Download Pain and health-related quality of life in patients with advanced solid

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DOI 10.1007/s00520-013-1932-2
ORIGINAL ARTICLE
Pain and health-related quality of life in patients
with advanced solid tumours and bone metastases: integrated
results from three randomized, double-blind studies
of denosumab and zoledronic acid
Roger von Moos & Jean-Jacques Body & Blair Egerdie & Alison Stopeck & Janet E. Brown &
Danail Damyanov & Lesley J. Fallowfield & Gavin Marx & Charles S. Cleeland &
Donald L. Patrick & Felipe G. Palazzo & Yi Qian & Ada Braun & Karen Chung
Received: 11 December 2012 / Accepted: 1 August 2013
# Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose This analysis evaluated patient-reported outcomes
and analgesic use in patients with bone metastases from solid
tumours across three comparative studies of denosumab and
zoledronic acid.
Methods Pooled data were analysed from three identically
designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic
acid 4 mg monthly in patients with bone metastases from
breast cancer (n =2,046), castration-resistant prostate cancer
Portions of this work were presented at the European Oncology Nursing
Society (EONS) 8th Spring Convention, 26–27 April 2012 in Geneva,
Switzerland.
Trial Registration: The three studies are registered at
www.clinicaltrials.gov as NCT00321464, NCT00321620 and
NCT00330759.
Electronic supplementary material The online version of this article
(doi:10.1007/s00520-013-1932-2) contains supplementary material,
which is available to authorized users.
R. von Moos (*)
Kantonsspital Graubünden, Loëstrasse 170, 7000 Chur, Switzerland
e-mail: [email protected]
L. J. Fallowfield
Sussex Health Outcomes Research & Education in Cancer
(SHORE-C), University of Sussex, Brighton, UK
J.<J. Body
Chu Brugmann, Université Libre De Bruxelles, Brussels, Belgium
G. Marx
Sydney Adventist Hospital, University of Sydney, Sydney,
NSW, Australia
B. Egerdie
Urology Associates/Urologic Medical Research, Kitchener,
ON, Canada
A. Stopeck
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
C. S. Cleeland
University of Texas MD Anderson Cancer Center, Houston,
TX, USA
D. L. Patrick
University of Washington, Seattle, WA, USA
J. E. Brown
Cancer Research UK Experimental Cancer Medicine Centres, Leeds
and Sheffield, UK
F. G. Palazzo
CAIPO, San Miguel de Tucuman, Argentina
D. Damyanov
National Hospital for Treatment in Oncology, Sofia, Bulgaria
Y. Qian : A. Braun : K. Chung
Amgen Inc., Thousand Oaks, CA, USA
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(n =1,901) or other solid tumours (n =1,597). Pain severity,
pain interference, health-related quality of life and analgesic
use were quantified.
Results At baseline, approximately half of patients had no/
mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/
2,578] zoledronic acid). Denosumab delayed onset of
moderate/severe pain by 1.8 months (median, 6.5 vs
4.7 months; hazard ratio, 0.83; 95 % CI, 0.76–0.92; p <
0.001; 17 % risk reduction) and clinically meaningful increases
in overall pain interference by 2.6 months (median, 10.3 vs
7.7 months; hazard ratio, 0.83; 95 % CI, 0.75–0.92; p <0.001;
17 % risk reduction) compared with zoledronic acid. Strong
opioid use and worsening of health-related quality of life were
less common with denosumab.
Conclusions Across three large studies of patients with advanced solid tumours and bone metastases, denosumab
prevented progression of pain severity and pain interference
more effectively than zoledronic acid.
Keywords Denosumab . Bone metastases . Pain . Solid
tumours . Zoledronic acid
Introduction
Development of bone metastases in patients with breast,
castration-resistant prostate or other solid tumours can herald
a range of complications and management problems. Bone
metastases may cause spinal cord compression, surgery or
radiation to bone or pathologic fracture [1, 2]. These events
have been combined in clinical studies under the collective
term, “skeletal-related events (SREs)” [3]. Surgery and radiation to bone can be effective treatment modalities in patients
with bone metastases [4], but it is desirable to reduce the need
for these interventions when possible. Bone metastases also
commonly lead to systemic complications, such as pain, impaired mobility, hypercalcaemia of malignancy and the need
to change antineoplastic therapy. Pain from bone metastases
or SREs interferes with patient function and health-related
quality of life (HRQoL) [5–7]. The pain is often inadequately
treated and may be intractable to opioid therapy [5–7].
For patients with solid tumours and bone metastases, bonetargeted therapy is indicated to prevent the development of
skeletal complications [8–10]. Three identically designed,
international, randomized, double-blind phase III studies enrolled patients with bone metastases secondary to breast cancer [11], castration-resistant prostate cancer [12] and other
solid tumours (or bone lesions from multiple myeloma) [13].
In a pooled analysis of these studies, denosumab was superior
to zoledronic acid in the prevention of first and multiple SREs
[14]. Patient-reported outcomes (pain severity, pain interference with activity and affect and HRQoL) and analgesic use
were assessed at monthly visits.
Methods
Study design
This report presents the results of a pooled analysis of these
endpoints among patients with bone metastases secondary to
solid tumours. Pooled data were analysed from three identically designed, international, randomized, double-blind,
double-dummy, phase III trials of denosumab vs zoledronic
acid in adult patients with bone metastases from solid tumours, including patients with breast cancer [11], castrationresistant prostate cancer [12] and other solid tumours [13].
The latter study also enrolled patients with multiple myeloma
[13], but they were excluded from the pooled analysis because
denosumab is not indicated for use in patients with multiple
myeloma in most of the countries where it is marketed.
Full designs of each study, along with efficacy and safety
results, have been reported previously [11–14]. Patients in
each study had radiographic evidence of at least one bone
metastasis or bone lesion and an Eastern Cooperative Oncology Group performance score of 0, 1 or 2. Patients were
excluded if they had creatinine clearance <30 mL/min (per
zoledronic acid prescribing information) [15]. Patients who
had previously received bisphosphonate treatment for bone
metastases were excluded from each study. Patients in each
study provided written informed consent, study protocols
were approved by an investigational review board or
independent ethics committee and the studies were conducted
in accordance with principles of the Declaration of Helsinki.
Randomization and masking
A computer-generated schedule prepared before each study by
an individual independent of the studies was used for randomization. An interactive voice response system was used to
assign patients to treatment groups using randomly generated
blocks, with a block size equal to four patients. For each study,
blinding of all patients, investigators and study sponsor personnel was maintained during the blinded treatment phase.
Study treatment
Patients were randomly assigned in a 1:1 ratio to receive
blinded investigational treatment once every 4 weeks (q4w)
consisting of either subcutaneous denosumab 120 mg and
intravenous placebo, or intravenous zoledronic acid 4 mg
and subcutaneous placebo. The prescribing information for
zoledronic acid was followed to adjust the dose for patients
with a creatinine clearance of ≤60 mL/min and withhold the
dose for rising creatinine levels on study. No dose adjustments
or withholding for renal function were required for
denosumab. All study participants were advised to take vitamin D and calcium supplements. For each study, blinding of
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all patients, investigators and study sponsor personnel was
maintained during the blinded treatment phase.
Outcomes measured
At each monthly visit, patients completed the Brief Pain
Inventory-Short Form (BPI-SF) [16]. The BPI-SF includes
four items that measure pain severity at its worst, least, average and at the time the form is completed. Pain severity scores
on the BPI-SF range from 0 (no pain) to 10 (pain as bad as you
can imagine). The “worst pain” scores from the BPI-SF were
used for pain severity analyses. A score of ≤4 was considered
no or mild pain and a score of >4 was considered moderate or
severe pain [17].
An additional seven items of the BPI-SF measure pain
interference with general activity, walking, work, mood, enjoyment of life, relations with others and sleep. Pain interference scores also range from 0 (does not interfere) to 10
(interferes completely). The seven BPI-SF interference item
scores were combined for subscale scores of pain interference
with activity (interference with walking, general activity and
work) and affect (interference with relations with others, enjoyment of life and mood) and an overall interference score
(all seven items) [17].
The Functional Assessment of Cancer Therapy-General
(FACT-G) questionnaire was completed at each monthly visit
to measure HRQoL [18]. The FACT-G is a validated instrument that includes 27 questions about physical, functional,
social/family and emotional well-being. The FACT-G total
score for all 27 items combined ranges from 0 (worst possible
HRQoL) to 108 (best possible HRQoL).
Analgesic medications were recorded as concomitant medications and were summarized at each monthly visit with the
eight-point Analgesic Quantification Algorithm (AQA) [19],
with scores ranging from 0 (no analgesic use) to 7 (>600 mg
oral morphine equivalents per day), where scores >2 represent
use of a strong opioid (Online Appendix 1).
Statistical analysis
Analyses were conducted on all randomized patients who
completed at least one patient-reported outcome assessment.
Kaplan–Meier estimates were generated for time-to-event
endpoints. Patients who had not achieved an event (as defined
for each endpoint below) were censored at their last BPI-SF
assessment. Hazard ratios (HR) and two-sided 95 % confidence intervals (CI) were estimated using Cox proportional
hazards models adjusted by covariates and stratified by study
and randomized stratification factors (prior SRE [yes or no]
and other study-specific or disease-specific factors). Responder analyses (defined below) were performed through
10 months, by which time 30 % of patients had dropped out
due to death, disease progression or consent withdrawal. To
address missing data, primary and multiple imputation
methods were applied in the responder analyses; the methods
are described in Online Appendix 2. The proportion of responders was summarized by study visit and generalized
estimating equations for binary data were used to evaluate
overall treatment differences.
A clinically meaningful change in pain severity was defined as a ≥2-point change (increase or decrease) from baseline [20, 21]. A ≥2-point change represents what a patient
would consider beneficial or detrimental when assessing pain,
and is therefore clinically relevant [20]. Time-to-event analyses for pain severity were conducted among all patients at risk
(≥2-point increase among patients with ≤8 points at baseline; ≥2-point reduction among patients with ≥2 points at
baseline), and separately for patients with no or mild pain at
baseline (for ≥2-point increase) or moderate or severe pain at
baseline (for ≥2-point reduction). The shift from no/mild pain
at baseline to moderate/severe pain on study signals the need
for a change in the pain management strategy, and was also
included in time-to-event and responder analyses.
A clinically meaningful change in pain interference (activity, affect and overall) was defined as a ≥2-point change
(increase or reduction) from baseline. Time-to-event analyses
for a clinically meaningful increase in pain interference were
conducted for all patients at risk, and for patients with no or
mild pain at baseline. Responder analyses for a clinically
meaningful change in pain interference were conducted for
all patients at risk, using a similar definition to the pain
severity analyses.
Responder analyses for FACT-G were based on clinically
meaningful changes in HRQoL, defined as a ≥5-point change
in FACT-G total score among patients at risk [22]. Responder
analyses for analgesic use measured the proportion of patients
that shifted from not taking a strong opioid at baseline (AQA
Score 0–2) to taking a strong opioid (AQA Score ≥3).
The analyses of decreases in worst pain severity (time to
a ≥2-point decrease and proportion of patients with a ≥2point decrease) were pre-specified before the first study was
unblinded. All other analyses were ad hoc. The endpoints
reported in this manuscript were exploratory. Given the
sample size (n =5,544) and a median time to event of
8 months in the ZA arm, there was roughly 93 % power
to detect a delay of 1 month in the denosumab arm with a
two-sided type I error of 0.05.
Results
Patient characteristics
This analysis included a total of 5,544 patients from the breast
cancer study (denosumab, 1,026; zoledronic acid, 1,020), the
castration-resistant prostate cancer study (denosumab, 950;
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zoledronic acid, 951) and the study in other solid tumours
(denosumab, 800; zoledronic acid, 797). Patients with multiple myeloma in the latter study were excluded from the
analysis. Patient disposition and reasons for discontinuation
are shown in Fig. 1. Reasons for discontinuation were balanced between treatment groups.
Baseline disease, demographic and treatment characteristics were also similar between treatment groups (Table 1). Of
note, 2,683 (52 %) of 5,198 patients reported no or mild pain
at baseline. Baseline pain severity was moderate or severe in
1,146 (57 %) of 2,008 patients with a prior SRE and 1,369
(43 %) of 3,190 patients with no prior SRE. Patients reporting
moderate or severe pain at baseline were more likely than
those with no or mild pain at baseline to have an ECOG score
>0 (69 vs 49 %, respectively). Compared with patients
reporting no or mild pain at baseline, patients with moderate
or severe pain at baseline also reported greater mean scores for
overall pain interference (4.9 vs 1.7) and pain interference
with activity (5.5 vs 1.9) and affect (4.4 vs 1.5). At baseline,
strong opioids were being used by 306 (11 %) of 2,683
patients with no or mild pain and 805 (32 %) of 2,515 patients
with moderate or severe pain.
Pain severity
Denosumab delayed the time to clinically meaningful (≥2point) increase in pain severity (Table 2). Among all patients
at risk, denosumab delayed the median time to a clinically
meaningful increase by 0.3 months (5.9 vs 5.6 months) and
reduced the risk of a clinically meaningful increase in pain
2049 enrolled with
breast cancer
1597 enrolled with
other solid tumors
1904 enrolled with
prostate cancer
5550 patients with advanced cancer
and bone metastases enrolled
Denosumab
Zoledronic Acid
5 excluded for incomplete
Institutional board activities
and oversight
1 excluded for incomplete
Institutional board activities
and oversight
2776 randomized
2768 randomized
1938 discontinued
760 died
377 withdrew consent
361 disease progression
132 patient request
118 adverse event
190 other*
1969 discontinued
746 died
408 withdrew consent
340 disease progression
157 patient request
127 adverse event
191 other*
838 on study at primary data
analysis cutoff date
799 on study at primary data
analysis cutoff date
Fig. 1 Patient disposition. Asterisks other included lost to follow-up,
noncompliance, administrative decision, protocol deviation, ineligibility
determined and other reasons
Table 1 Baseline characteristics
Characteristics
Denosumab
(N =2,776)
Zoledronic
acid (N =2,768)
Women, n (%)
Age, years
Median (range)
≥75 years, n (%)
1,287 (46.4)
1,310 (47.3)
63 (18–93)
466 (16.8)
63 (22–91)
469 (16.9)
1,512 (54.5)
536 (19.3)
498 (17.9)
230 (8.3)
1,474 (53.3)
534 (19.3)
494 (17.8)
266 (9.6)
2,353 (84.8)
423 (15.2)
2,320 (83.8)
448 (16.2)
1,142 (41.1)
1,373 (49.5)
257 (9.3)
4 (0.1)
1,120 (40.5)
1,352 (48.8)
286 (10.3)
10 (0.4)
1,026 (37.0)
950 (34.2)
800 (28.8)
350 (10.8)
1,020 (36.8)
951 (34.4)
797 (28.8)
352 (12.7)
70 (2.5)
61 (2.2)
85 (3.1)
48 (1.7)
Geographic region, n (%)
Europe
North America
Latin America
Othera
Ethnicity/race, n (%)
White or Caucasian
Other
ECOG status, n (%)
0
1
2
Other
Tumour type, n (%)
Breast
Prostate
Other solid tumours
Non-small cell lung
Renal
Small cell lung
Other (each <2 %)b
316 (11.4)
Months since bone metastasis,
2.2 (0.0–207.3)
median (range)c
Previous skeletal-related event, n (%) 1,055 (38.0)
Presence of visceral metastasis, n (%) 1,184 (42.7)
BPI-SF Worst Pain score
No. of patients
2,620
Mean (SD)
4.3 (2.9)
Category, n (%)
No pain (0)
410 (15.6)
Mild pain (1–4)
Moderate pain (5–6)
Severe pain (7–10)
FACT-G total scored
No. of patients
Mean (SD) score
BPI-SF Pain Interference score
No. of patients
Overall score, mean (SD)
Activity score, mean (SD)
Affect score, mean (SD)
AQA analgesic score, n (%)
0 (no analgesic)
1 (non-opioid analgesics)
315 (11.4)
2.3 (0.0–191.0)
1,096 (39.6)
1,152 (41.6)
2,578
4.4 (3.0)
395 (15.3)
976 (37.3)
571 (21.8)
663 (25.3)
902 (35.0)
566 (22.0)
715 (27.7)
2,603
72.0 (16.4)
2,579
72.6 (16.3)
2,594
3.2 (2.7)
3.6 (3.0)
2.9 (2.8)
2,562
3.3 (2.6)
3.7 (3.0)
3.0 (2.7)
1,333 (48.0)
476 (17.1)
1,319 (47.7)
474 (17.1)
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Table 1 (continued)
Characteristics
2 (weak opioids)
3 to 7 (strong opioids)
a
Denosumab
(N =2,776)
Zoledronic
acid (N =2,768)
377 (13.6)
590 (21.3)
362 (13.1)
613 (22.1)
Pain reduction, as measured by median time to clinically
meaningful (≥2-point) decrease in pain severity, was similar
between treatment groups among all patients at risk
(2.8 months in each group; HR, 1.01; p =0.881) and among
patients with moderate or severe pain at baseline (1.9 months
in each group; HR, 0.98; p =0.717).
Other included Australia, Japan, India, South Africa and New Zealand
b
Other tumour types were bladder, rectal, colon, unknown primary,
cervix, head and neck, gastric, non-Hodgkin lymphoma, soft tissue
sarcoma, endometrial, oesophageal, neuroendocrine or carcinoid, melanoma, ovarian, thyroid, pancreatic, renal pelvis and ureter, other gastrointestinal, Hodgkin disease, liver, anal, testicular, biliary tract, squamous
cell skin and other
c
Time from the first diagnosis of bone metastasis to the date of
randomization
d
Range from 0–108; a higher score indicates better health-related quality
of life
severity by 8 % (HR, 0.92; p =0.020). Among patients with no
or mild pain at baseline (BPI-SF Worst Pain score ≤4),
denosumab delayed the median time to a clinically meaningful increase by 1.5 months (4.6 vs 3.1 months) and reduced the
risk by 13 % (HR, 0.87; p =0.002).
Among patients with no or mild pain at baseline,
denosumab delayed the median time to onset of moderate or
severe pain (BPI-SF Worst Pain score >4) by 1.8 months
compared with zoledronic acid (6.5 vs 4.7 months; Fig. 2a)
and reduced the risk of experiencing moderate or severe pain
by 17 % (HR, 0.83; p <0.001). Also among patients with no or
mild pain at baseline, fewer denosumab-treated patients at each
visit experienced onset of moderate or severe pain than
zoledronic-acid-treated patients (average relative difference
of −13.5 %, favouring denosumab over zoledronic acid; overall treatment difference p <0.001; Fig. 2b).
Pain interference
Pain interference was delayed to a greater extent with
denosumab than with zoledronic acid (Table 2). Among all
patients at risk, denosumab delayed the median time to a clinically meaningful increase by 1.8 months for overall pain interference (11.1 vs 9.3 months; HR, 0.90; p <0.010), 0.9 months
for activity (8.3 vs 7.4 months; HR, 0.91; p =0.017) and
0.9 months for affect (8.4 vs 7.5 months; HR, 0.92; p =0.027)
compared with zoledronic acid. Among patients with no or mild
pain at baseline, denosumab delayed the median time to a
clinically meaningful increase by 2.6 months for overall pain
interference (10.3 vs 7.7 months; HR, 0.83; p < 0.001),
1.6 months for activity (7.6 vs 6.0 months; HR, 0.85;
p =0.002) and 1.8 months for affect (9.2 vs 7.4 months;
HR, 0.86; p =0.003) compared with zoledronic acid (Fig. 3).
Fewer denosumab-treated patients experienced clinically
meaningful worsening (≥2-point increase) in overall pain
interference from baseline relative to zoledronic-acid-treated
patients (average relative difference of −10.4 %, favouring
denosumab over zoledronic acid; overall treatment difference
p =0.040; Fig. 4a). Clinically meaningful reduction (≥2-point
decrease) from baseline in overall pain interference score was
not significantly different between the denosumab and zoledronic acid groups (average relative difference of +4.7 %
Table 2 Time-to-event estimates of clinically meaningful (≥2-point) increases in pain severity or pain interference with function
Endpoint
Incidence, n/N (%)
Denosumab
Patients at riska
Worst pain severity
1,432/2,408 (59.5)
Interference: activity 1,260/2,295 (54.9)
Interference: affect
1,318/2,418 (54.5)
Interference: overall
1,227/2,469 (49.7)
Patients with no or mild pain at baseline
Worst pain severity
984/1,386 (71.0)
Interference: activity 777/1,300 (59.8)
Interference: affect
753/1,314 (57.3)
Interference: overall
731/1,348 (54.2)
Median time to increase, months
p value
Zoledronic acid
Denosumab
Zoledronic acid
Difference
1,443/2,360 (61.1)
1,299/2,241 (58.0)
1,361/2,402 (56.7)
1,283/2,443 (52.5)
5.9
8.3
8.4
11.1
5.6
7.4
7.5
9.3
0.3
0.9
0.9
1.8
0.92 (0.85, 0.99)
0.91 (0.84, 0.98)
0.92 (0.85, 0.99)
0.90 (0.83, 0.98)
0.020
0.017
0.027
0.010
976/1,297 (75.3)
795/1,224 (65.0)
753/1,233 (61.1)
764/1,265 (60.4)
4.6
7.6
9.2
10.3
3.1
6.0
7.4
7.7
1.5
1.6
1.8
2.6
0.87 (0.79, 0.95)
0.85 (0.77, 0.94)
0.86 (0.77, 0.95)
0.83 (0.75, 0.92)
0.002
0.002
0.003
<0.001
A hazard ratio <1 favours denosumab
a
Hazard ratio
(95 % CI)
Patients at risk had a baseline score for that endpoint that was ≤8
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a
Median (Months)
Proportion of Patients
Without Moderate/Severe Pain
Fig. 2 Onset of moderate to
severe pain. a Time to first report
of moderate or severe pain among
patients with no or mild pain at
baseline. b Proportion of patients
at each study visit who progressed
from a baseline score of no or
mild pain to moderate or severe
pain
1.0
Denosumab
Zoledronic Acid
6.5 (5.8, 7.4)
4.7 (3.9, 5.6)
0.8
HR 0.83 (95 % CI: 0.76, 0.92)
p <0.001
0.6
0.4
0.2
0.0
BL
3
Risk Set:
Zoledronic Acid 4 mg Q4W 1297
Denosumab 120 mg Q4W 1386
100 %
712
859
Denosumab (n=1386)
9
506
621
386
480
Zoledronic Acid (n=1297)
(Average relative difference, –13.5 %)
(p<0.001 overall, denosumab vs zoledronic acid by Generalized Estimating Equation)
90 %
65.1 %
60.8 %
63.6 %
59.1 %
61.3 %
57.9 %
58.3 %
54.8 %
53.4 %
53.7 %
50.6 %
51.9 %
47.6 %
49.2 %
45.9 %
47.3 %
50 %
44.7 %
60 %
47.4 %
70 %
56.2 %
80 %
43.0 %
Proportion of Patients Who Progressed from No/Mild Pain at
Baseline to Moderate/Severe Pain, by Study Visit
b
6
Months
40 %
30 %
20 %
10 %
0%
1
2
3
4
5
6
7
8
9
10
Months
favouring denosumab over zoledronic acid; overall treatment
difference p =0.415).
zoledronic acid groups (average relative difference of
+8.2 % favouring denosumab over zoledronic acid; overall
treatment difference p =0.109).
HRQoL
Among all patients at risk, fewer denosumab-treated patients
experienced clinically meaningful worsening (decrease) from
baseline in HRQoL, as measured by FACT-G total score, than
zoledronic acid-treated patients (average relative difference
of -4.1 %, favouring denosumab over zoledronic acid;
overall treatment difference p =0.005; Fig. 4b). Among all
patients at risk, clinically meaningful improvement
(increase) in HRQoL, as measured by FACT-G total score,
was not significantly different between the denosumab and
Analgesic use
Fewer denosumab-treated patients shifted from not using a
strong opioid at baseline (AQA Score 0 to 2) to using a strong
opioid (AQA Score ≥3). The average relative difference was
−13.4 %, favouring denosumab over zoledronic acid, and the
p value for the overall treatment difference was p =0.041
(Fig. 4c). No more than 12 % of patients in either group shifted
to using a strong opioid at any study visit.
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a
Activity Score
Proportion of Patients Without a
≥ 2-Point Increase from Baseline
KM Estimate of
Median (Months)
1.0
Denosumab
Zoledronic Acid
7.6 (6.7, 9.3)
6.0 (5.5, 7.3)
0.8
HR 0.85 (95 % CI: 0.77, 0.94)
p =0.002
0.6
0.4
0.2
0.0
BL
3
6
9
517
613
395
491
Months
Zoledronic Acid 4 mg Q4W
Denosumab 120 mg Q4W
1224
1300
722
833
b
Affect Score
Proportion of Patients Without a
≥ 2-Point Increase from Baseline
KM Estimate of
Median (Months)
1.0
Denosumab
Zoledronic Acid
9.2 (7.6, 10.2)
7.4 (6.5, 8.3)
0.8
HR 0.86 (95 % CI: 0.77, 0.95)
p =0.003
0.6
0.4
0.2
0.0
BL
3
6
9
562
649
432
522
Months
Zoledronic Acid 4 mg Q4W
Denosumab 120 mg Q4W
1233
1314
c
775
865
Overall Score
KM Estimate of
Median (Months)
Proportion of Patients Without a
≥ 2-Point Increase from Baseline
Fig. 3 Time to clinically
meaningful increase in pain
interference. Time to first report
of a ≥2-point increase in pain
interference score among patients
with no or mild pain at baseline
1.0
Denosumab
Zoledronic Acid
10.3 (9.3, 12.1)
7.7 (6.9, 8.6)
0.8
HR 0.83 (95 % CI: 0.75, 0.92)
p <0.001
0.6
0.4
0.2
0.0
BL
3
6
9
597
697
463
565
Months
Zoledronic Acid 4 mg Q4W
Denosumab 120 mg Q4W
1265
1348
806
910
Support Care Cancer
100 %
Denosumab 120 mg Q4W (N=2469)
80 %
20 %
52.3 %
51.0 %
50.0 %
48.2 %
45.1 %
43.3 %
41.9 %
39.7 %
39.4 %
34.6 %
31.9 %
30.0 %
27.5 %
23.3 %
30 %
22.6 %
40 %
27.1 %
50 %
36.3 %
60 %
47.1 %
70 %
16.2 %
Proportion of At-Risk Patients With a 2-Point
Increase in Pain Interference, by Study Visit
Zoledronic acid 4 mg Q4W (N=2443)
(Average relative difference, –10.4 %)
(p=0.040 overall, denosumab vs zoledronic acid by Generalized Estimating Equation)
90 %
18.7 %
a
10 %
0%
1
2
3
4
5
6
7
8
9
10
Months
100 %
Denosumab 120 mg Q4W (N=2603)
40 %
64.4 %
65.3 %
62.5 %
61.3 %
59.5 %
58.1 %
57.2 %
54.0 %
53.3 %
52.0 %
49.7 %
45.2 %
44.6 %
42.0 %
33.5 %
50 %
39.0 %
60 %
47.6 %
70 %
56.3 %
80 %
66.9 %
90 %
Proportion of At-Risk Patients With a 5-Point
Reduction in FACT-G Total Score, by Study Visit
Zoledronic acid 4 mg Q4W (N=2579)
(Average relative difference, –4.1 %)
(p=0.005 overall, denosumab vs zoledronic acid by Generalized Estimating Equation)
36.9 %
b
30 %
20 %
10 %
0%
1
2
3
4
5
6
7
8
9
10
Months
25 %
Denosumab 120 mg Q4W (n=2174)
Zoledronic Acid 4 mg Q4W (n=2144)
(Average relative difference, –13.4 %)
(p=0.041 overall, denosumab vs zoledronic acid by Generalized Estimating Equation)
20 %
5%
0%
1
3
4
5
6
Months
7
8
9
12.0 %
9.7 %
11.4 %
9.1 %
10.0 %
8.9 %
10.1 %
9.2 %
10.3 %
8.2 %
10.4 %
7.6 %
9.0 %
7.6 %
6.8 %
6.0 %
2
6.0 %
4.2 %
10 %
7.5 %
15 %
4.2 %
c
Proportion of Patients Who Shifted from No Strong Opioid Use
at Baseline to Strong Opioid Use, by Study Visit
Fig. 4 Responder analyses for
pain interference, HRQoL and
opioid use. a Pain interference:
proportion of at-risk patients with
a ≥2-point increase from baseline
in overall pain interference score.
b Health-related quality of life:
proportion of at-risk patients with
a ≥5-point reduction from
baseline in FACT-G total score.
c Opioid use: proportion of
patients who shifted from
baseline use of no analgesic,
non-opioid analgesics or weak
opioids to use of strong
opioids on study
10
Support Care Cancer
Discussion
Skeletal pain is a significant complication of metastatic bone
disease and often responds poorly to treatment. Thus, it is
important to identify interventions that can prevent SREs and
worsening of bone pain. The biology of bone pain is complex
and incompletely understood, but it appears to differ from
inflammatory pain in its cellular and neurochemical characteristics [23, 24]. Increased osteoclast activity may contribute to
bone pain through bone resorption and acidification of the bone
microenvironment [23, 24]. In animal models, RANKL inhibition has been shown to prevent activation of pain fibres by
virtue of the blockade of osteoclastic bone resorption [25].
Thus, any differences between denosumab over zoledronic acid
in preventing pain progression may be related to the greater
inhibition of osteoclast formation and activity by denosumab.
In this pooled analysis based on individual patient data
from three identically designed phase III studies in patients
with solid tumours and bone metastases, denosumab
prevented the onset of worsening pain more effectively than
zoledronic acid. The largest differences were seen among
patients with no or mild pain at baseline (i.e. patients at risk),
which comprised more than 50 % of patients. Among these
patients, denosumab delayed the onset of moderate or severe
pain more effectively than zoledronic acid, with a risk reduction of 17 % and corresponding delay of 1.8 months.
In addition to the greater effectiveness of denosumab in
delaying onset of moderate or severe pain, denosumab
prevented worsening of pain severity and pain interference
more effectively than zoledronic acid, as defined by a clinically
meaningful increase (worsening) or decrease (improvement)
of ≥2-points. This change score is considered the minimally
important difference for the 11-point BPI-SF scale of worst
pain (i.e. ≥2-point response is meaningful to patients) [20, 21]
and is consistent with recommendations of a recent expert
consensus for pain assessment in cancer [26].
Denosumab and zoledronic acid had similar effects in
reducing pre-existing pain severity and pain interference. Because they are bone-modifying agents, not analgesics,
denosumab and zoledronic acid were not expected to reduce
pre-existing pain substantially. Barriers to use of strong opioids include concerns about (or occurrence of) systemic side
effects such as nausea, constipation, dizziness, fatigue, altered
mental status or mood or respiratory depression. Patients may
also limit or reject opioid treatment because of fears of dependency and addiction [27]. In some countries, national policies
and regulations also present obstacles to opioid use [28]. In
this study, the gap observed between pain severity and levels
of analgesic use demonstrated that denosumab effectively
reduced the introduction of strong opioids compared with
zoledronic acid.
In a previous analysis of data from the same studies [14],
denosumab was superior to zoledronic acid for preventing
SREs. Reduction of painful SREs such as spinal cord compression and pathologic fracture may have contributed to
better prevention of pain progression with denosumab. Conversely, after moderate to severe bone pain has developed,
radiation or surgery to bone may be effective alternatives to
strong opioids [27]. Thus, it is possible that differences in pain
progression favouring denosumab over zoledronic acid would
have been even greater if the requirement for these interventions had not also been reduced significantly by denosumab
administration.
Painful bone metastases impair HRQoL significantly [29].
Using a ≥5-point change in the FACT-G total score as the
criterion for a clinically meaningful difference in HRQoL
[30], worsening of HRQoL in this pooled analysis was significantly lower in the denosumab group compared with the
zoledronic acid group. Because the three trials used doubleblind designs where each patient received both subcutaneous
and intravenous administration of a study treatment (one
active and one placebo), it was not possible to evaluate the
possible influence of the mode of administration on HRQoL
in this analysis.
This report represents the largest analysis of prospective
data for pain prevention with any bone-targeted treatment to
date. Findings can be generalized to all patients with bone
metastases from solid tumours based on the large number of
patients and the variety of malignancies. This analysis was
limited to patient-level data from the first 10 months on study
(before 30 % of the patients had dropped out due to death or
disease progression, among other reasons), reflecting the advanced tumour stage at enrolment. The study results did not
appear to be influenced by dropouts because the reasons and
rates were similar between treatment groups and multiple
imputation results were similar to primary imputation results
in responder analyses.
A few limitations of the analysis are recognized. The ability
to detect reductions in pain intensity and pain interference
related to skeletal disease also may have been compromised
by cancer pain not related to skeletal disease, other tumour
symptoms or concomitant analgesic use. Results from this
study may underestimate the effect of denosumab on pain
palliation, given that opioid use was reduced on study in
patients receiving denosumab compared with those receiving
zoledronic acid. Pain assessments were conducted at regular
treatment visits, consistent with standard care. Use of a generalized pain questionnaire, instead of a bone-specific questionnaire, may have contributed to an underestimation of
treatment effect. However, improving overall pain intensity
and interference are likely more important to a patient than
improving only bone-specific pain, and generalized pain questionnaires have been used in several previous studies of the
effects of bisphosphonates on bone pain [31–34]. Additional
limitations include an inability to elicit patient preference for
subcutaneous versus intravenous administration, and time
Support Care Cancer
required for delivery of each drug, both of which would likely
impact on acceptability of treatment from a patient’s point of
view and therefore quality of life.
In conclusion, across three large phase III studies of patients with advanced solid tumours and bone metastases,
denosumab prevented progression of pain, increases in pain
interference with function and use of strong opioids more
effectively than zoledronic acid. These findings, combined
with significant prevention of skeletal morbidity as reported
previously [11–14], support the early initiation of denosumab
when patients present with bone metastases, including asymptomatic bone metastases, to delay SREs and the onset of worse
pain or use of strong opioids.
Acknowledgements This work was supported by Amgen Inc. Jonathan
Latham (whose work was funded by Amgen Inc.) and Vidya S. Beckman
of Amgen Inc. provided medical writing assistance in the preparation of
the manuscript.
Disclosures The authors disclose the following potential conflicts of
interest. Consultant—Amgen (RvM, JJB, AS, JEB, LJF, GM, CSC and
DLP); Novartis (RvM, JJB, AS and JEB); Roche (RvM) and Bristol Myers
Squibb (JEB). Remuneration—Amgen (RvM, JJB, JEB, LJF and GM);
Novartis (RvM and JJB) and Roche (RvM). Funding—Amgen (RvM and
JEB); Roche (RvM) and Novartis (JEB). Employment and stock ownership—Amgen (YQ, AB and KC).
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