•
`
`ClinicalStudies
`
`British Journal of Cancer (2005) 92, 1869 – 1876
`& 2005 Cancer Research UK All rights reserved 0007 – 0920/05 $30.00
`
`www.bjcancer.com
`
`Zoledronic acid significantly improves pain scores and quality of
`life in breast cancer patients with bone metastases: a randomised,
`crossover study of community vs hospital bisphosphonate
`administration
`
`A Wardley*,1, N Davidson2, P Barrett-Lee3, A Hong4, J Mansi5, D Dodwell6, R Murphy7, T Mason7 and
`D Cameron8
`1Christie Hospital NHS Trust, 550 Wilmslow Road, Manchester M20 4BX, UK; 2Broomf ield Hospital, Chelmsford CM1 7ET, UK; 3Velindre Hospital,
`Cardiff CF14 2TL, UK; 4Royal Devon & Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; 5St George’s Hospital, London SW17 ORE, UK; 6Cookridge
`Hospital, Leeds LS16 6QB, UK; 7Novartis Pharmaceuticals UK, Camberley GU16 5SG, UK; 8Western General Hospital, Edinburgh E4H 2XU, UK
`
`Patients with bone metastases from breast cancer often experience substantial skeletal complications – including debilitating bone
`pain – which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal
`complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home
`administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital
`setting in breast cancer patients with X1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg
`zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label
`infusions in the community or
`hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the
`European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were
`used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst
`pain (P¼ 0.008) and average pain in the last 7 days (P¼ 0.039), and interference with general activity (P¼ 0.012). In each case, there
`were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital
`crossover setting for worst pain (P¼ 0.021), average pain (P¼ 0.003), and interference with general activity (P¼ 0.001). Overall
`global health status showed a significant median improvement of 8.3% (P¼ 0.013) at study end. Physical, emotional, and social
`functioning also showed significant overall improvement (P¼ 0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and
`social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital
`crossover setting (P¼ 0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community
`administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the
`safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in
`the community setting.
`British Journal of Cancer (2005) 92, 1869 – 1876. doi:10.1038/sj.bjc.6602551 www.bjcancer.com
`Published online 3 May 2005
`& 2005 Cancer Research UK
`
`Keywords: breast cancer; skeletal metastases; bisphosphonates; bone pain; quality of life
`
`

`
`Each year, more than one million women will develop breast
`cancer worldwide with nearly half of these diagnoses occurring in
`the United States and Europe. Ultimately, more than 400 000 of
`these women will die of their disease (Parkin et al, 2005). Globally,
`breast cancer has the highest incidence of all cancers and is the
`leading cause of cancer mortality in women, accounting for
`approximately 23% of new cancer cases and approximately 14% of
`
`*Correspondence: Dr A Wardley;
`E-mail: Andrew.Wardley@christie-tr.nwest.nhs.uk
`Received 18 October 2004; revised 10 February 2005; accepted 7 March
`2005; published online 3 May 2005
`
`cancer deaths (Parkin et al, 1999). Metastasis to bone is
`common during disease progression and affects an estimated
`65 – 75% of patients with advanced breast cancer (Coleman, 2001).
`Resulting bone lesions lead to substantial skeletal complications
`that negatively affect quality of life (Coleman, 2001). Median
`survival for patients with advanced breast cancer is approximately
`18 – 26 months after the initial diagnosis of bone metastases,
`placing patients at long-term risk of developing skeletal complica-
`tions (Domchek et al, 2000; Coleman, 2001). Therefore, treatment
`and prevention of skeletal complications could improve quality-of-
`life outcomes and result in clinical benefits for these patients.
`Zoledronic acid is a new-generation nitrogen-containing bi-
`sphosphonate with evidence of significant efficacy in the treatment
`
`

`

`The 15-min infusion time required for zoledronic acid treatment
`makes it ideal for home or community administration, particularly
`for patients not receiving chemotherapy. Therefore, this study
`investigated the efficacy and safety of zoledronic acid administered
`in the community setting compared with the hospital setting
`in breast cancer patients with X1 bone metastasis receiving
`hormonal therapy.
`
`PATIENTS AND METHODS
`
`Patients
`
`The study enrolled adult patients with a histologically confirmed
`diagnosis of breast cancer and X1 bone metastasis confirmed by
`conventional radiograph. Patients had to be receiving hormonal
`therapy for their breast cancer and have an Eastern Cooperative
`Oncology Group (ECOG) performance status p2. Patients were
`not eligible if they were receiving chemotherapy or had abnormal
`renal function, defined as a serum creatinine level 41.5 times the
`upper limit of normal or a calculated creatinine clearance of
`1.
`o60 ml min
`
`Study design and treatment schedule
`
`This was a phase IIIb, multicentre, randomised, open-label,
`crossover study. The objective of the study was to determine
`efficacy and safety of zoledronic acid administered in the
`community setting vs the hospital setting. Patients received
`zoledronic acid (4 mg) via 15-min intravenous infusion every 3
`weeks for up to 9 months. All patients received treatment in the
`hospital setting for up to three cycles (hospital lead-in phase) to
`ensure disease stabilisation on hormone therapy. Patients were
`then randomised to receive treatment for three cycles in either the
`community setting or the hospital setting. After the three cycles,
`patients were crossed over to receive three cycles of treatment in
`the opposite setting. Thus, patients received a total of nine
`infusions over the course of the study (Figure 1). Infusion of
`zoledronic acid in the community setting was carried out by nurses
`from Healthcare at Home Limited (Burton-upon-Trent, UK). This
`study adhered to Good Clinical Practice (Declaration of Helsinki,
`
`•
`
`1870
`
`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`of bone lesions from multiple myeloma or a variety of solid
`tumours, including breast, prostate, lung, and renal cell cancer
`(Lacerna and Hohneker, 2003). In a long-term, randomised, phase
`III clinical trial, zoledronic acid (4 mg via 15-min infusion) was
`superior to pamidronate (90 mg via 2-h infusion), the previous
`standard of care, for reducing the risk of skeletal complications in
`patients with breast cancer metastatic to bone (Rosen et al, 2003,
`2004).
`Several studies have demonstrated that bisphosphonates have an
`analgesic effect in patients with bone metastases. In a long-term
`follow-up of two large, randomised trials in breast cancer patients,
`pamidronate (90 mg) significantly improved pain scores and
`reduced need for palliative radiation therapy compared with
`placebo (Po0.001) (Hortobagyi et al, 1998; Theriault et al, 1999;
`Lipton et al, 2000). In studies comparing zoledronic acid (4 mg)
`with pamidronate (90 mg) in patients with bone lesions from
`multiple myeloma or breast cancer, zoledronic acid significantly
`reduced the need for radiation to bone compared with pami-
`dronate (19 vs 24% for pamidronate; P¼ 0.037), and was at least as
`effective as pamidronate for the palliation of bone pain. Brief Pain
`Inventory (BPI) pain scores improved in 53 – 69% of patients with
`pain scores greater than zero at baseline, with no significant
`differences between treatment groups (Rosen et al, 2001, 2003).
`In recent years,
`interest has increased in home care as an
`alternative to hospital treatment. Several countries, including the
`United Kingdom, Australia, and the United States, have developed
`programmes to address this issue. In the United Kingdom, the
`National Health Service launched a Cancer Plan designed to
`improve patient access to care by providing home and community
`treatment options (National Health Service, 2000). Australia
`launched the Hospital in the Home pilot programme to provide
`short-term home care as an alternative to hospitalisation (Depart-
`ment of Human Services, 2003). Similarly, the US Medicare system
`provides short-term Post-Acute Care benefits for homebound
`individuals (Liu et al, 1999). Home care can provide several
`advantages for patients and caregivers. In several studies, home
`care was as effective as hospital care and resulted in fewer
`hospitalisations, decreased pain,
`improved quality of
`life,
`in-
`creased performance status, and greater patient satisfaction
`(Vinciguerra et al, 1986; Ventafridda et al, 1989; Hughes et al,
`1992; Shepperd et al, 1998; MacIntyre et al, 2002).
`
`Clinical Studies
`
`Hospital lead-in phase
`
`Hospital or community
`
`Hospital or community
`
`3 infusions
`
`3 infusions
`
`3 infusions
`
`I
`
`Screening
`n = 127
`
`I I
`
`Randomisation
`n = 101
`
`Crossover
`
`Community/
`hospital
`n = 56
`
`Hospital/
`community
`n = 45
`
`'1
`Completion
`n = 84
`
`-t< :~~
`IC]
`CJ
`
`Figure 1 Study design. Zoledronic acid (4 mg) was administered intravenously via 15-min infusion every 3 – 4 weeks for a maximum of nine infusions. The
`study was divided into a hospital lead-in phase with three infusions and two community vs hospital crossover phases with three infusions in each setting for a
`total of nine infusions.
`
`British Journal of Cancer (2005) 92(10), 1869 – 1876
`
`& 2005 Cancer Research UK
`
`

`

`•
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`1871
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`ClinicalStudies
`
`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`measurement carried forward to the end of the 3-month phase
`(hospital or home care). Patients in the ITT population had to
`provide efficacy data in all phases of the study.
`Raw scores from the EORTC QLQ-C30 questionnaires were
`transformed according to standard methods (Aaronson et al, 1993)
`to produce derived scores (range, 0 – 100). The derived scores were
`analysed using a mixed-effects model, in which period (second or
`third set of three cycles) and treatment (community care or
`hospital care) were fitted as fixed effects and subject fitted as a
`random effect. Mean differences between treatments (community
`care minus hospital care) were calculated and tested by analysis of
`variance. Model assumptions were checked and found to be
`adequately satisfied. Analyses were carried out using PROC
`MIXED of SASs. For BPI, the composite pain score was derived
`from the raw scores and analysed using a similar mixed model. All
`hypothesis tests for the efficacy and safety analyses were two-
`tailed, a¼ 0.05. Novartis UK Medical Information Processing and
`Statistics carried out statistical analysis using SASs software,
`version 8.2 (SAS Institute Inc.).
`
`RESULTS
`
`Patients
`A total of 127 patients were screened, and 101 patients with X1
`bone lesion secondary to breast cancer were enrolled (Figure 1).
`After the hospital
`lead-in phase, patients were randomised to
`treatment with 4 mg zoledronic acid administered in the commu-
`nity setting followed by the hospital setting (n¼ 56) or adminis-
`tered in the hospital setting followed by the community setting
`(n¼ 45). A total of 26 patients could not be randomised because of
`early progression of disease during the three initial hospital
`infusions. Of the 101 enrolled patients, 84 (83%) completed the
`study (44 patients in the community/hospital group and 40
`patients in the hospital/community group) and 79 (78%) patients
`were available for analysis, constituting the ITT population. Patient
`demographics and baseline disease characteristics were similar
`between treatment groups (Table 1).
`
`Directive 91/507/EEC) and was approved by Multi-Research Ethics
`Committee. All patients signed informed consent.
`
`Efficacy assessment
`
`The primary end point was to compare the efficacy of zoledronic
`acid administered in the community setting with the hospital
`setting. This end point was measured by evaluating bone pain,
`quality of life, performance status, resource utilisation, and patient
`satisfaction. Pain was assessed using the BPI, which measures
`intensity of pain and interference of pain with daily functioning
`(Cleeland and Ryan, 1994). Patients rated their pain and the degree
`to which pain limited their function at the time of response to the
`questionnaire, as well as their worst, least, and average pain over
`the previous 7 days. Quality of life was measured using the
`European Organisation for Research and Treatment of Cancer
`(Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) and
`the corresponding disease-specific BR23 breast cancer module
`(Aaronson et al, 1993; Sprangers et al, 1996). The EORTC QLQ-
`C30 questionnaire incorporates nine multi-item scales:
`five
`functional scales (physical, role (work and household activities),
`cognitive, emotional, and social); three symptom scales (fatigue,
`pain, and nausea and vomiting); and a global health and quality-
`of-life scale (Aaronson et al, 1993). The BR23 breast cancer module
`consists of 23 items covering symptoms and side effects related to
`different treatment modalities, body image, sexuality, and future
`perspective (Sprangers et al, 1996). The BPI was assessed at
`baseline, at the end of each cycle, and at the final visit. The EORTC
`QLQ-C30 and BR23 questionnaires were assessed at baseline, at the
`end of each treatment phase (hospital
`lead-in, community
`crossover, and hospital crossover), and at the final visit. Analyses
`of BPI and EORTC QLQ-C30 data were compiled for the 10-visit
`observation period: three cycles of the hospital lead-in phase, three
`cycles of the community crossover phase, three cycles of the
`hospital crossover phase, and final visit. Performance status was
`assessed using the ECOG scale. Resource utilisation was assessed
`by calculating time spent travelling to the hospital to receive the
`three infusions after randomisation.
`
`Safety assessment
`
`Safety
`
`The secondary end point was the safety and tolerability of
`zoledronic acid and was assessed by monitoring serum creatinine,
`calculated creatinine clearance, and the occurrence of adverse/
`serious adverse events. Serum creatinine was measured in the
`community setting using the i-STAT point-of-care analyser
`(Abbott Diagnostics, Abbott Park, Il, USA). Decreased renal
`function was defined as an increase in serum creatinine of X44
`1 from baseline for patients with baseline serum
`or X88 mmol l
`1, respectively, or at least twice
`creatinine of o124 or X124 mmol l
`the baseline value. These criteria were standard across all Novartis
`zoledronic acid registration protocols. Decreased renal function as
`measured by calculated creatinine clearance was defined as X1
`result more than 30% below baseline. Creatinine clearance was
`calculated using the Cockcroft-Gault equation. A serious adverse
`event was defined as any fatal or life-threatening event, any event
`that required a prolonged hospitalisation, any event that was
`significantly or permanently disabling or incapacitating, or any
`event that required medical or surgical intervention to prevent
`death, disability, or incapacitation.
`
`Statistical analysis
`
`Zoledronic acid (4 mg) was well tolerated. Renal function was
`normal throughout the study for the majority of patients. Serum
`
`Table 1 Patient demographic and baseline disease characteristics by
`treatment group
`
`Characteristic
`
`Mean (s.d.) age (years)
`Range (years)
`
`Race, n (%)
`White
`Black
`
`ECOG status, n (%)
`0 or 1
`X2
`Missing but scored 0 at visit 4
`Mean (s.d.) BPI composite pain score
`
`Community/
`hospital (n¼ 56)
`
`60 (11.8)
`37 – 87
`
`56 (100)
`0
`
`49 (88)
`6 (11)
`1 (1)
`2.6 (1.7)
`
`Hospital/
`community
`(n¼ 45)
`
`59 (10.7)
`37 – 76
`
`44 (98)
`1 (2)
`
`41 (91)
`4 (9)
`0
`2.7 (2.4)
`
`The efficacy analysis was carried out on an intention-to-treat (ITT)
`population defined as all patients who received X1 dose of trial
`medication, provided baseline efficacy data, and from whom X1
`postbaseline measurement was obtained. The end point measure-
`ment for each randomised patient was the last postrandomisation
`
`Baseline serum creatinine, n (%)
`1
`o124 mmol l
`56 (100)
`45 (100)
`s.d.¼ standard deviation; ECOG ¼ Eastern Cooperative Oncology Group; BPI¼ Brief
`Pain Inventory.
`
`& 2005 Cancer Research UK
`
`British Journal of Cancer (2005) 92(10), 1869 – 1876
`
`

`

`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`Hospital lead-in
`phase
`
`Group 1: Community
`Group 2: Hospital
`
`Group 1: Hospital
`Group 2: Community
`
`Follow-up
`
`--0--
`
`--D--
`
`Group 1: Community followed by hospital
`
`Group 2: Hospital followed by community
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Mean serum creatinine(♯mol l−1)
`
`•
`
`1872
`
`Clinical Studies
`
`BL
`
`1
`
`2
`
`3
`
`5
`4
`Visit number
`
`6
`
`7
`
`8
`
`9
`
`10
`
`Figure 2 Mean serum creatinine values remained stable throughout treatment with zoledronic acid. Serum creatinine values were measured at baseline
`(BL), after each cycle, and at follow-up. Measurements during home administration were performed using an i-STAT handheld analyser (Abbott Diagnostics).
`
`creatinine levels increased in only four of the 127 (3%) evaluable
`1 above baseline. Mean serum creatinine
`patients by 444 mmol l
`values were higher in the community phase of both treatment
`groups compared with the hospital lead-in phase or the hospital
`crossover phase; however, these fluctuations were related to the
`use of an i-STAT handheld analyser (Abbott Diagnostics). The
`differences between community and hospital serum creatinine
`values were not significant and levels returned to near baseline
`when patients returned to the hospital setting (Figure 2). All mean
`serum creatinine values were within the generally recognised
`1). Creatinine
`(54 – 98 mmol l
`normal
`range
`clearance was
`also normal for most patients; only 12 (9.4%) patients had one
`or more results 430% below baseline, and the majority of these
`patients only had one such decrease. Adverse events (regardless of
`relationship to study drug) were mild – most commonly flu-like
`symptoms, nausea, arthralgia, headache, pain, and vomiting
`(Table 2). Severe adverse events were experienced by 32 of 127
`(25%) evaluable patients; however, these events did not result in
`any discontinuations from the study and only two events were
`related to study medication. All serious adverse events were grade
`3; no grade 4 serious adverse events were reported. Eight (6.3%)
`patients died during the study:
`seven because of disease
`progression and one because of acute cardiovascular events not
`thought to be associated with zoledronic acid or their cancer.
`
`Efficacy
`
`BPI scores Over the 10-visit observation period, treatment with
`zoledronic acid resulted in overall improvement in the composite
`BPI score in the entire patient population compared with baseline
`that did not achieve statistical significance (mean, 0.5; P¼ 0.077).
`However, treatment with zoledronic acid resulted in significant
`reductions in worst pain in the last 7 days (P¼ 0.008), average pain
`in the last 7 days (P¼ 0.039), interference with general activity
`(P¼ 0.012), interference with walking ability (Po0.001), inter-
`ference with normal work (P¼ 0.005), interference with enjoyment
`life (P¼ 0.005), and interference with sleep (P¼ 0.015)
`of
`compared with baseline (Figure 3). All other assessments showed
`small, nonsignificant changes from baseline.
`
`Table 2 Adverse events (all grades), regardless of relation to study drug,
`occurring in X10% of patients (safety-evaluable population)
`
`Adverse event
`
`Any event
`Influenza-like illness
`Nausea
`Arthralgia
`Headache
`Pain NOS
`Vomiting NOS
`Back pain
`Constipation
`Fatigue
`Pain in limb
`NOS¼ not otherwise specified.
`
`Patients, n (%)
`Zoledronic acid 4 mg (n¼ 127)
`
`121 (95)
`40 (31)
`30 (24)
`27 (21)
`25 (20)
`25 (20)
`21 (17)
`19 (15)
`17 (13)
`17 (13)
`13 (10)
`
`Infusion of zoledronic acid in the community setting achieved
`significantly greater improvement in BPI pain scores compared
`with the hospital crossover setting (Figure 3). Significantly greater
`improvements were reported in the BPI
`composite
`score
`(P¼ 0.008), worst pain in the last 7 days (P¼ 0.021), average pain
`in the last 7 days (P¼ 0.003), pain right now (P¼ 0.013),
`interference with general activity (Po0.001),
`interference with
`mood (P¼ 0.036), and interference with walking ability (Po0.001)
`in the community crossover phase compared with the hospital
`crossover phase. In each case, pain scores significantly improved
`in the community phase compared with baseline, whereas no
`significant changes were reported in the hospital crossover phase.
`Interference with normal work improved significantly greater in
`the community crossover phase compared with the hospital
`crossover phase (Po0.001), and this score improved significantly
`in both the community crossover phase (P¼ 0.011) and the
`hospital crossover phase (P¼ 0.015) compared with baseline.
`
`British Journal of Cancer (2005) 92(10), 1869 – 1876
`
`& 2005 Cancer Research UK
`
`

`

`•
`
`1873
`
`ClinicalStudies
`
`EORTC QLQ-C30 score Over the 10-visit observation period,
`treatment with zoledronic acid resulted in a significant 5% increase
`in mean scores for overall global health status compared with
`baseline (P¼ 0.013). Specifically, 36 of the 79 (46%) patients
`available for analysis reported increases in global health status, 24
`(30%) patients reported no change, and 19 (24%) patients reported
`decreased health status. Assessment of
`the functional scales
`showed significant
`increases
`in mean scores
`for physical
`functioning (6% increase; P¼ 0.013), emotional functioning (8%
`increase; P¼ 0.005),
`and social
`functioning (7% increase;
`P¼ 0.043) compared with baseline (Figure 4). Overall cognitive
`and role scales remained stable throughout the course of the study.
`Infusion of zoledronic acid in the community crossover setting
`resulted in significantly greater improvement in physical function-
`ing (P¼ 0.018), role functioning (P¼ 0.001), and social functioning
`
`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`(P¼ 0.026) compared with the hospital crossover setting (Figure 5).
`Physical functioning scores during the community crossover phase
`showed a significant mean increase of 3% from baseline
`(P¼ 0.002) compared with a nonsignificant improvement in the
`hospital crossover phase. Similarly,
`role functioning scores
`increased significantly vs baseline in the community crossover
`phase (mean increase¼ 8%; P¼ 0.007), whereas a nonsignificant
`increase was reported during the hospital crossover phase. Social
`functioning scores were stable compared with baseline in both
`community crossover and hospital crossover phases.
`revealed
`Assessment of patient perception of
`symptoms
`significantly greater improvement in pain and diarrhoea scores
`in the community crossover phase (P¼ 0.031) compared with
`the hospital crossover phase (P¼ 0.01). Pain scores improved
`significantly by a mean of 4% from baseline in the community
`
`D
`
`Hospital crossover phase
`
`D
`
`Community crossover phase
`
`•
`
`Overall
`
`∗
`
`∗
`
`∗
`
`∗
`
`∗
`
`∗
`
`Composite
`Pain
`
`Worst pain
`
`Average
`pain
`
`Interference
`with general
`activity
`
`Interference
`with walking
`ability
`
`1.0
`
`0.5
`
`0.0
`
`−0.5
`
`−1.0
`
`−1.5
`
`−2.0
`
`Mean change from baseline in BPI score
`
`Figure 3 Zoledronic acid significantly improved Brief Pain Inventory (BPI) pain scores. Brief Pain Inventory was assessed at baseline, at the end of each
`cycle, and at final visit. Graph depicts mean change from baseline BPI scores reported during the hospital crossover phase, community crossover phase, and
`overall (score reported at final visit after nine infusions). *Po0.05; wPo0.005 compared with baseline values.
`
`∗
`
`∗
`
`∗
`
`∗
`
`Global
`health
`
`Physical
`functioning
`
`Role
`functioning
`
`Social
`functioning
`
`Emotional
`functioning
`
`10
`
`9 8 7 6 5 4 3 2 1 0
`
`EORTC QLQ-C30 score
`
`Mean change from baseline in
`
`Figure 4 Zoledronic acid significantly improved EORTC QLQ-C30 quality-of-life scores. Graph depicts overall mean change from baseline quality-of-life
`scores reported at final visit after nine infusions. *Po0.05 compared with baseline values. EORTC QLQ-C30¼ European Organisation for Research and
`Treatment of Cancer Quality of Life Core Questionnaire 30.
`
`& 2005 Cancer Research UK
`
`British Journal of Cancer (2005) 92(10), 1869 – 1876
`
`

`

`• D •
`
`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`Hospital crossover phase
`Community crossover phase
`
`t
`
`∗
`
`∗
`
`Physical
`functioning
`
`Role
`functioning
`
`Social
`functioning
`
`10
`
`9 8 7 6 5 4 3 2 1 0
`
`EORTC QLQ-C30 score
`
`Mean change from baseline in
`
`1874
`
`Table 3 Patient satisfaction with zoledronic acid treatment in hospital vs
`community setting
`
`Satisfaction 480%
`
`Patients, n (%)
`Satisfaction¼ 100%
`
`Hospital lead-in
`Community
`Hospital crossover
`Final visit
`
`57 (79)
`74 (94)
`65 (83)
`72 (91)
`
`32 (44)
`58 (73)
`40 (51)
`51 (65)
`
`time of more than 240 h travelling to and from the hospital
`(median, 2.5 h for all three visits; range, 0.25 – 13.5 h).
`
`Patient satisfaction Overall, patients were satisfied with zole-
`dronic acid treatment (Table 3). Patients were significantly more
`satisfied when zoledronic acid was administered in the community
`crossover setting compared with the hospital crossover setting.
`Significant differences were noted in the percentage of patients
`480% satisfied (94% for community vs 83% for hospital cross-
`over; P¼ 0.048) and 100% satisfied (73% for community crossover
`vs 51% for hospital crossover; P¼ 0.005).
`
`DISCUSSION
`
`Patients with breast cancer are at high risk for bone metastases,
`resulting in significant skeletal complications and bone pain that
`negatively affects their quality of life. Long-term treatment with
`zoledronic acid (4 mg) has been shown to reduce the risk of
`skeletal complications in these patients by an additional 20%
`compared with pamidronate, particularly in patients receiving
`hormonal therapy, in whom the risk was reduced by an additional
`30% (Rosen et al, 2003). Zoledronic acid is suited to home
`administration because of its short infusion time and its favourable
`safety profile. Furthermore, patients with breast cancer receiving
`hormonal therapy are particularly suited to home care because of
`the apparent earlier stage of their disease and better prognosis vs
`patients receiving chemotherapy. Therefore,
`this randomised
`crossover study investigated the efficacy and safety of zoledronic
`acid in the community setting vs the hospital setting in breast
`cancer patients with bone metastases receiving hormonal therapy.
`Results showed that zoledronic acid was safe in both the
`community and hospital settings, and analysis of BPI and EORTC
`QLQ-C30 quality-of-life scores demonstrated that zoledronic acid
`significantly improved composite pain scores and overall quality of
`life compared with baseline, particularly when administered in the
`community setting.
`In this study, zoledronic acid was safe and well tolerated;
`adverse events were mild, and no patient experienced a sustained
`decrease in renal function in either the community or hospital
`setting. Fluctuations in home serum creatinine measurements were
`noted but were related to the use of an i-STAT handheld analyser.
`Importantly, mean serum creatinine values were always within the
`normal range and returned to baseline during infusions in the
`hospital, where values were measured in the hospital laboratory.
`Analysis of BPI scores showed no changes in the overall
`composite score at end of study compared with baseline; however,
`significant decreases were noted in several subcategories. Notably,
`a significant improvement was observed in many aspects of pain,
`although these scores were relatively low at baseline. A recent
`analysis of
`treatment with zoledronic acid in women with
`metastatic breast cancer demonstrated that better baseline scores
`were associated with less improvement after treatment, whereas
`poorer initial scores were associated with higher rates of change
`
`Figure 5 Zoledronic acid achieved significantly greater improvement
`in EORTC QLQ-C30 quality-of-life scores when administered in the
`community crossover phase compared with the hospital crossover phase.
`The EORTC QLQ-C30 questionnaire was assessed at baseline, at the end
`of each treatment phase (hospital
`lead-in, community crossover, and
`hospital crossover), and at final visit. Graph depicts mean change from
`baseline quality-of-life scores reported during the hospital crossover phase
`and the community crossover phase. *Po0.05; wPo0.001 compared with
`lead-in score. EORTC QLQ-C30¼ European Organisation for
`hospital
`Research and Treatment of Cancer Quality of Life Core Questionnaire 30.
`
`crossover phase (P¼ 0.022) compared with a nonsignificant
`improvement in the hospital crossover phase. Similarly, diarrhoea
`scores improved significantly by 5% from baseline in the
`community phase (P¼ 0.005) compared with a nonsignificant
`improvement during the hospital crossover phase. All other
`symptoms remained stable, with changes o5%.
`Patients also experienced significantly fewer financial difficulties
`during the community crossover phase of the study compared with
`the hospital crossover phase (P¼ 0.004). During the community
`crossover phase, patients reported a significant mean decrease of
`4% in financial difficulties (P¼ 0.029), whereas during the hospital
`crossover phase a significant mean increase of 5% (P¼ 0.003) was
`reported compared with baseline. For all EORTC QLQ-C30 scales,
`an increase of 45% was considered to be clinically significant.
`
`BR23 breast cancer module Over the course of the study, patients
`reported significant declines in future perspective with a median
`change of 0 and a mean decrease of 17% (Po0.0001) in the entire
`patient population compared with baseline. However, sexual
`function significantly increased (median change of 0 and mean
`increase of 4%; P¼ 0.049). Body image and systemic therapy side
`effects remained stable. Hair loss and sexual enjoyment had too
`few respondents to assess meaningfully. Arm symptoms showed
`significant differences between the community crossover and
`hospital crossover settings. In the hospital crossover setting, arm
`symptoms improved 3% (P¼ 0.004), whereas the community
`setting arm symptoms worsened 4% (P¼ 0.076) compared with
`baseline.
`
`ECOG performance status No significant changes in performance
`status were noted during the study compared with baseline
`measurements. The majority of patients were either fully active or
`restricted in physically strenuous activity.
`
`Resource utilisation Time that patients spent travelling to the
`hospital was calculated for the three hospital
`infusions of
`zoledronic acid after randomisation. Patients spent a cumulative
`
`British Journal of Cancer (2005) 92(10), 1869 – 1876
`
`& 2005 Cancer Research UK
`
`Clinical Studies
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`ClinicalStudies
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`Home administration of zoledronic acid for breast cancer
`A Wardley et al
`
`In addition to improved patient satisfaction and quality of life,
`home treatment may also reduce patient and healthcare costs.
`Many studies reported decreased healthcare costs (reductions
`ranging from 18 to 85%) for treatment provided in the home
`compared with the hospital (Hughes et al, 1992; Ventafridda et al,
`1989). A randomised trial conducted by the US Department of
`Veterans Affairs evaluating the cost effectiveness of home care
`compared with customary hospital care for 171 terminally ill
`patients reported that patients receiving home care used 5.9 fewer
`hospital days (P¼ 0.03), resulting in a significant 47% per capita
`savings in hospital costs (P¼ 0.02) and an 18% reduction in total
`per capita healthcare costs (Hughes et al, 1992). This study also
`increase in patient (P¼ 0.02) and
`demonstrated a significant
`caregiver (P¼ 0.005) satisfaction with home care after 1 month of
`treatment. Therefore, home care may not only result in lowered
`healthcare costs and reduced expenses, but also a more satisfying
`and comfortable lifestyle for patients and caregivers.
`In summary, zoledronic acid