Download Value and role of PSA as a tumor marker of response/relapse

Session 3
Advanced prostate cancer
Oct-14
VALUE AND ROLE OF
PSA AS A TUMOUR
MARKER OF
RESPONSE/RELAPSE
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PSA is a serine protease and
the physiological role is
believed to be liquefying the
seminal fluid
PSA are regulated by
androgens (testosterone and
dihydrotestosterone)
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Prostate-specific antigen (PSA) is one of the few
molecular markers routinely used for
detection
risk stratification
monitoring
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PSA is specific to the prostate but not to
prostate cancer:
benign prostate diseases cause increases in
serum PSA and most men with increased
PSA do not have prostate cancer.
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PSA strongly discriminates different cancer
stages:
 Higher in men with localized disease
than in cancer-free controls,
 Is associated with stage and grade in
localized disease and
 Is higher in patients with metastatic
compared with localized disease.
 Men with a higher PSA at the time of
initial therapy have increased risk of
recurrence.
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Screening
The introduction of PSA as a screening test has
led to:
•
increase in the incidence of prostate
cancer
•
shift to diagnosis at earlier stages
The effects of PSA screening
•
substantial ‘overdiagnosis’
on prostate cancer mortality
are not yet clear.
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Relapse in 20–30% after
primary treatment of localized
prostate cancer
Often detected by rise in serum
PSA
Routinely monitoring of PSA
recommended by AUA, EAU,
National Comprehensive
Cancer Network
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NCCN
guideline
EAU
guideline
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• PSA every 6 to 12
months for 5 years
• Thereafter anually
• 3,6 and 12 months,
then every 6 months
• From third year
anually
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Postoperative:
detectable PSA after
radical
prostatectomy
If low and stable,
the reason could be
benign prostate
tissue left behind by
surgery
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After radiotherapy:
PSA decreases slowly. The time
to reach PSA nadir can be
months to years after
treatment
Dependent on the size of the
prostate and the pre-treatment
PSA
Predictive value:
Low PSA nadir is associated
with freedom from biochemical
relapse
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Definition: relapse
• Prostate Guideline from American Urological
Association
– Biochemical relapse after radical prostatectomy,
serum PSA level >0.2 ng/ml
– with a second confirmatory level above 0.2 ng/ml
to define recurrence
– After radiotherapy: PSA level by 2 ng/ml above
the nadir
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PSA doubling time - PSADT
• Mostly used to monitor disease progression for
patients after
– Surgery
– Radiotherapy
– surveillance
• No standardisation of calculation
– What is the lowest PSA
– The number of PSA values used
– Duration between PSA measures
• Several calculation tools available online
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PSA doubling time
Metastatic free survival
after PSA recurrence
oLonger PSADT is associated with a decreased
likelihood of prostate cancer progression,
othe development of metastasis, and
oProstate cancer mortality
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Antonarakis
ES et al. 2 011 B J U I N T E R N A T I O N A L | 10 9 , 3 2 –14
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Rapid PSADT
after RP or • Strongly associated with
RT
• Increased risk of metastasis
• All-cause mortality
• Prostate cancer specific
mortality
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Short
PSADT
No Level I
evidence
• Influence the timing of
initiation of ADT
• No support of early ADT in patients
with curative local treatment
• Asymptomatic and only PSA rise
• Randomised trials needed: will
early ADT improve survival and
delay metastatic disease
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The effect of ADT on PSA
• PSA in blood almost always
decreases and then
stabilizes for varying
intervals
• Initial decrease in PSA due
to
• Tumour regression
• ADT suppress
transcription of the PSA
gene, which is androgen
dependent
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The effect of ADT on PSA
• Failure of ADT to produce a
reduction in PSA indicates:
• Failure to arrest growth
• No production of
cytotoxicity in the tumour
• Reactivation of the
androgen receptor despite
castrate levels of
testosterone
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Treatment
Starting androgen deprivation therapy – PSA threshold
Matched comparison at first PSA of > 0.4, 1 and > 2
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Siddiqui SA et al. J Urol 2008,179,1830-1837
Whether pretreatment PSA
predicts response
to ADT is unclear
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PSA nadir post-ADT associated with
oTime to androgen-independent progression
oClinical progression
oDeath
oPSA nadir less than 0.2 ng/ml have significantly
longer interval to androgen-independent
progression
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Observation until development of
metastatic disease an option in
patients with:
Gleason score < 7
PSA recurrence > 2 years after surgery
PSADT > 10 months
Median time to metastasis is 8 years
Median time from metastasis to death 5 years
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Treatment
variable clinical course leaves uncertainty about
how and
when to treat
• life expectancy
• comorbidities
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Treatment
Hormones
• Systemic failure following radical
prostatectomy is predicted with >80%
accuracy if:
– PSA relapse < 1 year
– PSADT of 4-6 months
– Gleason score 8-10
– Stage pT3b, pTxpN1
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PSA progression or PSADT is not considered
valid surrogate endpoint for drug approval
Is often an enrolment criterion for clinical
trials
A trigger for clinical decision making
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PSA response/progression in castration resistant
prostate cancer
Prostate
Cancer
Clinical •PCWG2
Trials
in 2007
Working
Group
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Scher
H et al.
J Clin Oncol 2008,26,1148-1159 25
Eligibility for trials
based on PSA changes
PSA progression
PCWG2 (2007)
Obtain sequence of rising values at
a minimum of 1-week intervals
Increase of 2.0 ng/mL
Estimate pretherapy PSA-DT if 3 or
more values available 4 or more
weeks apart
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Eligibility based on PSA changes
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Suggested Outcome Measures for Phase II Clinical Trials in Prostate
Cancer
PCWG2
Recognize that a favorable effect on PSA may be delayed for 12 weeks or more, even for a
cytotoxic drug. Monitor PSA by cycle but plan to continue through early rises for a minimum
of 12 weeks unless other evidence of progression. Ignore early rises (prior to 12 weeks) in
determining PSA response
For control/relieve/eliminate end points:
Record the percent change from baseline (rise or fall) at 12 weeks, and separately, the maximal change (rise
or fall) at any time using a waterfall plot
Progression:
Decline from baseline: record time from start of therapy to first PSA increase that is > 25% and > 2 ng/mL above the nadir,
and which is confirmed by a second value 3 or more weeks later (ie, a confirmed rising trend)† The requirement of an
increase of 5 ng/mL is decreased to 2 ng/mL, and the requirement for a 50% increase is reduced to 25%. Recording the
duration of PSA decline of little value. No decline from baseline: PSA progression > 25% and > 2 ng/mL after 12 weeks
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Suggested Outcome Measures for Phase II Clinical Trials in Prostate
Cancer
Recognize that a favorable effect on PSA may
be delayed for 12 weeks or more, even for a
cytotoxic drug. Monitor PSA by cycle but
plan to continue through early rises for a
minimum of 12 weeks unless other evidence
of progression. Ignore early rises (prior to 12
weeks) in determining PSA response
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Suggested Outcome Measures for Phase II Clinical Trials in Prostate
Cancer
Progression:
Decline from baseline: record time from start of
therapy to first PSA increase that is >25% and > 2
ng/mL above the nadir, and which is confirmed
by a second value 3 or more weeks later (ie, a
confirmed rising trend).
No decline from baseline: PSA progression > 25%
and > 2 ng/mL after 12 weeks
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Recommendations
Use of PSA for clinical decision making
• PSA should not be used in isolation to make
clinical decisions
• In patients with rising PSA after local therapy
– Other predictive markers:
– PSADT of < 9 months
– Gleason score 8-10
• Despite PSA increase, metastasis-free survival
can be very long
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Recommendations
Use of PSA for clinical decision making
• PSA measurements should be taken every
three months in patients receiving ADT
• A PSA of < 0.2 ng/ml is desirable
• If low levels of PSA is not obtained – check
serum testosterone
• Bone scan should be done to monitor clinical
progression
• Important to be aware of how different
therapies affect PSA
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