Value and role of PSA as a tumor marker of response/relapse · Oct-14 ESMO preceptorship 3 monitoring risk stratification detection Prostate-specific antigen (PSA) is one of the few

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 ESMO preceptorship 3

monitoring

risk stratification

detection

Prostate-specific antigen (PSA) is one of the few molecular markers routinely used for


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.


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


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


• 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


Postoperative:

detectable PSA after radical

prostatectomy

If low and stable, the reason could be

benign prostate tissue left behind by

surgery


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


• 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


• 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



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


• Strongly associated withRapid PSADT after RP or

RT

• Increased risk of metastasis

• All-cause mortality

• Prostate cancer specific mortality


• 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


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


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


TreatmentStarting androgen deprivation therapy – PSA threshold

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Matched comparison at first PSA of > 0.4, 1 and > 2


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


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


• life expectancy

• comorbidities

Treatment

variable clinical course leaves uncertainty about how and

when to treat


• 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


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


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)


Eligibility based on PSA changes


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


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


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




• 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


• 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



Documents

Value and role of PSA as a tumor marker of response/relapse · Oct-14 ESMO preceptorship 3 monitoring risk stratification detection Prostate-specific antigen (PSA) is one of the few