, Dall P, Neumeister R, Park-Simon TW, Ruf-Dördelmann A, et al. Subcutaneous trastuzumab for HER2-positive breast cancer—evidence and practical experience in 7 German centers. Geburtshilfe Frauenheilkd. 2015;75(6):566–73.
Lee VW, Cheng F. Cost-minimization analysis of trastuzumab intravenous versus trastuzumab subcutaneous regimen for breast cancer management in Hong Kong. Value Health. 2018;21(Suppl 2):Abstract PCN57.
Lewis P, Jones H, Skelley K, Simpson R, Beresford M. Switching to subcutaneous trastuzumab administration: quantifying the benefits. Clin Oncol. 2017;29(6):Abstract E101.
López MA, Samanes MS, Tena IP, Alonso EF, Turlan VC, Sanchez MC, et al. Switching from intravenous to subcutaneous formulation of TRASTUZUMAB: Costs and safety. Eur J Hosp Pharm. 2017;24(Suppl 1):Abstract CP-127.
Lopez-Vivanco G, Salvador J, Diez R, López D, De Salas-Cansado M, Navarro B, et al. Cost minimization analysis of treatment with intravenous or subcutaneous trastuzumab in patients with HER2-positive breast cancer in Spain. Clin Transl Oncol. 2017;19(12):1454–61.
Nestorovska A, Naumoska Z, Grozdanova A, Stoleski D, Ivanovska A, Risteski M, et al. Subcutaneous vs intravenous administration of trastuzumab in HER2+ breast cancer patients: a Macedonian cost-minimization analysis. Value Health. 2015;18(7):Abstract PCN188.
Nierenberger A, Gessier F, Forges F, Simoens X. Subcutaneous trastuzumab versus intravenous trastuzumab: an impact study. Eur J Hosp Pharm. 2017;24(Suppl 1):Abstract PP-034.
North RT, Harvey VJ, Cox LC, Ryan SN. Medical resource utilization for administration of trastuzumab in a New Zealand oncology outpatient setting: a time and motion study. Clinicoecon Outcomes Res. 2015;7:423–30.
O’Brien GL, O’Mahony C, Cooke K, Kinneally A, Sinnott SJ, Walshe V, et al. Cost minimization analysis of intravenous or subcutaneous trastuzumab treatment in patients with HER2-positive breast cancer in Ireland. Clin Breast Cancer. 2019;19(3):e440–51.
Olofsson S, Norrlid H, Karlsson E, Wilking U, Ragnarson TG. Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer—an observational study prospectively recording resource utilization in a Swedish healthcare setting. Breast. 2016;29:140–6.
Olsen J, Jensen KF, Olesen DS, Knoop A. Costs of subcutaneous and intravenous administration of trastuzumab for patients with HER2-positive breast cancer. J Comp Eff Res. 2018;7(5):411–9.
Ponzetti C, Canciani M, Farina M, Era S, Walzer S. Potential resource and cost saving analysis of subcutaneous versus intravenous administration for rituximab in non-Hodgkin’s lymphoma and for trastuzumab in breast cancer in 17 Italian hospitals based on a systematic survey. Clinicoecon Outcomes Res. 2016;8:227–33.
Tjalma WAA, Van den Mooter T, Mertens T, Bastiaens V, Huizing MT, Papadimitriou K. Subcutaneous trastuzumab (Herceptin) versus intravenous trastuzumab for the treatment of patients with HER2-positive breast cancer: a time, motion and cost assessment study in a lean operating day care oncology unit. Eur J Obstet Gynecol Reprod Biol. 2018;221:46–51.
Vangheluwe E, Giraud J, Pingaud C. Medico-economic impacts of use of subcutaneous formulations of rituximab and trastuzumab in outpatient care units. Eur J Oncol Pharm. 2018;1(3S):Abstract 191.
Coombes M, Yin L, Liu I, Shek N, Rusu F, Mukherjee S. Subcutaneous trastuzumab for the treatment of HER2+ breast cancer in Canada: a cost-minimization study. Cancer Res. 2020;80(4 Suppl):Abstract P6-13-02.
Ghosh W, Lim S, Wong A. Cost-minimisation analysis of subcutaneous versus intravenous trastuzumab for the treatment of early breast cancer and metastatic breast cancer in Singapore. Value Health. 2018;21:Abstract PCN55.
Rojas L, Muñiz S, Medina L, Peña J, Acevedo F, Pinto MP, et al. Cost-minimization analysis of subcutaneous versus intravenous trastuzumab administration in Chilean patients with HER2-positive early breast cancer. PLoS ONE. 2020;15(2): e0227961.
A N, Ali A, Al-Tweigeri T, Zekri J, Awad N, Safwat M, et al. Financial impact of introducing SC trastuzumab (Herceptin) versus currently used IV trastuzumab (Herceptin) on the budgets of different hospitals across Kingdom of Saudi Arabia (KSA). Value Health. 2017;20(9):Abstract PCN60.
Kashiura D, Souza PV, Garrido SD, Nardi E, Alves M. Budget impact model of subcutaneous trastuzumab compared with intravenous trastuzumab on the treatment of HER-2 positive breast cancer in the brazilian private healthcare system. Value Health. 2018;21(Suppl 3):Abstract PCN75.
Poquet-Jornet JE, Carrera Hueso J, Crespo C, Cuesta-Grueso C, Ramón Barrios MA, Gasent-Blesa JM, et al. Budget impact analysis with use of subcutaneus trastuzumab. Value Health. 2018;21(Suppl 3):Abstract PCN80.
Calvache J, Briceno V. Budget impact analysis of the use of trastuzumab SC in the treatment of HER2 positive in public health institutions of Ecuador. Value Health. 2017;20.
Agirrezabal I, Gaikwad I, Cirillo L, Lothgren M. Predicted treatment costs and savings per patient of Kanjinti® (trastuzumab biosimilar) vs. subcutaneous (SC) and intravenous (IV) Herceptin® and other trastuzumab biosimilars in italy. Value Health. 2018;21(Suppl 3):Abstract PCN103.
D'Arpino A, Savoia M, Cirillo L, Despiégel N, Haffemayer B, Giannopoulou A, et al. Comparative cost analysis of subcutaneous trastuzumab originator (Herceptin®) vs intravenous trastuzumab biosimilar (Kanjinti) from a hospital perspective in Italy. Value Health. 2019;22(Suppl 3):Abstract PCN72.
Jang Y, Byrne A, Toron F, Yoon S. Budget impact analysis of intravenous biosimilars compared with intravenous originators and subcutaneous products. Value Health. 2018;21(Suppl 3):Abstract PMU26.
Todorovic V, Durutovic I, Ivanovska A, Zajmovic A. Subcutaneous vs intravenous administration of trastuzumab in HER2+ breast cancer patients: a montenegrin cost-minimization analysis. Value Health. 2017;20(9):Abstract PCN172.
Villarreal-Garza C, O-Maldonado CDl, Díaz-Pérez H, Mesa-Chavez F, García-García M, Cardona-Huerta S, et al. Cost and time savings of subcutaneous trastuzumab (SC-T) in a public health system in Mexico. J Clin Oncol. 2019;37(15 Suppl):Abstract e18387.
De La Vega ZI, Celia A, Manuel P, Agustín S, Miguel C. Economic impact of the introduction of subcutaneous trastuzumab in the pharmacotherapeutic guide. Eur J Clin Pharm. 2017;19(3):213–5.
Lazaro Cebas A, Cortijo Cascajares S, Pablos Bravo S, Del Puy Goyache Goni M, Gonzalez Monterrubio G, Perez Cardenas MD, et al. Subcutaneous versus intravenous administration of trastuzumab: preference of HER2+ breast cancer patients and financial impact of its use. J BUON. 2017;22(2):334-9.
Kulikov A, Rybchenko Y. Pharmacoeconomic evaluation of the use of trastuzumab for subcutaneous administration compared to intravenous dosage form in the treatment of breast cancer. Value Health. 2015;18(7):Abstract PCN189.
Martin C, Alcedo J, Araúz E. Comparative analysis of costs between subcutaneous formulation of trastuzumab versus intravenous formulation from the perspective of the Instituto Oncológico Nacional of Panamá from January to December 2016. Cancer Res. 2018;78(4 Suppl):Abstract P4-12-3.
Mitchell H, Morrissey D. Intravenous versus subcutaneous trastuzumab: an economic and patient perspective. Br J Nurs. 2019;28(10):S15–20.
Mylonas C, Skroumpelos A, Fountzilas G, Maniadakis N. Cost minimization analysis of Herceptin subcutaneous versus herceptin intravenous treatment for patients with HER2+ breast cancer in Greece. J Cancer Policy. 2017;13:11–7.
Mylonas C, Kourlaba G, Fountzilas G, Skroumpelos A, Maniadakis N. Cost-minimization analysis of trastuzumab intravenous versus trastuzumab subcutaneous for the treatment of patients with HER2+ early breast cancer and metastatic breast cancer in Greece. Value Health. 2014;17(7):A640–1.
De Cock E, Kritikou P, Sandoval M, Tao S, Wiesner C, Carella AM, et al. Time savings with rituximab subcutaneous injection versus rituximab intravenous infusion: a time and motion study in eight countries. PLoS ONE. 2016;11(6): e0157957.
Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017;102(11):1913–22.
Mihajlovic J, Bax P, van Breugel E, Blommestein HM, Hoogendoorn M, Hospes W, et al. Microcosting study of rituximab subcutaneous injection versus intravenous infusion. Clin Ther. 2017;39(6):1221–32.
Fargier E, Ranchon F, Huot L, Guerre P, Safar V, Dony A, et al. SMABcare study: subcutaneous monoclonal antibody in cancer care: cost-consequence analysis of subcutaneous rituximab in patients with follicular lymphoma. Ann Hematol. 2018;97(1):123–31.
Rule S, Collins GP, Samanta K. Subcutaneous vs intravenous rituximab in patients with non-Hodgkin lymphoma: a time and motion study in the United Kingdom. J Med Econ. 2014;17(7):459–68.
Lakhal RB, Kacem K, Raoudha M, Jabeur D, Denguir MS, Bouattour H, et al. Cost-minimization and budget impact analysis of mabthera subcutaneous formulation in non-Hodgkin’s lymphoma (NHL): a case study from Tunisia. HemaSphere. 2019;3:Abstract PB2294.
Chansung K, Chuncharunee S, Khuhapinant A, Bunworasate U, Norasetthada L, Prayongratana K. Preference of rituximab subcutaneous (R-SC) in Thai patients with diffused large b-cell lymphoma (DLBCL) and follicular lymphoma (FL): a Thai context. Value Health. 2018;21(Suppl 2):Abstract PCN67.
Delgado Sánchez O, Gutiérrez A, do Pazo F, Ginés J, Martorell C, Boyeras B, et al. Comparative cost analysis of intravenous and subcutaneous administration of rituximab in lymphoma patients. Clinicoecon Outcomes Res. 2019;11:695-701.
Di Rocco A, Scerbo G, Ansuinelli M, al e. Efficacy, safety and cost analysis of subcutaneous vs intravenous rituximab in patients with diffuse large b-cell lymphoma treated with RCHOP. Haematologica. 2017;102:108.
Fisher MD, Wallick C, Miller PJ, Walker MS, Lash S, Dawson KL, et al. How time spent on rituximab infusion impacts patient satisfaction, stress, employment, and caregiver burden. Blood. 2017;130(Suppl 1):Abstract 5666.
Irwin S, Rowntree C, Cosh H, Bloodworth C. Positive benefits of changing from intravenous rituximab administration to subcutaneous administration: a single centre experience. British Journal of Haematology. 2017;176:Abstract E1151.
Lebas E, Guillotel R, Evrard J, Kugarajah R, Lassiaz C, Diakhate C. Time and money: the issues of setting up a rituximab biosimilar in hospital. Eur J Oncol Pharm. 2018;1:Abstract 197.
McBride A, Balu S, Campbell K, MacDonald K, Abraham I. Economic modeling for the US of intravenous vs subcutaneous rituximab in non-Hodgkin’s lymphoma treated with R-CHOP. Value Health. 2018;21(Suppl 3):Abstract PCN93.
McBride A, Balu S, Campbell K, MacDonald K, Abraham I. Economic modeling for the U.S. of intravenous versus subcutaneous rituximab as single-agent maintenance therapy in follicular lymphoma. J Manag Care Spec Pharm. 2018;24(10A Suppl):Abstract C29.
McBride A, Balu S, Campbell K, MacDonald K, Abraham I. Subcutaneous versus intravenous rituximab in non-Hodgkin lymphoma treated with R-CHOP: Economic modeling for the US. Blood. 2018;132(Suppl 1):Abstract 4776.
Nikolov O, Sterjev Z, Dimovski A, Kapedanovska-Nestorovska A, Naumovska Z, Grozdanova A, et al. Cost-minimization analysis of rituximab subcutaneous formulation versus intravenous administration of rituximab for the treatment of non-hodgkin’s lymphoma in the Republic of Macedonia. Haematologica. 2017;102:Abstract E1471.
Tomarchio V, Surano MA, Tafuri MA, Becilli M, Sarlo C, Berti P, et al. Management, economic and social impact of sub-cutaneous rituximab administration in lymphoproliferative malignancies. Haematologica. 2017;102(Suppl 1):Abstract P736.
Cicchetti A, Coretti S, Mascia D, Mazzanti N, Refolo P, Rolli FR, et al. Assessing social and economic impact of subcutaneous mAbs in oncology. Glob Reg Health Technol Assess. 2018;5(1):1–9.
Chansung K, Sirijerachai C, Teawtrakul N. Cost minimization study between intravenous rituximab (r-iv) vs subcutaneous rituximab (R-SC) in Thai patients with diffused large b-cell lymphoma (DLBCL): a simulation of electronic health record (E-HR) and evidence synthesis. Value Health. 2018;21(Suppl 2):Abstract PSY9.
Annibali O, Tomarchio V, Becilli M. Management, economic and social impact of sub-cutaneous rituximab administration in diffuse large b cell lymphoma (DLBCL) and follicular lymphoma. Haematologica. 2017;102:111.
Gomes G, Ho R, Rufino C, Alves M. Budget impact analysis of rituximab IV versus SC from public Brazilian hospital. Value Health. 2017;20(5):Abstract PCN63.
Kashiura D, Souza PV, Sa AB, Santos BR, Nardi E, Alves M. Budget impact model of subcutaneous rituximab compared with intravenous rituximab on the treatment of CD-20 positive non-Hodgkin lymphoma in the Brazilian private healthcare system. Value Health. 2018;21:Abstract PCN67.
Rauf M, Dada R, Awad N, Safwat M, Narang A, Goyal R. To determine the financial imapct of introducing SC rituximab (MABTHERA) vs. currently used IV rituximab (MABTHERA) on the budgets of different hospitals across the Kingdom of Saudi Arabia (KSA). Value Health. 2017;20(9):Abstract PCN69.
Stewart DA, Boudreault JS, Maturi B, Boras D, Foley R. Evaluation of subcutaneous rituximab administration on Canadian systemic therapy suites. Curr Oncol. 2018;25(5):300–6.
Cristino J, Finek J, Jandova P, Kolek M, Pásztor B, Giannopoulou C, et al. Cost-effectiveness of denosumab versus zoledronic acid for preventing skeletal-related events in the Czech Republic. J Med Econ. 2017;20(8):799–812.
Li S, Wu X, Chen P, Pei Y, Zheng K, Wang W, et al. Interferon-alpha versus interleukin-2 in Chinese patients with malignant melanoma: a randomized, controlled, trial. Anticancer Drugs. 2019;30(4):402–9.
Raje N, Roodman GD, Willenbacher W, Shimizu K, García-Sanz R, Terpos E, et al. A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in the United States of America. J Med Econ. 2018;21(5):525–36.
Stopeck A, Rader M, Henry D, Danese M, Halperin M, Cong Z, et al. Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ. 2012;15(4):712–23.
Zhang TT, Wang S, Wan N, Zhang L, Zhang Z, Jiang J. Cost-effectiveness of daratumumab-based triplet therapies in patients with relapsed or refractory multiple myeloma. Clin Ther. 2018;40(7):1122–39.
Body JJ, Gatta F, De Cock E, Tao S, Kritikou P, Wimberger P, et al. An observational time and motion study of denosumab subcutaneous injection and zoledronic acid intravenous infusion in patients with metastatic bone disease: Results from three European countries. Support Care Cancer. 2017;25(9):2823–32.
Despiau F, Zagala Y, Delord JP, Montastruc M, Lacaze JL, Ferrand R, et al. Observational study of outpatient unit duration of stay depending on the route of administration (intravenous vs subcutaneous) for a targeted therapy. Bull Cancer. 2017;104(10):869–74.
Mateos MV, Nahi H, Legiec W. Efficacy and safety of the randomized, open-label, non-inferiority, phase 3 study of subcutaneous (SC) versus intravenous (IV) daratumumab (DARA) administration in patients (pts) with relapsed or refractory multiple myeloma (RRMM): COLUMBA. J Clin Oncol. 2019;37(15 Suppl):Abstract 8005.
Wynne C, Harvey V, Schwabe C, Waaka D, McIntyre C, Bittner B. Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. J Clin Pharmacol. 2013;53(2):192–201.
Lai AG, Pasea L, Banerjee A, Hall G, Denaxas S, Chang WH, et al. Estimated impact of the COVID-19 pandemic on cancer services and excess 1-year mortality in people with cancer and multimorbidity: near real-time data on cancer care, cancer deaths and a population-based cohort study. BMJ Open. 2020;10: e043828.
Tagliamento M, Agostinetto E, Bruzzone M, Ceppi M, Saini KS, de Azambuja E, et al. Mortality in adult patients with solid or hematological malignancies and SARS-CoV-2 infection with a specific focus on lung and breast cancers: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;163: 103365.
Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA. Humanistic and economic impact of subcutaneous versus intravenous administration of oncology biologics. Future Oncol. 2019;15(28):3267–81.
Tetteh E, Morris S. Systematic review of drug administration costs and implications for biopharmaceutical manufacturing. Appl Health Econ Health Policy. 2013;11(5):445–56.
Bittner B, Richter W, Schmidt J. Subcutaneous administration of biotherapeutics: an overview of current challenges and opportunities. BioDrugs. 2018;32(5):425–40.
Inotai A, Agh T, Karpenko AW, Zemplenyi A, Kalo Z. Behind the subcutaneous trastuzumab hype: evaluation of benefits and their transferability to Central Eastern European countries. Expert Rev Pharmacoecon Outcomes Res. 2019;19(2):105–13.
Roche Registration Ltd. Herceptin® (trastuzumab). Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/herceptin-epar-product-information_en.pdf. Accessed Sept 2021.
Genentech Inc. Herceptin® (trastuzumab). Prescribing Information. 2021. https://www.gene.com/download/pdf/herceptin_prescribing.pdf. Accessed Sept 2021.
Roche Registration GmbH. PHESGO® (pertuzumab and trastuzumab). Summary of Product Characteristics. 2022. https://www.ema.europa.eu/documents/product-information/phesgo-epar-product-information_en.pdf. Accessed 1 June 2022.
Kolberg HK, Jackisch C, Hurvitz SA, Winstone J, Barham H, Hanes V, et al. Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review. Breast. 2021;57.
Wright JM, Jones GB. Developing the subcutaneous drug delivery route. Med Res Archiv. 2017;5(12).
Anderson KC, Landgren O, Arend RC, Chou J, Jacobs IA. Humanistic and economic impact of subcutaneous versus intravenous administration of oncology biologics. Fut Oncol. 2019;15(28):3267–81.
Altini M, Gentili N, Balzi W, Musuraca G, Maltoni R, Masini C, et al. The challenge of sustainability in healthcare systems: economic and organizational impact of subcutaneous formulations for rituximab and trastuzumab in onco-hematology. Expert Rev Pharmacoeconomics Outcomes Res. 2020:1–7.
Wardley A, Canon JL, Elsten L, Pena Murillo C, Badovinac Crnjevic T, Fredriksson J, et al. Flexible care in breast cancer. ESMO Open. 2021;6(1): 100007.
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Support for third-party medical-writing assistance for this manuscript, furnished by Katie Wilson, PhD, and Brian Law, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd.
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All authors received research funding support in the form of third-party medical writing support from F. Hoffmann-La Roche Ltd. CM is an employee of Clarivate, which was commissioned to perform this systematic review by F. Hoffmann-La Roche Ltd, and received travel expenses from F. Hoffmann-La Roche Ltd to attend a project scoping meeting. MTO and SN are employees of Clarivate, which was commissioned to perform this systematic review by F. Hoffmann-La Roche Ltd. MJG and FM are employees of and hold shares in F. Hoffmann-La Roche Ltd.
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McCloskey, C., Ortega, M.T., Nair, S. et al. A Systematic Review of Time and Resource Use Costs of Subcutaneous Versus Intravenous Administration of Oncology Biologics in a Hospital Setting. PharmacoEconomics Open 7, 3–36 (2023). https://doi.org/10.1007/s41669-022-00361-3
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DOI: https://doi.org/10.1007/s41669-022-00361-3