Transcript ASCO_2008_files/Dueck Endpoints Osteoporosis ASCO 2008

Endpoint Comparison for Osteoporosis Assessment in Cancer Control Studies (N02C1 and N03CC)
A. C. Dueck1, P. J. Atherton2, H. Liu2, S. L. Hines3, C. L. Loprinzi2, E. A. Perez3, A. D. Tan2, K. Burger2, X. Zhao2, B. Diekmann2, J. A. Sloan2
1 Mayo
Abstract
Background: Methodological issues hamper efficacy
assessment of agents to prevent osteoporosis in
cancer survivors. The diagnosis of osteoporosis can
vary depending upon which bone mineral density
(BMD) site is used, which machine is used for the
assessment, and which set of normative values are
applied. This analysis compared different endpoints
for the assessment of efficacy in 2 cancer control
studies.
Methods: Data from 2 NCCTG phase 3 cancer
control studies were employed involving 216 (N02C1)
and 558 (N03CC) patients each comparing 2
treatments for the prevention of osteoporosis. BMD
data were collected from spine (primary endpoint),
femoral neck, and total hip. Endpoints included raw
BMD score (RawBMD); raw machine-based T-score
(TRaw); sample-standardized T-score (TSamp);
reference population standardized T-score (TRef); and
Z-score percentile corresponding to TRef (TPerc). For
each of the 5 endpoints, summary statistics were
computed and the analytical comparison of treatment
arms was carried out via Student’s t-test, Wilcoxon
rank-sum, and baseline BMD-adjusted ANCOVA using
change from baseline (CB) and percentage change of
baseline (%CB) at 1 year. Each study was analyzed
separately.
Results: Results differed by BMD site and whether
CB or %CB was used. Among the 5 endpoints, TRaw,
TSamp, and TRef had 11, 8, and 7 statistically
significant results out of 36 tests, respectively. TPerc
and RawBMD produced the most statistically
significant results, 13 and 14, respectively.
Correlations among the 5 endpoints at baseline
ranged from .79 to >.99.
Conclusions: Treatment comparisons differed
across BMD site and endpoint used. Transforming via
sample statistics provided similar results to
transforming via reference or machine norms.
RawBMD and the new approach (TPerc) may be more
sensitive to change with TPerc having the added
benefit of being readily interpretable as a percentage.
Background
Clinic, Scottsdale, AZ; 2 Mayo Clinic, Rochester, MN; 3 Mayo Clinic, Jacksonville, FL
Methods
Number of Significant Tests for Different BMD locations and estimates
Data for two clinical trials were used:
Which bone mineral density (BMD)
statistic is the “best” one to use?
In our studies we have a variable amount
of data per person, ranging from a single
value to a series of BMD measures for
various sites (spine femoral neck, total
hip). There are numerous possible
entities that could be used as the basis
for analysis:
Raw BMD = the raw BMD values
T Raw = the observed t-score
(presumably using a machine-based
reference sample)
T Samp = the transformed t-score using
the sample mean and sample standard
deviation
T Ref = the transformed t-score using the
mean and standard deviation from a
reference population
T Perc = the z-score percentile
corresponding to the t-score for the
reference population (new idea)
N02C11: A Phase III Randomized, PlaceboControlled, Double-Blind Trial of Risedronate for
Prevention of Bone Loss in Premenopausal
Women Undergoing Chemotherapy for Primary
Breast Carcinoma
N03CC2: A Randomized, Controlled, OpenLabel Trial of Empiric Prophylatic vs. Delayed
Use of Zoledronic Acid for Prevention of Bone
Loss in Post-menopausal Women with Breast
Cancer Initiating Therapy with Letrozole After
Tamoxifen
1) For each of the five study endpoints,
change from baseline and
percentage change from baseline
were calculated using all available
data for eligible patients for three
anatomical sites: spine (L Total),
femoral neck (Femur Neck), and
total hip (Femur Total).
2) Summary statistics were calculated.
3) Student’s t-test, Wilcoxon rank-sum
test, and analysis of covariance
(baseline BMD value used as a
covariate) were used to compare
treatment arms for each study
endpoint.
Raw BMD
T Raw
T Samp
T Ref
T Perc
Total
Change from Baseline
Spine Fem Neck Total Hip
0
0
0
1
0
0
0
0
0
0
0
0
3
1
0
4 / 15
1 / 15
0 / 15
N02C1
% Change from Baseline
Spine Fem Neck Total Hip
0
0
0
0
0
0
0
0
0
0
0
0
1
0
0
1 / 15
0 / 15
0 / 15
Total
0
1
0
0
5
6 / 90
Change from Baseline
Spine Fem Neck Total Hip
3
3
1
3
3
3
3
3
1
3
3
1
3
3
3
15 / 15 15 / 15
9 / 15
N03CC
% Change from Baseline
Spine Fem Neck Total Hip
3
3
1
1
0
0
1
0
0
0
0
0
1
1
3
6 / 15
4 / 15
4 / 15
N02C1
Raw BMD
N03CC
N02C1
T Raw
N03CC
N02C1
T Samp
N03CC
N02C1
T Ref
N03CC
4) All analyses were completed
separately for each clinical trial.
N02C1
T Perc
N03CC
N
83
77
197
198
83
82
202
209
83
77
197
198
83
77
197
198
83
77
197
198
Mean
-0.06
-0.07
0.04
-0.02
-0.47
-0.6
0.26
-0.26
-0.35
-0.41
0.22
-0.12
-0.51
-0.59
0.33
-0.18
-0.07
-0.12
0.09
-0.03
Std Dev
0.07
0.08
0.12
0.1
0.49
0.65
0.51
0.73
0.43
0.49
0.71
0.64
0.62
0.71
1.07
0.95
0.14
0.16
0.18
0.16
Median
-0.05
-0.06
0.03
-0.02
-0.4
-0.5
0.3
-0.2
-0.3
-0.36
0.19
-0.14
-0.44
-0.52
0.28
-0.21
-0.03
-0.07
0.04
-0.02
Total
14
10
8
7
14
53 / 90
14
11
8
7
19
59 / 180
Discussion
Summary Statistics -- Spine BMD Change from Baseline
Arm
Risedronate
Placebo
Upfront Zometa
Delayed Zometa
Risedronate
Placebo
Upfront Zometa
Delayed Zometa
Risedronate
Placebo
Upfront Zometa
Delayed Zometa
Risedronate
Placebo
Upfront Zometa
Delayed Zometa
Risedronate
Placebo
Upfront Zometa
Delayed Zometa
Total
Min
-0.39
-0.45
-0.97
-0.99
-3.1
-3.8
-2.7
-7.3
-2.46
-2.84
-5.91
-6.05
-3.56
-4.12
-8.83
-9.03
-0.8
-0.55
-0.57
-0.96
Max
0.17
0.09
0.82
0.47
0.3
0.6
3.1
1.4
1.04
0.59
4.99
2.86
1.51
0.85
7.45
4.26
0.49
0.32
0.89
0.71
• SELECTING THE PROPER ENDPOINT IS IMPORTANT!
• SPINE (L TOTAL) appears most sensitive among the
anatomical sites.
• CHANGE FROM BASELINE appears more sensitive than %
change from baseline.
• RAW BMD and T PERC appear most sensitive among the
five endpoints.
• T PERC has the added benefit of being readily interpretable
as a percentage.
References
1) N02C1 ASCO ref
2) N03CC ASCO ref