Metastatic Prostate Cancer

in Men Initially Managed

with Active Surveillance
dr.

Introduction
World Health Organization the main goals of
a cancer diagnosis and treatment programs are
to cure or considerably prolong the life of
patients and to ensure the best possible
quality of life for cancer survivors.
Prostate specific antigen (PSA)-based screening
for prostate cancer has enhanced the early
diagnosis and treatment of prostate
cancer.

 Previous research suggests that current

radical treatment, such as surgery and
radiation for localized prostate cancer, may
cause significant side effects and may also
have a long-term impact on quality of life .
Active surveillance has some uncertainties,
such as lack of a standardized protocol and
uniform criteria for eligibility.

Methods
A prospective, single-arm cohort study was initiated in
1995 to assess the feasibility of a surveillance protocol with
selective delayed therapy using PSA kinetics and/or
histological progression as triggers for intervention.
Patients were followed with serial PSA determinations
every 3 months for 2 years and then every 6 months if
stable.
A confirmatory biopsy was performed within 12 months
after the initial biopsy and then every 3 to 4 years. At the
trial inception in 1995 sextant biopsies were performed.

Methods
In 2000, patients had an 8- to 14-core
biopsy based on the Vienna nomogram.
Patients were reclassified as higher risk and
offered radical intervention for the criteria
of PSA doubling time (DT) of less than 3
years or histologic upgrade on repeat
prostate biopsy or clinical progression.
PSA DT was calculated by modeling the log
(PSA) using a general linear mixed model

Methods
Metastasis-free survival was defined:
survival without objective metastasis
Data was plural, censored at the time of
metastasis.
For patients who died of prostate
cancer without a prior diagnosis of
metastasis, the time to metastasis was
considered to be the time at which
clinical progression was identified.

Methods
Results were expressed as the mean and as proportions
for categorical findings
We used Cox's proportional-hazards model to estimate
the risk of developing metastases.
Survival curves were generated by the Kaplan-Meier
method.
Results were considered significant at the 5% level (p
<0.05).
All calculations were performed using SAS (v9.3 for
Windows).

Result
Patients characteristics

993 patients in the surveillance cohort 980 evaluable patients

Median follow up: 6.4 years (range 0.2 20.2)
211 patients were intermediate risk group
109 patients were baseline
133 patients had GS 7
30 develop metastases
15 died of prostate cancer
4 died of other causes
Patients with metastases were older and included a higher GS 7
However, PSA and clinical stage were not statistically different

Result
Reason for intervention and treatment

15 patients had a short PSA DT and 5 among these 15, were also
upgraded at a subsequent repeat biopsy
7 patients were treated based on grade progression alone,
3 patients for stage progression,
1 patient for patient preference, and
2 patients based on the presence of metastasis, these 2 patients had had
no radical intervention until metastasis was identified.
20 (67%) of 30 patients received definitive treatment

14 (46.7%) had radiation therapy with or without ADT,

6 (20%) had radical prostatectomy (RP).

8 (27%) patients received androgen deprivation therapy (ADT) alone for

rising PSA,
2 (7%) patients received no treatment other than ADT after developing
metastasis.

 Mortality outcomes

The median time to metastasis was 6.3 years.

10 of 30 (33%) patients developed metastasis in 5 years
15 (50%) cases developed within another 5 years.
The 10- and 15-year MFS rates were 95.1% and 91.4%

Pathological results after treatments

6 patients managed with radical prostatectomy (RP)
5 were GS <=6 at initial diagnosis, and one was GS 3+4.

1 patient had organ confined cancer,

4 had extraprostatic extension and one was unknown.
1 had positive surgical margins.
Of the 5 who had lymph node dissections, 4 had lymph node metastases.

 In univariate analysis, GS 7, number of positive cores, core positivity >50% at

initial biopsy, intermediate risk group and short PSA DT were significant factors
for metastases.
The intermediate risk group had a 2.7 times higher risk of developing
metastasis.
In multivariate analysis, GS 7, 3 total positive cores and PSA DT remained
significant.
The HR for metastasis based on PSA DT 3 years, GS 7 and 3 total positive
cores were 3.7, 3.0 and 2.7, respectively.
In subgroup analysis, the group of PSA >10 ng/ml with GS 6 had a significantly
lower risk of metastasis than the group of GS 3+4 with PSA 10 (p=0.359)
In the GS 6 cohort, there was no difference in metastasis rate whether the PSA
was greater or less than 10.

Discussion
Since PSA testing became widely prevalent, prostate cancer
mortality has decreased by 40%. Much of this decrease has been
ascribed to early detection
Active surveillance has been increasingly accepted as an option
for favorable-risk prostate cancer
Three percent of our cohort (30 patients) have developed
metastatic disease, despite re- classification and treatment
The metastasis rate in this cohort reflects the inclusive inclusion
criteria for active surveillance that were employed.. The
underlying principle of active surveillance is to reduce the harms
related to the treatment without exposing the patient to a
significant risk of cancer progression.

 We excluded all high risk and high-intermediate risk patients (PSA

20 ng/mL or GS 4+3 with PSA > 10).
In the low risk group, only 16 (2.0%) of 769 developed any
metastasis, all of whom, except for one case (described above),
were risk-reclassified prior to the development of metastases.
Our results reveal that the intermediate risk group, including GP4,
has a significantly higher rate of metastasis.
While most men with GS 3+4 managed with surveillance are not
destined to die of prostate cancer, the risk of eventual disease
progression to metastasis is 3-4 times higher; patients with life
expectancies greater than 10 years may be at increased risk of
metastatic disease if they are managed initially on AS.

 The baseline PSA level was the least relevant parameter

for predicting outcomes.
A PSA DT < 3 years was strongly associated with an
increased risk of metastases.
This study had the following limitations. Our study
cohort was from a largely referral based centre which
introduces the potential of selection bias and limits
generalizability.

Conclusion
A low percentage (3.1%) of surveillance patients
developed metastasis at a median of 6.3 years after
diagnosis. Gleason score 7, PSA DT less than 3 years and
total positive cores (3) were associated with the
development of metastasis.
No patients with surgical grading with GS 6 metastasized.
The presence of Gleason pattern 4 on the diagnostic
biopsy confers a 3-4 times increased risk of metastatic
disease, and such patients should be offered surveillance
with caution.

 Further evaluation with MRI, genetic biomarkers, or

both, should be strongly encouraged if surveillance is
chosen as an option for these patients.