Treating PSA Recurrence

1
Treating PSA Recurrence

• Freddie C. Hamdy
• Academic Urology Unit
• University of Sheffield, UK

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PSA Rise An Ugly Woman?
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PSA Rise in Prostate Cancer

• Men receiving active monitoring
• Men treated with radical prostatectomy
• Men treated with radiotherapy
• Men treated with brachytherapy
• Men treated with androgen suppression

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PSA and Active Monitoring
PSA
PSA
7
16.0
14.0
6
12.0
5
10.0
4
PSA Readings
8.0
PSA Readings
PSA
3
6.0
4.0
2
2.0
1
0.0
0
100
200
300
400
500
0
0
200
400
600
800
1000
Time, days
Time, days
PSA
8.0
7.0
6.0
5.0
4.0
PSA Readings
3.0
2.0
1.0
0.0
0
100
200
300
400
500
Time, days
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PSA in Active Monitoring

• 1095 patients with localised prostate cancer from
  St Louis, USA
• Screened with repeat PSA between 1989 and 2002
• Median follow-up gt 5 years
• Median PSA at diagnosis 4.3ng/ml
• PSA velocity measured before diagnosis
• Treatment outcome analysed after radical
  prostatectomy

DAmico et al, NEJM 2004
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PSA velocity before treatment and survival after
radical prostatectomy
DAmico et al, NEJM 2004
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PSA in Active Monitoring

• Conclusion
• Men whose PSA level increases by more than 2.0
  ng/ml during the year before the diagnosis of
  prostate cancer may have a relatively high risk
  of death from prostate cancer despite undergoing
  radical prostatectomy

DAmico et al, NEJM 2004
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PSA Rise After RP

• Questions
• Local or distant recurrence?
• Timing to PSA rise
• PSA doubling time
• Histopathological criteria
• Immediate or deferred treatment?
• ? Salvage radiotherapy?
• ? Androgen suppression?

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PSA Rise After Radical Prostatectomy

• Poor apical dissection and residual benign
  prostate tissue will lead to a detectable PSA
• Hypersensitive PSA assays allow detection of
  biochemical progression at a very early stage
• 0.2 ng/ml reasonable threshold
• Slow rise of PSA after radical surgery leads to
  clinical recurrences as late as 9 years after the
  first rise
• It is important to stratify the patients into
  potential for local recurrence or systemic
  disease
• PSA rise within 1-2 years after surgery systemic
  disease
• PSA rise after 2 years local recurrence

Pound et al, 1997 Partin et al, 1994 Pound et
al, 1999 Freedland et al, 2003 Witherspoon et
al, 1997 Haese et al, 1999
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PSA Rise After Radical Radiotherapy

• The radiotherapist does not remove the prostate !
• BPH and benign prostatic epithelium contribute to
  PSA values
• Positive biopsies are not interpretable
• ASTRO guidelines 3 consecutives rises of PSA (at
  3-6-month intervals) ? Or 2ng/ml
• No level of PSA is an appropriate surrogate to
  trigger additional treatment interventions

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Rising PSA after RP Further investigations

• Bone scan - Of no use if PSA
• is lt40 ng/ml
• Cher et al. 1998 J Urol 160 1387
• CT scan - Of no value if PSA is lt10 ng/ml and
  only in very rapidly increasing PSA
• Johnstone et al. 1997 Urol Oncol 3 108

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Rising PSA After RP Further Investigations ?

• TRUS and Biopsy
• If suspicion of local recurrence AND
• If treatment decision is affected
• More than one set of biopsies is often needed
• Connolly et al. Urology 1996 47 225
• BUT...
• A positive biopsy does not affect the outcome
  after radiotherapy
• Koppie et al. J Urol 2001 166 111

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PSA After Radical Prostatectomy or Radical
Radiotherapy

• 1136 patients with localised prostate cancer from
  Connecticut registry
• Period 1990-1992
• Treated with surgery or radiation androgen
  ablation
• Analysed for death from prostate cancer
• Significant reduction in disease-specific
  survival if PSA DT is lt 12 months

Albertsen et al, J Urol 2004
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PSA After Radical Prostatectomy or Radiation
Therapy

• Patients whose post-treatment PSA doubling time
  before the initiation of androgen withdrawal
  therapy is less than 1 year are at HIGH RISK of
  dying of prostate cancer within 10 years of
  diagnosis
• Men with PSA recurrences that are doubling at
  rates greater than 1 year are at LOW RISK of
  death from prostate cancer within 10 years of
  diagnosis

Albertsen et al, J Urol 2004
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Salvage RP After Failed RT
Bianco et al, 2005
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PSA Kinetics and Failure After RP/RT
DAmico et al, 2004 Zagars Pollack 1997
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Salvage RT After Failed RP
Stephenson et al, JAMA 2004
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Proposed Algorithm for the Use of HM on PSA
Failure After RT
PSA failure
PSA DT ? 12 months
PSA DT ? 12 months
PSA nadir ? 1.5
PSA nadir lt 1.5
Gleason 7-10
Gleason 2-6
Gleason 2-6
Gleason 7-10
Immediate HM
Consider observation
HM
Consider HM
Observation
Cannon et al, Urology 2003
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PSA Rise After Treatment - Summary

• For patients on Active Monitoring, PSA velocity
  appears helpful in determining risk factor of
  dying from prostate cancer
• For patients receiving radical treatment PSA
  doubling time of lt 12 months is a poor prognostic
  indicator of disease-specific and all cause
  mortality, as well as histopathological criteria
  such as seminal vesicle invasion
• Fast rise of PSA after radical treatment is
  likely to be associated with systemic disease
• Delayed rise of PSA after radical treatment is
  associated with local disease recurrence
• Treat the patient, not his PSA !

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PSA After Androgen Ablation

• Should come down to very low levels if
• Majority of prostate cell are androgen sensitive
• Adequate castrate levels of testosterone are
  reached
• The tumour is a PSA producer
• Rise of PSA after hormonal treatment
• Usually signifies hormonal escape
• Typically occurs within 2-3 years from starting
  therapy
• Can take a long time to reach clinical
  significance28

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Hormonal Escape Secondary Therapy

• Adding an anti-androgen to castration?
• Response in 20-40 of patients
• Kucuk Urology 5853-58, 2001
• Increasing the dose of anti-androgens in maximum
  androgen blockade?
• No clinical studies
• Adding castration to anti-androgen monotherapy?
• About 50 response
• Boccardo et al ASCO abstract 2002

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Secondary Hormonal Therapy

• AA withdrawal
• Shown for all anti-androgens (flutamide,
  nilutamide, bicalutamide, cpa)
• Response seen within 4-8 weeks
• Response rate about 30

Scher et al Urology 4761-69, 1996
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Hormone Resistant Prostate Cancer Management

• Further hormonal manipulations
• Steroids
• Bisphosphonates
• Radionuclide treatment
• Chemotherapy
• Other palliative options
• Convert a previously debilitating condition into
  a chronic, manageable disease with improved
  quality of life irrespective of PSA.