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Risk Factors for the Development of Bone Metastases in Prostate Cancer

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Title: Risk Factors for the Development of Bone Metastases in Prostate Cancer


1
Risk Factors for the Development of Bone
Metastases in Prostate Cancer
  • Daniel P. Petrylak
  • Columbia-Presbyterian Medical Center

2
Questions to Urologists Treating Patients With
Early PC
  • Should bone scans be performed at baseline?
  • What are risk factors for bone metastases?
  • How can bone health be maintained in PC patients?
  • Bone metastases
  • Bone mineral density

3
Should bone scans be performed at baseline?
4
Current Guidelines for Bone Scans in Patients
With PC
  • Recommendations suggest that bone scans be
    performed on patients with chronic bone painor
    fracture

EAU European Association of Urology NCCN
National Comprehensive Cancer Network ESMO
European Society for Medical Oncology PSA
Prostate-specific antigen N/A Not applicable.
Patients with life expectancy gt 5 years or
symptomatic disease.1. Aus G, et al. Eur Urol.
200548546-551 2. NCCN Clinical Practice
Guidelines in Prostate Cancer V.1.2007 3. ESMO
Guidelines Task Force Ann Oncol. 200516i34-i36.
5
Current Guidelines for PSA Measurementsin
Patients With PC
EAU European Association of Urology NCCN
National Comprehensive Cancer Network PSA
Prostate-specific antigen. Patients with life
expectancy gt 10 years.1. Aus G, et al. Eur Urol.
200548546-551 2. NCCN Clinical Practice
Guidelines in Prostate Cancer V.1.2007.
6
Prostate-Specific Antigen (PSA) Levels May
Predict Positive Bone Scans After Local Therapy
for PC
  • Bone metastases are more common in patients
    withhigh PSA levels1
  • Radionuclide bone scans are recommended when
    serum PSA level is gt 20 µg/L after local therapy
  • Retrospective study of 96 patients with prostate
    cancer with (n 29) and without (n 67) bone
    metastases2
  • Retrospective study of 406 patients with prostate
    cancer who received bone scans irrespective of
    their serum PSA levels3
  • Retrospective study of protocol-specified bone
    scans and PSA data from 4,061 patients randomized
    to standard therapy within the Early Prostate
    Cancer program4

1. Salonia A, et al. Urology. 200668362-366 2.
Wang ZL and Wang XF. 200511825-827 3. Klatte
T, et al. Urologe A. 2006451293-1299 4. Chodak
GW, et al. Presented at AUA 2005 Abstract 1003.

7
Relationship of Serum PSA and Alkaline
Phosphatase Levels With Bone Metastases in
Patients With PC
  • Methods
  • Retrospective study of 96 cases of PC with (n
    29) and without (n 67) bone metastases
  • Baseline levels of serum PSA and ALP were
    assessed and a radionuclide bone scan was
    performed
  • Results
  • The median concentrations of serum PSA and ALP
    were statistically higher in patients with bone
    metastases (P lt .01)
  • The percentage of bone-scan positive patients was
    higher in patients with PSA gt 20 ?g/L or ALP gt 90
    U/L than in patients with PSA lt 20 ?g/L or ALP lt
    90 U/L
  • Conclusions
  • Patients with bone metastases from PC have higher
    levels of PSA and ALP than those without
  • Radionuclide bone scans are recommended when
    serum PSA gt 20 ?g/L or ALP gt 90 U/L

Wang ZL and Wang XF. Zhonghua Nan Ke Xue.
200511825-827.
8
Relationship of Serum PSA and Alkaline
Phosphatase Levels With Bone Metastases in
Patients With PC
  • Methods
  • Retrospective study of 406 patients who had
    received a staging bone scan irrespective of
    their PSA serum level and histology
  • Current guidelines and recommendations were
    evaluated, cost analyses were performed, and
    classification systems for bone metastases were
    reviewed
  • Results
  • The bone scan was positive in 41 (10) of 406
    patients
  • EAU guidelines were useful with respect to
    clinical value and cost efficiency
  • The Rigaud classification of bone metastases
    predicted outcome better than the Soloway or
    Crawford classification systems
  • Conclusions
  • According to the EAU guidelines supported by the
    authors, a bone scan should be performed in
    patients with PSA levels gt 20 ng/mL with a G1/G2
    histology and in patients with G3 histology and
    locally advanced disease irrespective of PSA level

Klatte T, et al. Urologe A. 2006451293-1299.
9
PSA Levels as a Predictor of Positive Bone Scans
During Follow-up After Standard Care for Prostate
Cancer
  • Methods
  • Early Prostate Cancer (EPC) program investigation
    into the optimal PSA level for recommending a
    bone scan following local therapy for PC
  • Data from protocol-specified bone scans and PSA
    reports from 4,061 patients randomized to
    standard care alone within the EPC program
  • Results
  • 5,048 bone scans were included in this analysis
  • The incidence of positive bone scans was low in
    patients with PSA lt 5 ng/mL or lt 20 ng/mL (in
    patients managed by watchful waiting) and in
    patients who have undergone radical prostatectomy
    or radiotherapy
  • Conclusions
  • In the absence of other clinical indicators, bone
    scans are not indicated when PSA level is lt 5
    ng/mL in patients who have undergone radical
    prostatectomy or radiotherapy, and lt 20 ng/mL in
    patients managed by watchful waiting

Chodak GW, et al. Presented at AUA 2005
Abstract 1003.
10
What are risk factors for bone metastases in
asymptomatic biochemically relapsed PC patients?
11
Natural History of Bone Metastasis Failing ADT
Insight From a Clinical Trial
  • Purpose
  • Randomized placebo-controlled trial to evaluate
    the effects of zoledronic acid on time to first
    bone metastasis in men with nonmetastatic
    prostate cancer
  • Trial was terminated early because of low event
    rate, and the placebo group was studied to
    describe the natural history of prostate cancer
  • Patients and Methods
  • Patients had nonmetastatic prostate cancer and
    castrate testosterone levels at study entry,
    documentation of PSA progression (3 serial
    increases), no radiographic evidence of bone
    metastases
  • Bone scans were obtained every 4 months

ADT Androgen-deprivation therapy PSA
Prostate-specific antigen. Smith MR, et al. J
Clin Oncol. 2005232918-2925.
12
Natural History of Rising Serum Prostate-Specific
Antigen in Men With Castrate Nonmetastatic PC
SD Standard deviation PSA Prostate-specific
antigen ADT Androgen-deprivation therapy.
Adapted with permission from Smith MR, et al. J
Clin Oncol. 2005232918-2925.
13
Two-Year Analysis of Bone Metastases and
Survival
  • At 2 years, 42 of patients had developed bone
    metastases or died
  • 33 of patients had developed 1 bone metastasis
  • 21 of patients had died
  • Median bone metastasis-free survival was 907 days

1.0
Death Bone metastasis Bone metastasis or death
0.8
0.6
Proportion of patients with an event
0.4
0.2
0
0.5
1.0
1.5
2.0
2.5
3.0
0
Years since random assignment
Adapted with permission from Smith MR, et al. J
Clin Oncol. 2005232918-2925.
14
High Baseline PSA Levels and PSA Velocity Are
Significant Risk Factors for Shorter Time to
First Bone Metastasis
P value
Univariate analysis
2.96
Baseline PSA gt 10 ng/mL
lt .001
1.47
High PSA velocity
lt .001
Multivariate analysis
3.18
Baseline PSA gt 10 ng/mL
lt .001
1.50
High PSA velocity
lt .001
0
1
2
3
4
5
6
7
For each log (ng/mL)/year increase in PSA
velocity. Data from Smith MR, et al. J Clin
Oncol. 2005232918-2925.
15
High Baseline PSA Levels and PSA Velocity Are
Significant Risk Factors for Shorter Bone
Metastasis-Free Survival
P value
Univariate analysis
2.95
Baseline PSA gt 10 ng/mL
lt .001
1.44
High PSA velocity
lt .001
1.62
Gleason score gt 7
.07
Multivariate analysis
3.19
Baseline PSA gt 10 ng/mL
lt .001
1.48
High PSA velocity
lt .001
0
1
2
3
4
5
6
7
For each log (ng/mL)/year increase in PSA
velocity. Data from Smith MR, et al. J Clin
Oncol. 2005232918-2925.
16
Higher PSA Levels and Shorter PSA Doubling Time
Are Associated With Shorter Metastasis-Free
Survival
PSADT PSA doubling time. Adapted with
permission from Smith MR, et al. J Clin Oncol.
2005232918-2925.
17
How can bone health be maintained in prostate
cancer patients?
  • Bone metastases
  • Bone mineral density

18
Patients With Prostate Cancer Have Many Factors
That Can Erode Bone Health
  • Bone health of men with prostate cancer is at
    risk throughoutthe disease course

Adapted with permission from Crawford ED. Eur
Urol. 20043(suppl.)10-15.
19
Patients With PC May Benefit From Early
Bisphosphonate Therapy
  • Patients with PC develop primarily osteoblastic
    lesions, but these lesions are associated with
    increased osteolytic activity and increased bone
    resorption
  • Bone metastases can lead to painful and
    debilitating SREs
  • Do patients with hormone-sensitive prostate
    cancer benefit from bisphosphonate therapy?

20
Early Bisphosphonate Treatment May Provide
Greater Clinical Benefit to Patients With HSPC
  • Patients with at least 1 bone metastasis from
    prostate cancer (N 308) received IV zoledronic
    acid 4 mg every 4 weeks for 15 months
  • In patients with HSPC, PSA lt 2 ng/mL, and no
    previous treatment with chemotherapy (n 29), 2
    (6.9) had at least 1 SRE on study

n
65/283
2/29
Wirth M, et al. Presented at ESMO 2006
Abstract 457P.
21
Prospective Data Are Needed to Determine the
Optimal Role of Bisphosphonates in Patients With
HSPC
  • CALGB-90202
  • Phase III randomized trial of zoledronic acid for
    the prevention of skeletal-related events in
    patients with prostate cancer and bone metastases
    undergoing ADT

22
How can bone health be maintained in prostate
cancer patients?
  • Bone metastases
  • Bone mineral density

23
ADT Decreases BMD1 and Increases Fracture Risk2
12-month analysis
P lt .001
ADT
Change from baseline,
Fracture incidence, patients
Lumbar spine
Total hip
ADT
Years
1. Mittan D, et al. J Clin Endocrinol Metab.
2002873656-3661 2. Daniell HW. J Urol.
1997157439-444.
24
Bisphosphonates May Provide Benefits to Patients
With HSPC by Preventing BMD Loss During ADT
1. Bruder JM, et al. J Clin Densitom.
20069431-437 2. Smith MR, et al. N Engl J Med.
2001345948-955 3. Casey R, et al. Presented
at European Association of Urology 2006
Abstract 136 4. Smith MR, et al. J Urol.
20031692008-2012.
25
Conclusions
  • PSA and AP levels correlate with risk for
    positive bone scans in patients with newly
    diagnosed or biochemically relapsing HSPC
  • Absolute PSA level and PSA doubling-time in
    non-metastatic HRPC can identify high-risk
    patients
  • Bisphosphonates may preserve bone health during
    ADT and in patients with metastatic HSPC
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