value and role of psa as a tumor marker of response/relapse · oct-14 esmo preceptorship 3...
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VALUE AND ROLE OF PSA AS A TUMOUR MARKER OF RESPONSE/RELAPSE
Session 3
Advanced prostate cancer
Oct-14 1ESMO preceptorship
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)
Oct-14 2ESMO preceptorship
Oct-14 ESMO preceptorship 3
monitoring
risk stratification
detection
Prostate-specific antigen (PSA) is one of the few molecular markers routinely used for
Oct-14 ESMO preceptorship 4
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.
The introduction of PSA as a screening test has led to:
• increase in the incidence of prostate cancer
• shift to diagnosis at earlier stages
• substantial ‘overdiagnosis’
Screening
Oct-14 6ESMO preceptorship
The effects of PSA screening on prostate cancer mortality
are not yet clear.
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
Oct-14 7ESMO preceptorship
• PSA every 6 to 12 months for 5 years
• Thereafter anuallyNCCN
guideline
• 3,6 and 12 months, then every 6 months
• From third year anually
EAU guideline
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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
Oct-14 10ESMO preceptorship
• 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
Definition: relapse
Oct-14 11ESMO preceptorship
• 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
PSA doubling time - PSADT
Oct-14 12ESMO preceptorship
PSA doubling time
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 – 3 9
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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• Strongly associated withRapid PSADT after RP or
RT
• Increased risk of metastasis
• All-cause mortality
• Prostate cancer specific mortality
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• Influence the timing of initiation of ADT
Short PSADT
• No support of early ADT in patients with curative local treatment
• Asymptomatic and only PSA rise
No Level I evidence
• Randomised trials needed: will early ADT improve survival and delay metastatic disease
Oct-14 16ESMO preceptorship
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
Oct-14 17ESMO preceptorship
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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TreatmentStarting androgen deprivation therapy – PSA threshold
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Matched comparison at first PSA of > 0.4, 1 and > 2
Oct-14 19ESMO preceptorship
Whether pre-treatment PSA
predicts response to ADT is unclear
PSA nadir post-ADT associated withoTime to androgen-independent progressionoClinical progressionoDeathoPSA nadir less than 0.2 ng/ml have significantly longer interval to androgen-independent progression
Oct-14 20ESMO preceptorship
Observation until development of metastatic disease an option in patients with:
Gleason score < 7PSA recurrence > 2 years after surgeryPSADT > 10 months
Median time to metastasis is 8 yearsMedian time from metastasis to death 5 years
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• life expectancy
• comorbidities
Treatment
variable clinical course leaves uncertainty about how and
when to treat
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• 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
TreatmentHormones
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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
•PCWG2 in 2007
Prostate Cancer Clinical Trials
Working Group
Scher H et al. J Clin Oncol 2008,26,1148-1159Oct-14 25ESMO preceptorship
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
Eligibility for trials based on PSA changesPSA progressionPCWG2 (2007)
Oct-14 26ESMO preceptorship
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
Suggested Outcome Measures for Phase II Clinical Trials in Prostate CancerPCWG2
Oct-14 28ESMO preceptorship
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
Suggested Outcome Measures for Phase II Clinical Trials in Prostate Cancer
Oct-14 29ESMO preceptorship
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
Suggested Outcome Measures for Phase II Clinical Trials in Prostate Cancer
Oct-14 30ESMO preceptorship
• 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
RecommendationsUse of PSA for clinical decision making
Oct-14 33ESMO preceptorship
• 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
RecommendationsUse of PSA for clinical decision making
Oct-14 34ESMO preceptorship