Transcript Expectant Management of Prostate Cancer

Expectant Management of
Prostate Cancer
James A. Eastham, MD and Peter
T. Scardino, MD
June 23, 2010
Presented by: K. Witzke, DO
Background
Histologically apparent cancer can be
found in 42% of men older than 50
years who die of other causes, the
lifetime risk that an American man will
be diagnosed with CaP is 17%, the
risk of dying of the disease is 3.6%
PSA Doubling time
2-4 years
Biologic potential of histologically
detectable cancers is difficult to
characterize with certainty.
Biopsy may underestimate the extent of
cancer
Conservative Management
Deferring definitive therapy until
evidence that the cancer is sufficiently
aggressive to warrant therapy, may
be appropriate for many patients with
a favorable (low-risk) cancer
Identification of such cancers before
treatment would be a significant benefit
to these patients
Watchful Waiting
Traditionally: no active treatment until a
patient develops evidence of symptomatic
disease progression, at which time
androgen deprivation therapy is initiated
Limits the morbidity from the disease, not to
administer potentially curative treatment.
Recently: to delay curative local therapy
until the natural history and threat posed by
the cancer can be more accurately
characterized.
Active Surveillance
Selective delayed definitive therapy
Distinguish clinically insignificant cancers from
life-threatening cancers while they are still
localized to the prostate.
Risk posed by a given cancer can be assessed
with some degree of certainty and that delayed
treatment will be as curative as immediate
treatment.
Avoid over treatment in the majority of patients
but also to administer curative therapy
Active Surveillance vs. WW
Active Surveillance
Aim
To individualize treatment
Patient characteristics
Fit for radical treatment
Age 50-80 yr
Tumor characteristics
T1-T2, GS ≤7, initial PSA <15 ng/mL
Monitoring
Watchful Waiting
To avoid treatment
Age >70 yr or life expectancy <15 yr
Any T stage, GS ≤7, any PSA
Frequent PSA testing
PSA testing unimportant
Repeated biopsies
No repeated biopsies
Indications for treatment
Short PSADT
Symptomatic progression
Higher grade or more extensive cancer on biopsy
Treatment timing
Early
Delayed
Treatment intent
Radical
Palliative
Watchful Waiting
For those expected to live less than 5
years, most prostate cancers will grow
locally, and some patients will develop
metastases, but few will die of the disease.
(Chodak, et al 1994) The risk of
metastasis at 10 years was 19% for welldifferentiated cancers, 42% for
moderately differentiated cancers, and
74% for poorly differentiated cancers.
If the primary tumor was not controlled, the risk
for development of metastases persisted, even
accelerated, after 10 years
Although most prostate cancers diagnosed at an early stage
have an indolent course, local tumor progression and
aggressive metastasis disease may develop in the long term,
and early radical treatment should be considered for men with
a life expectancy exceeding 15 years.
Most cancers had an indolent course during the first 10 to
15 years.
15 to 20 years revealed a substantial decrease in
cumulative progression-free survival (from 45% at 15
years to 36% at 20 years)
Survival without metastases (from 77% to 51%)
Prostate cancer-specific survival (from 79% to 54%)
» Johansson and colleagues (2004)
Impact on Mortality
Patients with a well-differentiated
cancer (Gleason sum 2 to 4) had a
low probability of death from cancer
within 20 years; higher grade cancers
took a substantial toll even among
older men.
Gleason sum and patient age at
diagnosis
Probability of dying of CaP w/n 15 years of
diagnosis in men with clinically localized CaP
treated conservatively:
Age (years)
Gleason Sum
2-4
5
6
7
8-10
50-59
4%
6%
18%
70%
87%
60-64
5%
8%
23%
62%
81%
65-69
6%
10%
27%
53%
72%
70-74
7%
11%
30%
42%
60%
Scandinavian Trial
695 men clinically localized CaP
Randomized to radical prostatectomy or WW
with systemic tx deferred until the development
of symptomatic progression
Endpoint: death from CaP
F/u 8.2 years:
50/348 WW died of CaP
30/347 RP
Men RP had lower relative risk of distant metastases
than did men assigned to watchful waiting
Scandinavian Trial
ED and incontinence were higher in
men with RP
Obstructive voiding and bowel
complaints for WW group
Retrospective review showed these
patients had palliative treatments such
as TURP, radiation, or upper urinary
tract diversion.
Identifying Men with Low Risk CaP
Systematic Biopsy Results
Epstein (1994) preop and path features 157
T1C w/radical prostatectomy to find features
that could predict “insignificant” tumors
No Gleason grade of 4 or 5
PSA density of 0.1 ng/mL per gram or less, fewer
than 3 biopsy cores with cancer (six core min), no
core with more athn 50% involvement or
PSA density of 0.15 ng/mL per gram or less and
cancer smaller than 3 mm on only one prostate
biopsy sample (min 6 cores)
– Model had positive predictive vale 95%, negative value
of 66%, predicted that 73% of their cases were
insignificant tumors.
Systematic Biopsy Results
Goto (1996) predicted 75% probability
of indolent cancer in 170 patients.
PSA density <0.1, no Gleason 4 or5, and
cancer smaller than 2mm in a single
core.
None of the models have been
validated prospectively or on a
separate cohort
Indolent Cancer Nomogram
Based on 400 patients diagnosed by
needle bx, who had low-risk cancer
features (clinical T1C or T2a, bx Gleason
patterns 2 or3, PSA less than 20)
Analysis of RP specimens 80 (20%) had
indolent cancer.
Using such prognostic information, physicians
can identify, with reasonable accuracy, patients
with low tumor burden for whom aggressive
management may not be indicated initially,
especially in men who are older or with
significant comorbidity.
(Figure 96-3) Nomogram for predicting
an "indolent" prostate cancer
Physician:
Locates the
patients PSA on
PRETX PSA
axis, draw line
upward to the
points axis
(points toward
have indolent
cancer). Repeat
this process for
remaining axes.
Add the points
locate on Total
Points axis.
Draw a line
down to
probability of
having indolent
cancer.
Active Surveillance with Selective
Delayed Definitive Therapy
AS for a healthy man with a life expectancy longer
than 10 years risks permitting a curable cancer to
become metastatic
Initial evaluation seriously underestimates the grade and
extent of the present cancer
Indolent cancer grows undetected and becomes metastatic
before it is treated.
The initial evaluation of a candidate for AS aims to
reduce the chance that a large, aggressive cancer
has been missed.
Subsequent evaluations aim to detect progression before the
cancer metastasizes.
AS patients must accept frequent, regular detailed
evaluations of the status of their cancer for as long as they
are healthy and young enough to be a candidate for
definitive therapy.
Authors recommendation for lowrisk patients:
Complete reevaluation at baseline
DRE, free and total PSA determinations
Imaging study of the prostate (endorectal magnetic
resonance imaging with spectroscopy)
And Ultrasound-guided systematic needle biopsy
If confirm a low-risk cancer, patient chooses AS:
Recommend a check-up every 6 months with DRE and
PSA determinations indefinitely
Repeated imaging and biopsy 12 to 18 months after the
baseline evaluation
Every 2 to 3 years.
The goal is to detect progression of the cancer while cure is
still possible
Biopsy on follow up vs. PSA
Annual surveillance biopsies are necessary for
men on AS, since PSA criteria are not likely to
reveal disease progression accurately. (Study
of 81 men thought to have small vol CaP T1c)
Although PSA criteria were significant predictors of
cancer progression, extensive overlap in PSA density
and percentage free PSA values in men with and without
progression, suggesting that accurate prediction of
progression would be difficult by these criteria
39 men in whom every follow-up biopsy specimen
showed cancer, 22 (56%) had disease progression,
compared with 3 of 42 men (7%) with normal findings on
one or more follow-up biopsies (P < .001).
AS feasible alternative to initial
curative treatment
Select patients with favorable, localized
prostate cancer.
About half of these patients remain free of
progression at 10 years, and definitive
treatment appeared effective in those with
progression.
Consistent with the study by Carter and
associates (2002), authors found that absence
of cancer on repeated needle biopsy early after
initial diagnosis identified cases unlikely to
progress during 10 years.
Point system of evaluating progression in pts
treated with deferred therapy:
1 Point
Gleason score increase
PSA velocity (ng/mL/yr)
1
2 Points
>1
3 Points
Any new
Gleason pattern
4 or 5
>0.75 during 12 months
>0.75/yr during
24 months
DRE/transrectal ultrasonography
Increasing old lesion
New lesion not biopsy proven
New biopsyproven lesion
Biopsy specimens
Bilateral or multifocal cancer
>4 cores with
cancer
University of Toronto (Klotz 2004)
299 patients with good-risk prostate cancer or intermediaterisk prostate cancer in men older than 70 years
PSA level was less than 15 ng/mL, Gleason sum 7 or lower,
and clinical stage T2b or lower
Observed until they met specific criteria:
PSA progression (defined by all of three conditions): PSA
doubling time (PSADT) of 2 years or less, final PSA level of
more than 8 ng/mL, and P < .05 from a regression analysis of
ln(PSA) on time;
Clinical progression (defined by meeting any of four conditions):
more than a doubling of the product of the maximum
perpendicular diameters of the primary lesion as measured by
DRE, local progression of prostate cancer requiring
transurethral resection of the prostate, development of ureteral
obstruction, and radiologic or clinical evidence of distant
metastasis; and
histologic progression: Gleason sum 8 or higher on repeated
biopsy of the prostate at 12 to 18 months.
University of Toronto
Patients with progression offered RP
Median PSA DT was 7 years, 35% had 10
years or more.
Follow up at 55 months 60% patients remained
on AS
12% biochemical progression
8% clinical progression
4% histological progression
16% patient preference
At 8 years: 85% actuarial survival, 99% disease
specific survival
For Men on AS, What are the
Factors Predicting Progression?
Although PSADT is a predictor of
cancer progression for men on AS,
“the exact trigger point at which to
recommend treatment requires further
investigation.”
One study suggested that the definition
of progression for men on AS include a
PSADT of less than 2 years on the basis
of at least three separate measurements
during a minimum of 6 months
What are the Factors Predicting
Progression?
Although all AS studies have included
periodic DRE as part of routine follow-up,
none has found this to be an independent
predictor of cancer progression
It remains important, however, as an
indicator that a repeated prostate biopsy is
warranted during AS and in clinical staging
and the prediction of outcome if active
treatment is recommended.
What are the Factors Predicting
Progression?
Serial imaging studies have also proved to be of
limited value in the AS population.
Study of 136 men who underwent two or more serial
transrectal ultrasound examinations, there was no
correlation between changes in either gland volume or
the number of peripheral zone hypoechoic lesions and
the rate of change of PSA.
The role of serial pelvic imaging (CT or endorectal MRI)
has not been investigated but is likely to be limited.
These men are at low risk for macroscopic extraprostatic
disease, so interval changes in any of these
examinations are unlikely.
Bone scans are not useful, especially if PSA <15
What are the Factors Predicting
Progression?
Repeated prostate biopsies are considered an
important aspect of continued evaluation of men
managed with AS, not only to identify men with
cancer progression but also to identify men
unlikely to progress.
Author’s cohort of 88 men on AS, an abnormal finding on
second biopsy was the most significant prognostic factor
for progression
Progression in 5 of the 43 men (11%) who had a first
repeated biopsy that was negative for cancer, compared
with 12 of 27 (40%) with an abnormal finding on first
repeated biopsy (P = .004).
Actuarial progression-free probability at 5 years was
83% in patients with normal findings on repeated
biopsy compared with 43% in those with abnormal
findings on repeated biopsy.
– Increase in Gleason sum noted in 59% of repeat biopsy
Summary
Patients with a life expectancy (based
on age and comorbidities) of less than
10 years and cancer with Gleason score
of 6 or lower may be suitable for
watchful waiting, especially if clinical
stage and PSA values are favorable.
Intervention is palliative and delayed until
symptoms develop.
AS may be a safe alternative to
immediate treatment in compliant men
with a low risk of cancer progression
Goodbye and Good Luck ;)
Thanks for the
memories!