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Session 3 Advanced prostate cancer May-15 VALUE AND ROLE OF PSA AS A TUMOUR MARKER OF RESPONSE/RELAPSE ESMO preceptorship 1 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) May-15 ESMO preceptorship 2 Prostate-specific antigen (PSA) is one of the few molecular markers routinely used for detection risk stratification monitoring May-15 ESMO preceptorship 3 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. May-15 ESMO preceptorship 4 May-15 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. ESMO preceptorship 5 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. May-15 ESMO preceptorship 6 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 May-15 ESMO preceptorship 7 NCCN guideline EAU guideline May-15 • PSA every 6 to 12 months for 5 years • Thereafter anually • 3,6 and 12 months, then every 6 months • From third year anually ESMO preceptorship 8 Postoperative: detectable PSA after radical prostatectomy If low and stable, the reason could be benign prostate tissue left behind by surgery May-15 ESMO preceptorship 9 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 May-15 ESMO preceptorship 10 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 May-15 ESMO preceptorship 11 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 May-15 ESMO preceptorship 12 May-15 ESMO preceptorship 13 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 May-15 ESMO preceptorship 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 39 Rapid PSADT after RP or • Strongly associated with RT • Increased risk of metastasis • All-cause mortality • Prostate cancer specific mortality May-15 ESMO preceptorship 15 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 May-15 ESMO preceptorship 16 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 May-15 ESMO preceptorship 17 Treatment Starting androgen deprivation therapy – PSA threshold For patients with systemic disease: • Goal is delaying progression, reducing morbidity and mortality • Start early before clinical development of metastases or after? May-15 ESMO preceptorship 18 Treatment Starting androgen deprivation therapy – PSA threshold Siddiqui SA et al. J Urol 2008,179,1830-1837 Matched comparison at first PSA of > 0.4, 1 and > 2 May-15 ESMO preceptorship 19 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 May-15 ESMO preceptorship 20 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 May-15 ESMO preceptorship 21 Treatment variable clinical course leaves uncertainty about how and when to treat • life expectancy • comorbidities May-15 ESMO preceptorship 22 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 May-15 ESMO preceptorship 23 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 May-15 ESMO preceptorship 24 PSA response/progression in castration resistant prostate cancer Prostate Cancer Clinical •PCWG2 Trials in 2007 Working Group May-15 ESMO preceptorship 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 May-15 ESMO preceptorship 26 Eligibility based on PSA changes May-15 ESMO preceptorship 27 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 May-15 ESMO preceptorship 28 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 May-15 ESMO preceptorship 29 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 May-15 ESMO preceptorship 30 May-15 ESMO preceptorship 31 May-15 ESMO preceptorship 32 Recommendations Use of PSA for clinical decision making • PSA should not be used in isolation to make clinical decisions May-15 ESMO preceptorship 33 Initiating imaging in asymptomatic patients on ADT and no known metastases, if treatment is planned in case of M1 disease – St Gallen 2015 Initiate imaging PSA-DT 60 50 40 30 20 10 0 May-15 Initiate imaging 80 70 60 50 40 30 20 10 0 ESMO preceptorship PSA-DT 34 Recommendations Use of PSA for clinical decision making • At least two out of three criteria (PSA progression, radiographic progression, and clinical deterioration), should be fulfilled to stop treatment – 82% • If low levels of PSA is not obtained – check serum testosterone • Important to be aware of how different therapies affect PSA May-15 ESMO preceptorship 35 May-15 ESMO preceptorship 36 May-15 ESMO preceptorship 37