Transcript Options after Radical Prostatectomy

Management of Prostate Cancer
Post-Prostatectomy
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
cancers
• Example: percentage of low risk disease has
increased from 29.8% (1989-92) to 45.3%
(1999-2001); p<0.001
Ergo……
• 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
cancer.
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
controversial
• 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
health
• 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 postoperatively 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
characteristics
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
complications
• 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
surgery
• Active observation: High grade tumors, pt
preference, expected survival of 10 or more
years.
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 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
brachytherapy).
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
cancer
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,
respectively.
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 relapsefree 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
radiotherapy:
– 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
effective.
• Systemic failures, which may occur with or
without local recurrence, cannot be addressed by
ART
• Toxicity from ART may outweigh potential
benefits.
• ? 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
evidence
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
prostatectomy
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
mitoxantrone.
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 followup 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
care.
Glode L., et al., J Clin Oncol 2009; 27:237s
Prostate Cancer–Specific Mortality
After Radical Prostatectomy for
Patients Treated in the ProstateSpecific 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
PCSM.
• 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
cancers.
• 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 Summary
• 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 Summary
• 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
failure.
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 hormonerefractory prostate cancer)
Thank you!
Questions?