Prostate 20Cancer 20Post Prostatectomy by O0i1oX


									Management of Prostate Cancer
      Ajita Narayan, MD, PhD
       Lafayette Cancer Care
  To paraphrase Benjamin Disraeli

“Lies, more lies and then there is statistics…….”
           In prostate cancer

“Controversy, more controversy and then there
  are statistics…”
Relative power struggle!!
                                         Statistics (cancer)
       • A total of 1,529,560 new cancer cases and
         569,490 deaths from cancer are projected to
         occur in the United States in 2010.

Jemal, A., Siegel, R., Xu, J., Ward, E., CA Cancer J Clin 2010;60;277-300; Cancer Statistics, 2010
               New cases & Death rates 2010

Jemal, A., Siegel, R., Xu, J., Ward, E., CA Cancer J Clin 2010;60;277-300; Cancer Statistics, 2010
• It is generally accepted that the increase in
  number of newly diagnosed prostate cancers
  in US men has resulted from PSA screening
  that detected many early-stage prostate
• Example: percentage of low risk disease has
  increased from 29.8% (1989-92) to 45.3%
  (1999-2001); p<0.001
• The comparatively low death rate suggests that
  unless prostate cancer itself is becoming
  biologically less aggressive, increased public
  awareness with earlier detection and treatment
  has begun to affect mortality from this prevalent
The “Manogram”
 Since we do not have one of those…..
• Prostate ca often diagnosed while asymptomatic
  with a PSA. However, screening with serum PSA is
• Either by digital rectal examination (DRE) or due
  to genitourinary symptoms:
• On DRE, asymmetric areas of induration or frank
  nodules are suggestive of prostate cancer
• Urinary urgency, nocturia, frequency, and
  hesitancy are usually limited to patients with
  relatively advanced prostate cancer.
Pretreatment risk stratification for
         prostate cancer
          Serum PSA elevation
• PSA is a prostate-specific marker, and elevations
  can be caused by either prostate cancer or
  benign conditions such as BPH.
• Measure BEFORE biopsy
• There is significant overlap in the serum PSA
  values that accompany prostate cancer and BPH,
  but the likelihood of finding cancer on a prostate
  biopsy increases with higher PSA values
• Normal intra-individual and intra-assay
  fluctuations in serum PSA
       Gleason grade and score
• The pathologist assigns a grade to the most
  common tumor pattern, and a second grade
  to the next most common tumor pattern. The
  two grades are added together to get a
  Gleason score.
• For example, if the most common tumor
  pattern was grade 3, and the next most
  common tumor pattern was grade 4, the
  Gleason score would be 3+4 = 7.
              Gleason Score
• The Gleason grade ranges from 1 to 5, with 5
  having the worst prognosis.
• The Gleason score ranges from 2 to 10, with
  10 having the worst prognosis.
• For Gleason score 7, a Gleason 4+3 is a more
  aggressive cancer than a Gleason 3+4.
    Estimates of Life Expectancy
• Key determinant in treatment decision-making
• Difficult to extrapolate the rates of life
  expectancy when calculated for groups of
  men, to an individual patient
• Minnesota Metropolitan Life Insurance Tables
  or Social Security Administration Life
  Insurance Table-examples of tables used to
  calculate life expectancy
• Should be modified by overall health
          Why does it matter?
• Rx recommendations could change drastically
  if referring to prostate cancer in a young man
  in poor health or an older man in excellent
       • Normograms can be used to inform treatment
         decision-making for men contemplating active
         surveillance, RP, neurovascular bundle
         preservation, or omission of PLND during RP,
         brachytherapy or EBRT.
       • Biochemical PFS can be reassessed post-
         operatively using age, diagnostic serum PSA
         and pathologic grade and stage.

Kattan, M, Eastham J et al, J Urol 2003 170 (5) 1792-7; Stephenson, A, Scardino P et al., J Natl Cancer Inst 2006 98 (10) 715-717; Graefen, M et
al., J Urol 2001 165: 857-863; Ohori M et al., J Urol 2004 171: 1844-1849
               Partin Tables
• Originally developed by urologists Alan W.
  Partin, M.D., Ph.D., and Patrick C. Walsh, M.D.
• Tables combine clinical stage, Gleason grade,
  preop PSA level to predict pathologic stage:
1. Organ confined
2. Extracapsular (extraprostatic) extension
3. Seminal Vesicle invasion
4. Lymph node mets
                 Treatment options
                   T1/T2 disease
• The standard approaches for men with organ-confined
  T1/T2 prostate cancer are
   –   radical prostatectomy (RP)
   –   external beam radiation therapy (EBRT),
   –   brachytherapy, and
   –   active surveillance

  For patients receiving definitive treatment for T1/T2
  prostate cancer, the choice of therapy is largely a matter
  of patient preference. There is no evidence that the cure
  rate is different with RP, EBRT, or brachytherapy when
  patients are stratified based upon prognostic
    Intermediate- or high-risk T1/T2
           prostate cancer
• For these patients definitive treatment rather
  than active surveillance
• Intermediate-risk disease- EBRT, brachytherapy,
  or RP
• High-risk disease- ADT plus EBRT or RP plus
  adjuvant EBRT
    Advantages of main treatment for
       early prostate cancer: EBRT
• Effective long term control with high dose Rx
• Low risk of urinary incontinence
• Wide range of ages
• When combined with hormonal therapy,
  offers a chance of cure in high-risk of disease
• Treatments can eradicate extension of tumor
  beyond the margins of prostate
  Advantages of main treatment for
 early prostate cancer: Brachytherapy
• Cancer control rate equal to surgery and EBRT
  for organ-confined tumor
• Quicker than EBRT (one treatment)
• Available for cure in a wide range of ages and
  in those with comorbidities
Advantages of main treatment for early
prostate cancer: Radical Prostatectomy
• Effective long-term cancer control
• Prediction of prognosis can be more precise
  based on pathologic features in specimen
• Pelvic lymph node dissection is possible
  through the same incision
• PSA failure easy to predict
 Advantages of main treatment for early
  prostate cancer: Active Observation
• Reduces overtreatment
• Avoids or postpones treatment-associated
• Has no effect on work or social activities
 Contraindications to main treatment
   options for early prostate cancer
• RP: High operative risk, ‘medical age’ of 70 or
  more, neurogenic bladder, morbid fear of
• Active observation: High grade tumors, pt
  preference, expected survival of 10 or more
               Other Approaches

• Include various forms of ablation therapy and
  systemic hormonal therapy rather than
  therapy directly to the prostate:
  – Ablation therapy:
     • Cryotherapy and high-intensity focused ultrasound
       (HIFU) have been used to destroy tissue, either by
       freezing or by generating local thermal energy. These
       ablation techniques can be applied focally, subtotally,
       or to the entire prostate gland
      Primary hormone therapy
• Has been used in patients seeking active
  therapy but wishing to avoid the side effects
  of RP or RT.
• The available evidence suggests that this
  approach does NOT have a role in patients
  with clinically localized disease.
       Benefit of early treatment
• Detection of early asymptomatic recurrence following
  treatment for localized prostate cancer is useful only if
  it decreases morbidity or mortality. While data directly
  addressing this issue are lacking, there is some indirect
  evidence that early detection and treatment of a
  recurrence can improve outcomes.
• Potential benefits and secondary treatment options are
  dictated by whether recurrence is systemic or local,
  and whether the initial treatment was surgery or
  radiation (EBRT or brachytherapy).
      Post prostatecomy options
• Post prostatectomy treatment options varies with
  the individual patient and needs to be done in a
  multidisciplinary setting i.e. Medical Oncologist,
  Radiation Oncologist, Urologist

Options include
• Post op Surveillance
• Radiation therapy
• Hormonal therapy
• Chemotherapy
Follow-up surveillance after treatment
         for prostate cancer
• No widely accepted, evidence-based
  guidelines that define optimal surveillance for
  men who have been treated for localized
  prostate cancer
• Potential benefits and secondary treatment
  options are dictated by whether recurrence is
  systemic or local, and whether the initial
  treatment was surgery or radiation (EBRT or
Digital Rectal Exam
The lion’s DRE

 No fuss, no complaints……..
        If there is recurrence…..
• The majority of recurrences following RP or RT for
  localized prostate cancer are asymptomatic
• Digital rectal examination (DRE)
• Serum PSA is the mainstay of surveillance testing
  in men who have undergone therapy for localized
  prostate cancer
• While the use of PSA for cancer screening is
  controversial, it is an excellent tumor marker in
  men with an established diagnosis of prostate
    Definition of PSA recurrence
• Depends upon the initial treatment
• All prostate tissue is removed during a
  successful RP. Thus, any detectable PSA in the
  serum using the standard immunoassay
  (typical limit of detection is 0.05 ng/ml)
  theoretically indicates remaining prostate
  tissue, and presumably represents persistent
  or recurrent disease
    Definition of PSA recurrence
• Biochemical failure following RT is more
  complicated, since there is benign tissue
  remaining after RT
• ASTRO (American society for radiation
  oncology) guidelines on PSA recurrence were
  revised in 2005 (Phoenix Criteria)
             Phoenix criteria
• PSA rise by ≥2 ng/mL above the nadir PSA is
  considered the standard definition for
  biochemical failure after external beam RT,
  regardless of whether or not a patient
  receives androgen deprivation therapy.
• The date of failure is defined by the time the
  rise in PSA is noted
                PSA bounce
• Serum PSA levels typically fall after RT and can
  then rise ("bounce") transiently, at a median
  of 12 to 18 months after treatment.
• Can occur in the absence of recurrent disease
  and does not necessarily constitute an
  indication for therapeutic intervention.
American Urological Association Best Practice
 Policy regarding the use of PSA in the post
 treatment management of prostate cancer
Follow-up strategy after radical prostatectomy
     based on pathologic grade and stage

• All men: post-prostatectomy baseline PSA at 3
             months, then as follows:
• Bone scan remains a sensitive and reliable
  test for detecting the presence of skeletal
  metastases: But role for early detection of
  asymptomatic recurrence has been largely
  supplanted by serial PSA testing
• No role for transrectal ultrasound (TRUS) of
  the prostate or prostatic fossa as a screening
  test for recurrence of localized prostate cancer
• Routine pelvic CT scans are not indicated
  because of the limited sensitivity of CT to
  detect low volume recurrent disease
• The ProstaScint scan is a radiolabeled monoclonal
  antibody imaging test that is approved in the
  United States as an aid to determining the site of
  recurrence (local versus distant) in men with a
  PSA-only recurrence after RP
• National Comprehensive Cancer Network (NCCN)
  recommend PSA testing every 6 mths for the first
  5 years, then annual testing thereafter. The NCCN
  also recommends annual DRE.
Adjuvant RT vs. Postop surveillance
• Adj RT decreases the risk of biochemical relapse,
  but it requires administering RT to some patients
  who would otherwise never require treatment.
• Postoperative surveillance without treatment
  followed by salvage RT at the first evidence of a
  rising serum PSA entails the risk that distant
  metastases might develop in some men who
  would have been rendered disease-free with
  immediate adjuvant treatment
                 Adjuvant RT
• Extended follow-up from large clinical trials
  provides evidence that adjuvant RT
  – is well tolerated
  – it improves the biochemical and local control rates
    in men who are found to have pT3 disease or
    diffusely positive resection margins at RP
  – improves metastasis-free and overall survival
       • No randomized trials specifically comparing early
         adjuvant RT (ART) compared to Salvage RT (SRT)
       • 2 published randomized series comparing ART
         with no ART (various delayed therapies including
         SRT were employed in the latter group).
       • EORTC study 229111 and the SWOG study 8794
         (including NCIC [National Cancer Institute of
         Canada] PR-2), with 1005 and 410 patients,

Bolla M, et al. Lancet 2005; 366:572-4; Thompson IM, et al., JAMA 2006;296:2329-35.
               Adjuvant RT: EORTC trial 22911
       • Randomly assigned 1005 men with pT3 disease
         or positive margins following RP to postoperative
         EBRT (60 Gy) or observation
       • Median follow-up of 5 years
       • RT group had higher rates of biochemical relapse-
         free survival (RFS) (74 versus 53 %, HR 0.48) as
         well as clinical RFS (85 versus 78 %, HR 0.61)
       • The cumulative incidence of locoregional failure
         at five years was also significantly lower (5.4
         versus 15.4 %) but there was no difference in
         overall survival.

Bolla, M., et al., Lancet 2005 Aug 13-19;366(9485):572-8.
                                    SWOG 8794/PR-2
      • 425 men with pT3 or margin-positive prostate
        cancer were randomly assigned to immediate RT
        (60 to 64 Gy) or observation
      • Median follow-up of 12.6 years
      • Progression-free survival advantage with early
             – 67% versus 48% (p < 0.001) for the SWOG/NCIC study
               with an HR of 0.52
      • Metastatic-free survival (SWOG 8794/PR-2):
             – 84% versus 69% at 5 years, and 68% versus 49% at 10
               years with an HR of 0.62 (confidence interval 0.46–
               0.82, p = 0.001)
Thompson IM, et al., JAMA 2006;296:2329-35
                                              Adjuvant RT
       • Meta-analysis of 1743 patients from the 3
         randomized trials
       • ART resulted in improved biochemical PFS (HR
         = 0.47, p < 0.001) and deferred requirement
         for adjuvant therapies (radiation and
         androgen ablation) with their associated
         adverse effects

Morgan SC, et al., Urol Oncol 2009;27:87-8.
            Opponents of ART

• Only a certain percentage of “high-risk” patients
  have local failure and SRT is probably just as
• Systemic failures, which may occur with or
  without local recurrence, cannot be addressed by
• Toxicity from ART may outweigh potential
• ? lack of OS benefit for ART
        Overall Survival Benefit
• Updated analysis of SWOG 8794, presented in
  2008 shows increased metastatic-free survival
  (p = 0.021) and increased overall survival
  (median 15.2 yr compared with 13.5 yr, p =
  0.031), in addition to increased biochemical
  control (p < 0.001) for the ART group
• Unequivocal benefit for ART with level I
What if seminal vesicle invasion (SVI)?
• Even those with SVI who received ART
  compared with those who were initially
  observed had an improved 10 years freedom
  from biochemical failure (FFBF) survival from
  12% to 36% (p = 0.001) and 10-year OS from
  51% to 71%.6
• Thus, even with SVI, some patients appear to
  benefit from adjuvant local radiotherapy.
    What about concurrent ADT with adjuvant
              RT in pT3 disease?
        • Less certain, although some retrospective
          series suggest that this approach is beneficial ,
          the role of ADT has not been established in
          randomized trials.
        • Two trials from the RTOG (RTOG 86-01 and
          RTOG 85-31 ) provide additional information
          about the use of ADT in this situation and in
          men with a rising PSA following a prior radical

Pilepich, M et al., Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1243-52; Widmark A., et al, Lancet. 2009 Jan 24;373(9660):301-8.
        What about adjuvant hormone therapy
             without RT in pT3 disease?
        • Extremely uncertain!
        • Retrospective, nonrandomized cohort of men s/p RP, node
          negative; 580 men received adjuvant ADT while 1160 were
          managed expectantly without adjuvant ADT
        • 30 % pts on observation arm subsequently received ADT
          for either a biochemical or systemic recurrence
        • Adjuvant ADT was associated with statistically significant
          improved rates of 10-year biochemical and systemic PFS
          compared to delayed treatment (95 versus 90 and 98
          versus 95 percent, respectively).
        • No improvement in overall survival (84 versus 83 percent)

Siddiqui, S et al., J Urol. 2008 May;179(5):1830-7; discussion 1837.
       What about adjuvant hormone therapy
              alone in pT3 disease?
   • Early Prostate Cancer program: 8113 men with
     localized (T1, T2) or locally advanced (T3, T4)
     nonmetastatic prostate cancer
           – high-dose bicalutamide monotherapy (150 mg daily)
             added to standard care (watchful waiting, RP, RT)
           – Median f/u of 10 years
           – Rx with bicalutamide was associated with a statistically
             significant improvement in PFS in men with locally
             advanced (T3, T4) disease regardless of the initial
             management approach.
           – No statistically significant difference in overall survival in
             these patients.
Iversen, P et al., BJUI 2010; 105:1074.
         What about adjuvant chemotherapy in
                    pT3 disease?
        • SWOG trial 9921: patients with high-risk prostate
          cancer s/p RP were randomly assigned to two
          years of combined androgen deprivation therapy
          (goserelin plus bicalutamidee), with or without
          six cycles of mitoxantrone plus prednisone.
        • The trial was terminated after 983 of the planned
          1360 patients were enrolled, when AML was
          observed in 3 patients who had received

Flaig, T et al., J Clin Oncol. 2008 Mar 20;26(9):1532-6
                                               SWOG trial 9921
        • 5-yr PSA relapse-free survival rate was 93 % for the two
          treatment arms, and there was no significant
          difference between those arms
        • The SWOG considered a follow-up trial in which
          patients would be randomly assigned to either one or
          two years of adjuvant hormone therapy. However, the
          trial would require nearly 20,000 patients and a follow-
          up of 23 years to detect a 10 percent difference in the
          two arms.
        • Such a trial is not feasible, and 2 yrs of adjuvant
          hormone therapy after definitive surgery with or
          without adjuvant RT remains the de facto standard of

Glode L., et al., J Clin Oncol 2009; 27:237s
  Prostate Cancer–Specific Mortality
   After Radical Prostatectomy for
   Patients Treated in the Prostate-
         Specific Antigen Era

Andrew J. Stephenson, Michael W. Kattan, et al.,
  J Clin Oncol 27:4300-4305. 2009
• The long-term risk of prostate cancer–specific
  mortality (PCSM) after radical prostatectomy
  is poorly defined for patients treated in the
  era of widespread PSA screening
• A multi-institutional cohort of 12,677 patients
  treated with radical prostatectomy between
  1987 and 2005 was analyzed for the risk of
• Fifteen-year PCSM and all-cause mortality
  were 12% and 38%, respectively.
• Estimated PCSM : 5% - 38% for patients in the
  lowest and highest quartiles of predicted risk
  of PSA-defined recurrence, based on a popular
  nomogram. Biopsy Gleason grade, PSA, and
  year of surgery were associated with PCSM.
• Neither preoperative PSA velocity nor body
  mass index improved the model’s accuracy.
                             The A-ha! moment…….
       • Few patients will die from prostate cancer within 15
         years of radical prostatectomy, despite the presence
         of adverse clinical features.
       • Favorable prognosis may be related to the
         effectiveness of RP (with or without secondary
         therapy) or the low lethality of screen-detected
       • Given the limited ability to identify contemporary
         patients at substantially elevated risk of PCSM on
         the basis of clinical features alone, the need for
         novel markers specifically associated with the
         biology of lethal prostate cancer is evident.

Andrew J. Stephenson, Michael W. Kattan, et al., J Clin Oncol 27:4300-4305. 2009
       Local recurrence following RP -

• RT may represent a reasonable option for men
  who are candidates for salvage therapy following a
  localized recurrence after RP.
• Salvage RT is most successful when the disease
  burden is low and when the relapse-free interval is
  12 months or longer
• Effect of salvage RT on life expectancy in this
  setting is unclear
       Local recurrence following RT -

• RP may provide effective salvage therapy for some
  men with recurrence following definitive RT

• Cryotherapy has been proposed as a potentially
  less morbid alternative to salvage RP in men who
  recur locally after RT, especially in those who with
  clinical T3 disease
 PSA only Recurrence - Summary
• Routine serum PSA monitoring after treatment of
  localized prostate cancer leads to the identification
  of men with a PSA-only (biochemical) recurrence.

• A rising PSA may not be accompanied by any other
  evidence of recurrent or metastatic disease.

• Biochemical failure by itself is not necessarily a
  predictor of death from prostate cancer. Overt
  metastatic disease may not become evident for
  many years in men who develop a biochemical
Newer agents in advanced disease
•   Docetaxel
•   Cabazitaxel
•   Sipulicel-T (Provenge)
•   Abiraterone: currently under investigation for
    use in castration-resistant prostate cancer
    (formerly hormone-resistant or hormone-
    refractory prostate cancer)
Thank you!


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