Wie ich mit Prostatakrebs umgehe Stephen B. Strum, MD, FACP Medical Oncologist Stuttgart, Germany 11.05.2009 Active Objectified Surveillance & Other Strategies Active Objectified Surveillance • • • • • • Patients with “insignificant” PC.
Download ReportTranscript Wie ich mit Prostatakrebs umgehe Stephen B. Strum, MD, FACP Medical Oncologist Stuttgart, Germany 11.05.2009 Active Objectified Surveillance & Other Strategies Active Objectified Surveillance • • • • • • Patients with “insignificant” PC.
Slide 1
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 2
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 3
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 4
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 5
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 6
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 7
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 8
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 9
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 10
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 11
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 12
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 13
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 14
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 15
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 16
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 17
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 18
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 19
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 20
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 21
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 22
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 23
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 24
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 25
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 26
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 27
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 28
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 29
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 30
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 31
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 32
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 33
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 34
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 2
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 3
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 4
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 5
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 6
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 7
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 8
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 9
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 10
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 11
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 12
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 13
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 14
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 15
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 16
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 17
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 18
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 19
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 20
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 21
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 22
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 23
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 24
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 25
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 26
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 27
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 28
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 29
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 30
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 31
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 32
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 33
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf
Slide 34
Wie ich mit Prostatakrebs umgehe
Stephen B. Strum, MD, FACP
Medical Oncologist
Stuttgart, Germany
11.05.2009
Active Objectified Surveillance & Other
Strategies
Active Objectified Surveillance
•
•
•
•
•
•
Patients with “insignificant” PC based on set
clinical & pathological criteria
Patients with significant age & co-morbidity
factors
Patients able to be monitored over time
Determine thresholds relating to treatment
intervention
Patients who are reclassified as higher risk
can be treated with cure
Reduce psychological stress of living with
untreated cancer
“Insignificant” Prostate Cancer
•
•
•
•
•
•
•
Gleason score 6 or less
PSA 10 or less
Clinical stage T2a or less
Free to total PSA percent > 15%
Less than 3 cores involved
50% or less of any one core with PC
PSA doubling time > 3 years
AOS (active objectified surveillance): Key Role of Status
7
Importance of Milieu in PC Behavior
A Key Ingredient in any Active Surveillance Strategy
Klotz L: Active surveillance with selective
delayed intervention is the way to manage
'good-risk' prostate cancer. Nat Clin Pract Urol
2:136-42; 2005.
Key Findings
1. Study begun in 1995 involving 299 patients
2. Median PSADT 7 yrs with 42% having DT > 10
yrs
3. At 8 yrs, overall actuarial survival 85% with PCspecific survival of 99%
Optimal ADT
(androgen deprivation therapy)
6 Ways to Optimize ADT
1) Block androgen access to the PC cell
2) Ensure significant lowering of Testosterone
3) Measure testosterone using accurate lab assay
4) Use US-PSA as biologic endpoint for ADT
5) Use measures that down-regulate (dR) sensitivity
of the androgen receptor (AR)
6) Block bone-derived growth factors that are
released due to excessive osteoclast activity
(induced by androgen deprivation)
15
16
Are We Using the Optima Dose of
Dutasteride ?
Dr. Mostaghel's group looked for gene changes in 75
men with localized PC. Twenty-five had RP alone, 26
were given neoadjuvant dutasteride at 0.5 mg, and the
remaining 24 received dutasteride, 3.5 mg orally per day
for 4 months prior to RP.
•
•
•
ADT is about Androgen
Availability
PC growth is mediated by
androgens.
•
We call it Androgen
Dependent PC (ADPC) or
Androgen Independent PC
(AIPC) or Castration
Resistant PC (CRPC) but
PC growth is androgen
related.
•
PC mets even synthesize
their own androgens.
Testosterone assays inaccurate at
low T levels: need to use
LC/MS/MS based assays.
•
•
Testosterone level (T) is a
key Biological End Point.
T not measured in 95% of
men with PC.
“Castration” threshold
should be < 20 ng/dl.
Further lowering of T may
enhance response.
Huggins won Nobel Prize 43
years ago showing PC dependence
on Androgens.
Lowest T level with impact on survival
was 32 ng/dl.
<20
Mean survival, free of developing AIPC,
in men with breakthrough increases in T >
32 ng/dl was 88 months (CI 55-121 mos).
20-50
Mean survival in men with T < 20 ng/dl
> 50
and no breakthrough increases > 32 ng/dl
was 137 mos (CI 104-170).
In men with breakthrough increases > 50
ng/dl, those men with maximal ADT had a
significantly longer survival free of AIPC.
•
Importance of US-PSA (ultrasensitive)
to Monitor ADT
PSA nadir > 0.05 highly correlated with shorter
time to progressive PC & prostate cancer-specific
survival.
The achievement of a PSA nadir of 0.05 or less was the
most significant endpoint insofar as time to progressive
PC and PC mortality.
Androgen Receptor (AR) Related
Dysfunction
•
(1) Reduce AR sensitivity
•
•
•
•
•
•
•
•
Prolactin Inhibitors
5AR inhibitors
•
(2) Avoid Drugs
Stimulating
“Promiscuous” AR
•
EGCG
HSP inhibitors
PPAR-G ligands
DIM & POMx
Silymarin
Melatonin
•
Avoid or use
cautiously standard
glucocorticoids such
as prednisone &
dexamethasone
Use triamcinolone
instead e.g. HDK
with triamcinolone
instead of
Hydrocortisone (HC)
Androgen Receptor (AR) Related Dysfunction
•
(3) Evaluate for ARM (androgen receptor mutation)–
see http://www.prostatecancer.org/education/andeprv/Strum_IADT.html
•
•
•
Withdraw anti-androgen, progestin, estrogen to see
if PSA or other marker is reduced.
If possible ARM due to Casodex need 6 weeks to
eliminate Casodex (bicalutamide) from body.
(4) Avoid agents that stimulate ARM
•
•
Steroidal anti-androgens such as CPA
(cyproterone acetate)
Progestins, in certain contexts.
•
•
•
•
•
•
Androgen Deprivation Therapy (ADT)
immediately induces bone resorption
Orchiectomy
LHRH agonists (Lupron, Zoladex)
LHRH antagonists (Plenaxis)
Anti-androgens, Ketoconazole, Estrogens
Androgen Receptor Antagonists
Clarke NW, McClure J, & George NJR: The effects of
orchidectomy on skeletal metabolism in metastatic prostate
cancer. Scand J Urol Nephrol 27: 475-483, 1993.
Testosterone Inhibits Osteoclast Formation
Lowering of Testosterone removes an
osteoclast inhibitor.
ADT (androgen deprivation therapy)
lowers Testosterone.
Increased osteoclast function leads to
net bone loss due to excessive
resorption.
Chen Q, Kaji H, Sugimoto T, et al:
Testosterone inhibits osteoclast formation
stimulated by parathyroid hormone
through androgen receptor. FEBS Lett
491:91-3, 2001.
Graphic per Strum, A Primer on PC
All of Biology is a Two Edged Sword
•
•
•
•
Part of optimizing ADT is recognition of the above
statement.
We need to start therapies to minimize the downsides of any treatment we use, including ADT.
A key focus should be to prevent osteoclast
activation with release of bone-derived growth
factors.
Agents like bisphoshonates & Denosumab should
be used early in the treatment of men with PC.
Monoclonal antibody to Receptor Activator of
Nuclear Kappa Ligand (RANKL) Stops Bone
Resorption & Decreases Skeletal-Related
Events Better then Aredia or Zometa.
27
When we decrease the
side-effects of any
treatment, we improve
the therapeutic index
(TI)
Treatment Benefits
Treatment Side Effects
= TI
http://www.prostatecancer.org/resource/pdf/Is21.pdf