Download Coping with rising PSA post

Secret men’s business...
coping with a rising PSA after
treatment for prostate cancer
Martin Stockler
University of Sydney
Sydney Cancer Centre, RPA and Concord Hospitals
Oncology Trials Group, NHMRC Clinical Trials Centre
Cancer Trials NSW, The Cancer Council NSW
Coping with rising PSA
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What is a rising PSA?
What does it mean?
What can we do about it?
What should we do about it?
What’s next?
What does a rising PSA
mean after treatment?
• After surgery
– all of the prostate & cancer should be gone and
there should be no PSA in the blood soon after surgery
• After radiation
– some normal prostate tissue remains,
PSA should fall to low levels for some time
• After any treatment, a rising PSA means that
– there are cells in the body making PSA
– there are areas of prostate cancer to small to find
– the prostate cancer cells are no longer being controlled
Hormone therapy in advanced prostate cancer
• Testosterone makes prostate cancer grow
• Blocking testosterone 
–  tumour size, PSA & symptoms (>80%)
– often works for several years
• How to block testosterone
– reduce production
• Remove testicles – orchidectomy
• LHRH agonists – zoladex, lucrin
– block effects (anti-androgens)
• Cyproterone – androcur
• ~utamides – eulexin, cosudex, anandron
– do both
• maximal androgen blockade
Side effects of hormone therapy
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Inability to get erections (impotence)
Inability to hold urine (incontinence)
Loss of sexual desire (libido)
Hot flashes
Enlarged breasts (gynecomastia)
Weaker bones (osteoporosis)
Immediate versus delayed endocrine therapy for
advanced prostate cancer. Br J Urol 1997; 79: 235.
• N=938, locally advanced or asympt metastatic
• immediate orchiX or LHRHA vs deferred till indicated
Path Fractures
Def Imm
(465) (469)
21
11
2p
Cord Compression
23
9
.03
Ureteric Obstruction
55
33
.03
Prostate Deaths
257
203 .001
All Deaths
361
328
.01
When to start hormone therapy?
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Symptomatic Advanced Disease
Asymptomatic Advanced Disease
Rising PSA after local treatment
After local treatment – adjuvant
Before local treatment – neoadjuvant
Who could tell and
who could feel better?
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PSA
Scans
Physical
Symptoms
Biochemist
Biochemist & radiologist
Biochemist, radiologist &clinican
Biochemist, radiologist, clinican & patient
Natural history of progression with
a rising PSA after radical prostatectomy
Pound et al. JAMA 1999; 281: 1591.
• 1997 men who had Radical Prostatectomy
from 1982-97 with a single surgeon
• no adjuvant therapy
• no treatment for PSA relapse alone
• endocrine therapy for clinical recurrence
• median follow-up = 5y, range = 0.5-15y
Natural history of progression with a
rising PSA after radical prostatectomy
Pound et al. JAMA 1999; 281: 1591.
• PSA Rise in 315 / 1997 (15%)
• Metastases detected in 103 / 304 (34%)
of those with untreated PSA relapse
• median time from PSA Rise to Metastates = 8y
• median survival from metastases = 5y
• predictors of time from PSA relapse to Mets:
time to and rate of PSA rise, Gleason score
• predictor of survival from Metastases:
time from surgery to Metastases
Natural history of progression with a rising PSA
after radical prostatectomy – Metastasis-free survival
Pound et al. JAMA 1999; 281: 1591.
Current twists on hormone therapy
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Maximum androgen blockade
Intermittent androgen blockade
High dose anti-androgens
Depot injections
Anti-androgen withdrawal
Hormone-refractory disease
Maximum androgen blockade in
advanced prostate cancer
Lancet 2000; 355: 1491
27 randomised trials
8,275 men
5,932 deaths (80% cancer)
98% ever randomised
88% metastatic
12% locally advanced
Maximum Androgen Blockade in
advanced prostate cancer Lancet 2000; 355: 1491
Management of advanced
hormone resistant disease
• Waiting for symptoms
• Good symptomatic treatment
– co-analgesics, opioids, laxatives, &c
• ~utamide withdrawal responses
• radiation for localised symptoms
• chemotherapy for symptoms
not controlled by simpler measures
• strontium for widespread bone symptoms
Mitoxantrone for advanced prostate cancer
Tannock IF, Osoba D, Stockler M et al. J Clin Oncol 1996; 14: 1756
Sustained, substantial  pain
with
no  analgesics
Mitoxantrone
23 / 80
=
29%
No mitoxantrone
10 / 81
=
12%
2p
=
.01
Survival 2p
=
0.8
International randomised trial of
Taxotere vs Mitoxantrone in
Advanced Prostate Cancer
R
Advanced
A
hormone
N
resistant
D
prostate
O
cancer
M
N=800
I
(33%  Sm) S
E
Mitoxantrone 3 weekly
+ pred
Docetaxel 3 weekly
+ pred
Docetaxel 1 weekly
+ pred
Overall Survival
Time to Progression
Pain
PSA
QOL
Tumour response
Safety
PK
Tax 327
Docetaxel q3w 
better survival
pain
quality of life
PSA response rates
Bisphosphonates for bone metastases
Bloomfield DJ. J Clin Oncol 1998; 16:1218.
• inhibits bone resorption provoked by metastases
– skeletal events: destruction, deformity, path #
– pain
• reduction in skeletal events and pain
– multiple myeloma - 2/3 randomised trials
– breast cancer - 4/5 randomised trials
• reduction in pain
– mixed cancers - 2/3 randomised trials
• pamidronate and clodronate work
• etidronate doesn't work
International placebo-controlled trial of
Zoledronate in hormone resistant prostate cancer
with bone metastases – JNCI 2002; 1954: 1458
hormone
resistant
prostate cancer
>2 bone mets
N=643
(16%
bone mets or †)
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R
A
N
D
O
M
I
S
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Zoledronate 8mg q3w
Zoledronate 4mg q3w
Placebo q4w
Any Skeletal Event
39%
Skeletal events
Disease progression
Objective response
Biochemical markers
Quality of life
33%
44%
Modest reduction in skeletal event rates
Moderate side effects, regular infusions
Reasonable for high risk or failed other treatments
Can not yet be recommended as standard therapy
International placebo-controlled randomised trial of
Zoledronate in hormone resistant prostate cancer
without bone metastases
hormone
resistant
prostate cancer
no bone mets
N=500
(30%
bone mets or †)
R
A
N
D
O
M
I
S
E
Zoledronate q4w
Placebo q4w
Bone-met-free survival
Skeletal events
QOL
Overall survival
Bone mineral density
Strontium in advanced prostate cancer
with painful bone metastases
Quilty. Radiother Oncol 1994; 31: 33.
Porter. IJROBP 1993; 25: 805.
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• N=126
• external beam +/- Sr
• placebo controlled
N=284
external beam Vs Sr
open label
sustained improvement
in 66%
• less new pains with Sr
• No difference in survival
• less new pains with Sr
• No difference in survival
Prostate cancer - key points
• Slow natural history
– People often stay well for a long time without treatment
– side effects and other health problems are important
• Aim: be as well as possible for as long as possible
• Watching and waiting is often the best approach
– Reserve treatment for problems
– Treat problems on their merits
– PSA is a tool, not the point
• Treatments work
– Blocking hormones, radiation, chemotherapy,
bisphosphonates, other supportive treatments
– But have side effects and are inconvenience
• Ensure they do more good than harm
Questions for research
•Which cancers need to be treated?
•When is it best to treat them?
•How to best use and combine treatments?
Anti-cancer treatments
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Endothelin A
Aflibercept
Satraplatin
Cabazitaxel
Lenalidomide
Vaccines
Other new targets
Supportive treatments
– Zoledronate
– Denosumab
Hormonal therapies
– Abiraterone
– MDV3100