SURVEILLANCE FOR FAVORABLE RISK PROSTATE CANCER: What Are The Results, and How
Safe Is It?
Laurence Klotz, Professor of Surgery, University of Toronto and Chief, Division
of Urology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario
cancer (PC) screening based on prostate biopsy for men with levels of serum prostate-specific
antigen (PSA) above an empirical level, or abnormal digital rectal examination
(DRE), results in diagnosing many men with prostate cancer for whom the disease
does not pose a threat to their life. Welch has recently calculated that there
are 2.74 million U.S. men who are 50-70 with a PSA > 2.5. If all American men
in this age group had a PSA, and a PSA > 2.5 is used as an indication for biopsy,
775,000 cases would be diagnosed this year in the U.S. alone. This is 543,000
more than the 232,000 cases diagnosed in 2005, and 25 times more than the 30,350
men expected to die of PC per year in the U.S. (1)
Several autopsy studies
of men dying of other causes have documented the high prevalence of histologic
prostate cancer.(2) A large proportion of this histological, or 'latent' prostate
cancer is never destined to progress or affect the lifespan of the patient. Since
the introduction of PSA screening, the lifetime risk of being diagnosed with prostate
cancer has almost doubled from around 10%, in the pre-PSA era, to 17%. (3)
means that many cases of localized prostate cancer are over-treated, since some
patients not destined to experience prostate cancer death or morbidity will be
subjected to radical therapy. (4)
Cancer aggressiveness can be predicted
to some degree using existing clinical parameters. The ones mostly widely used
are tumor grade, or Gleason score; PSA; and tumor stage. Favorable-risk prostate
cancer is characterized as a Gleason 6 or less, a PSA 10 or less, and T1c-T2a
disease.(5) As a result of stage migration due to PSA screening, the proportion
of newly diagnosed patients who fall into the 'favorable-risk' category has increased,
and now constitutes 50-60% of patients.
While patients with these characteristics
have a much more favorable natural history and progression rate than those with
a higher Gleason grade or PSA, some of them still progress to advanced, incurable
prostate cancer and death.
An update of a large group of patients in Connecticut
treated with watchful waiting has recently reported the results of a 20-year follow-up.(6)
The study data confirms the powerful predictive value of Gleason score. In that
pre-PSA screening cohort, 23% of untreated Gleason 6 patients died of prostate
cancer within 20 years. For Gleason 7 prostate cancer, about 65% of untreated
men died of prostate cancer within 20 years. In addition, the author recently
subjected the original slides to re-analysis using contemporary Gleason scoring.(7)
This demonstrated clearly that there has been a shift in grade interpretation
over the last 20 years (as reported in the August 2006 issue of Insights). Many
Gleason 6 cancers diagnosed 20 years ago would be called Gleason 7 today. Thus
it is likely that the Connecticut results represent a 'worst case' scenario for
the expected mortality from untreated Gleason 6 cancer. This means that the prostate
cancer mortality of untreated, non-screen-detected, contemporary Gleason 6 cancer
may be as low as 10% at 20 years.
Autopsy studies have demonstrated that
prostate cancer typically begins in the third or fourth decade of life.(1) This
means that, in most patients, there is a period of slow subclinical tumor progression
that lasts approximately 30 years, followed by a period of clinical progression
(potentially to metastatic disease and death) lasting about 15 years. The implication
is that most patients have a long window of curability. This is particularly true
for patients with favorable risk, low volume disease. One approach to achieving
prediction of tumor aggressiveness is to use this window of curability to identify
patients at higher risk for progression based on a rapid PSA doubling time (PSADT)
and/or a histologic progression over time.
Numerous cohorts have reported
the results of a watchful waiting approach where there was no treatment until
there was progression to metastatic or locally advanced disease, at which point
androgen ablation therapy was implemented. (8-17) These older studies consistently
describe non-progression in many patients. However, the results are difficult
to apply in the current era for two reasons: (1) because the cohorts described
are from the pre-PSA era, and constitute patients with more extensive disease
at the time of diagnosis, and (2) because patients were not offered the opportunity
for selective definitive therapy at an earlier stage when their disease was still
potentially curable. In the era of PSA monitoring, patients who are treated conservatively
receive periodic PSA tests. This raises the tantalizing prospect that treatment
of favorable prostate cancer could be deferred indefinitely in the majority; and
that effective delayed therapy need only be offered to the patient subset in whom
PSA progresses rapidly or the tumor grade increases. (18-19)
Cancer Prevention Trial (PCPT), a 19,000-member trial comparing the effectiveness
of Proscar and a placebo in preventing prostate cancer, incorporated a strategy
of routine systematic biopsies of the prostate, regardless of PSA level. Twenty
four percent of patients in the placebo arm were diagnosed with prostate cancer
over a seven- year period, even though their PSAs were still in the normal range.
(20) This high proportion means that, in sharp contrast to accepted wisdom, a
routine prostate biopsy will result in the detection of latent micro-foci of disease
in many men.
The lifetime risk of dying from prostate cancer remains less
than 3%. (3) As the lifetime risk of being diagnosed approaches the known rate
of histological (mostly insignificant) prostate cancer, there is a greater risk
of over-treatment. At least two studies have attempted to model the rate of diagnosing
clinically insignificant disease, suggesting that it ranges from 30% to 84%. (4-5)
The current incidence-to-mortality ratio of about 7:1 suggests that the higher
(84%) figure is more likely. Factors contributing to this are the increasing use
of PSA screening and more extensive biopsy strategies that employ eight to 13
cores. (21) Additionally, biopsies are often repeated over and over until a cancer
diagnosis is made. More biopsies mean the diagnosis of more prostate cancer and
of more clinically insignificant disease (as well as more clinically important
disease). A large series of patients from Johns Hopkins treated with radical prostatectomy
(22) showed that a median period of 16 years elapsed from surgery until death
in patients dying of prostate cancer following disease recurrence. Many watchful
waiting studies, most of which accrued patients from the pre-PSA era, also demonstrate
that disease-related mortality in populations of prostate cancer patients only
becomes substantial after 10 years. (23-34) Low-grade prostate cancer in particular
is associated with low progression rates and high survival rates in the intermediate
to long term. This is also supported by the Albertson's Connecticut data. (6)
the estimated lead-time between diagnosis based on PSA, and diagnosis based on
clinical factors such as a palpable nodule in the prostate as was reported in
the Connecticut series has also been estimated to be around 10 years by many authors.
(35,36) Thus, many patients currently diagnosed by PSA screening with favorable
prognostic factors are diagnosed considerably earlier in the development of the
disease than was the average patient in this unscreened population in the older
watchful waiting studies. Therefore, these screened patients are likely to have
prostate cancer with an even longer and more benign natural history. And since
patients on active surveillance who become re-classified as higher risk over time
still have the opportunity for radical intervention, it seems obvious that the
expected prostate cancer mortality in this group is likely to be exceptionally
the prediction of clinically insignificant disease is problematic and inaccurate,
an alternative strategy has been developed that allows patient entry into an expectant
management protocol with rigorous monitoring and the option of curative salvage
therapy, should signs of progression develop. This is referred to as active surveillance.
Klotz and Choo were the first to report on a prospective active
surveillance protocol incorporating selective delayed intervention for the subset
with rapid PSA progression or grade progression on repeat biopsy. (37,38) The
eligibility criteria for this included patients with T1c or T2a prostate cancer
who had a Gleason of 6 and a PSA of 10. For patients over age 70, these were relaxed
to include Gleason d 7 (3+4) and/or PSA d 15. The current cohort comprises 331
patients. The median age was 70 years with an age range of 49 to 84 years. 80%
of the patients had a Gleason score of 6 or less, and the same proportion had
a PSA <10 ng/ml (median 6.5 ng/ml). With a median follow-up of 72 months, 101
patients (34%) came off active surveillance, while 198 have remained on surveillance.
Of patients discontinuing surveillance, the reason was rapid biochemical progression
(PSA rise) in 15%, clinical progression in 3%, histologic progression (new or
enlarging nodule in the prostate gland) in 4%, and patient preference (deciding
to treat even though nothing had changed) in 12%. With a median follow up of seven
years (range 2-11 years), the overall survival was 85% and the disease-specific
survival was 99%.
Only three out of the 331 patients had died of prostate
cancer at the time of writing this review. All three patients had PSADTs of <2
years, and death occurred 3.0, 5 .1, and 5.2 years after diagnosis. All three
exhibited the same pattern of clinical progression: initial favorable prognostic
factors, but subsequently a rapid rise in PSA which led to treatment in 6, 9,
and 11 months after the initial diagnosis; after treatment, all three had a progressive
rise in PSA and clinically apparent bone metastases within a year after treatment,
leading to androgen deprivation therapy. All three patients died within three
years of the initiation of ADT. This very rapid progression after diagnosis suggests
that these patients had occult metastases outside the prostate at the time of
their initial disease presentation, and that their outcome would not have been
altered by earlier treatment. Even in the Swedish trial, (39) there were almost
no 'saves' before five years had elapsed. The median PSADT for all of the men
in our study, calculated by logarithmic regression, was seven years. Twenty-two
percent of the patients had a PSADT of less than three years, whereas 42% had
a PSADT of over 10 years that suggests an indolent course of disease in these
At the time of repeat biopsy, the Gleason score remained stable
in 92% of patients; only 8% demonstrated a significant rise in Gleason score,
classed as an increase of equal or greater than 2. It is not known whether this
represents true grade progression or initial under-sampling; however, it is consistent
with other similar series reported by other researchers, demonstrating a 4% rate
of grade progression over 2-3 years. (40) In our group, 29 patients (10% of the
cohort) had a radical prostatectomy as a result of a short PSA doubling time or
grade progression. Of these patients, all had an initial Gleason score of 5-6,
a PSA < 10 ng/ml, and a tumor stage pT1-2 at study entry. The final pathology
was stage pT2 in 18 patients (64%%), pT3a in 11, T3c in 1, and N+ in 1. Among
the 18 patients with a PSA DT < 3 years (18 patients), only seven had positive
margins. This suggests that even among the worst subset of the cohort, i.e. those
reclassified as higher risk over time, the majority remained curable despite having
Benefits from Treatment?
recent landmark trial from Sweden demonstrated, for the first time, that radical
prostatectomy improves survival. (39) In that study, the treatment of about 600
patients was randomized between radical prostatectomy and watchful waiting. The
study showed a 5% absolute survival benefit at 10 years, and a 50% reduction in
prostate cancer mortality with surgery.
However, this cohort was a group
with many patients who had intermediate-to- high-risk disease that was much worse
than the proposed candidates for active surveillance. in this study only 5% were
diagnosed based on PSA screening, and the median PSA was 12.8. The volume of disease
in these patients represented a pre-stage migration cohort.(Even in this group,
however, the number needed to treat to prevent each prostate cancer death was
19). The distribution of disease volume and grade is higher than the expected
distribution in a contemporary screened population, where a substantial proportion
of newly diagnosed patients have small volume low-grade disease.
study should not be interpreted to mean that all patients with localized prostate
cancer should be treated radically. Many studies emphasize that the patients with
Gleason 4-5 pattern disease are at the greatest risk for death from prostate cancer.
In the Swedish study, the mortality improvement began to appear at five years.
It would be most unusual for a patient with low grade, low volume disease to die
within 5-7 years of diagnosis. (In the Toronto surveillance cohort, this is 1%
of patients (37).) This means that the majority of the benefit seen in the Swedish
trial likely represented mortality reduction in the high-risk group.
have used this data and the Connecticut watchful waiting data to estimate, for
each prostate cancer death averted at 20 years, the number of patients with favorable-risk
prostate cancer that would have to be treated at the time of diagnosis. The number-needed-to-treat
(NNT) for each death avoided at 10 years in the Swedish trial was 20. It is likely
that with additional (i.e. 20 year) follow up, the survival benefit in the Swedish
trial, now 10 years, will increase. This is likely to be balanced by the lead-time
inherent in PSA screening. Thus, in a screened patient with intermediate grade
and PSA similar to the Swedish cohort, the NNT at 20 years is estimated to also
be around 20. The Albertsen data (6) indicate that the mortality for intermediate-risk
disease was about 2.5 times greater at 20 years than it was for favorable-risk
disease. This number may be an under-estimate if the shift in contemporary Gleason
scoring is factored in. Thus, compared to no treatment, about 50 favorable-risk
patients need to be treated for each death that will be prevented by surgery.
However, if one offers selective delayed intervention to those patients who progress,
it can be conservatively estimated that at least 50% can be salvaged. The conclusion
is that about 80-100 radical prostatectomies would be required for each prostate
cancer death averted in favorable risk disease. Correcting the Connecticut data
for grade migration, as referred to earlier, would increase this even further.
Finally, how much benefit does that one patient whose prostate cancer
death is averted by all those radical treatments achieve? Experience from 2000
patients at Johns Hopkins suggests that the prostate cancer deaths averted would
have occurred on average 16 years after diagnosis, meaning that the number of
life years saved in each of these 1 in 100 averted deaths is modest. Unfortunately,
no one lives forever. The rare individual who benefits from surgery (who is typically
60 years old on average lives to be 82, so his life would be prolonged an average
of five years by having his prostate cancer death averted. (7) If each prostate
cancer death averted adds five years to that individual's life, each radical prostatectomy
would add 0.6 months of life (60 months per 100 operations). This is of dubious
some apparently low risk patients may re-classify as high risk over time, patients
should be followed carefully and treated if they show evidence of rapid PSA progression
or Gleason grade progression on repeat biopsy.
In young, healthy patients
on surveillance, the optimal PSADT threshold for radical intervention should be
around three years. In our series at Sunnybrook Health Services Centre, patients
with a PSADT of three years or less constituted 22% of the cohort. The decision
to use this cut point for intervention remains empirical and speculative. However,
the selection of this cut point is supported by findings reported by others. For
example, 20-25% of patients with a three-year doubling time represents a rough
approximation of the proportion of good risk patients 'at risk' for disease progression.
(38) For patients with a PSA in the 6-10 range, it also approximates an annual
rise of 2 ng/ml, an adverse predictor of outcome as described by D'Amico. (41)
The psychological effects of living for many years with untreated cancer
are a potential concern. Does the cumulative effect, year after year, of knowing
one is living with untreated cancer lead to depression or other adverse effects?
The best data on this comes from a companion study to the Holmberg randomized
trial of surgery vs. watchful waiting in Sweden. It found absolutely no significant
psychological difference between the two groups be after five years. Worry, anxiety,
depression, all were equal between the two arms. (29) While surveillance may be
stressful for some men, the reality is that most patients with prostate cancer,
whether treated or not, are concerned about the risk of progression. Anxiety about
PSA recurrence is common among both treated and untreated patients. It is hoped
that with education patients will begin to understand the very indolent natural
history of most good-risk prostate cancers and, with the realization that the
disease is not life-threatening, may avoid much of this anxiety.
strategy for managing patients with active surveillance and selective delayed
intervention is described in Table 1.
management has been resisted in many constituencies due to concern about the inaccuracies
of clinical staging and grading. The advent of widespread PSA screening has the
positive effect of identifying patients with life threatening prostate cancer
at a time when they are more curable, and the negative effect of identifying many
patients with non-life threatening cancer who are susceptible to over-treatment.
In a population subjected to regular screening, the latter group is far more prevalent.
PSA testing will result in hundreds of thousands of patients needlessly subjected
to the side effects of therapy. A rational approach to therapy is to offer aggressive
treatment to the intermediate and high-risk group, and little or no treatment
to the low risk group
However, some apparently favorable-risk patients
harbor more aggressive disease. In these patients, there are benefits of curative
treatment. A policy of close monitoring with selective intervention for those
whose cancers exhibit characteristics of higher risk disease over time is an appealing
way to deal with this. Intervention is offered for a PSADT greater than 3 years
(depending on patient age, co-morbidity, etc.), or grade progression to a predominant
Gleason 4 pattern. This approach is currently the focus of several clinical trials,
and preliminary analysis of these has demonstrated that it is feasible. Most patients
who understand the basis for this approach will remain on long-term surveillance.
If patients are selected properly (i.e. good-risk and low-volume disease) and
are followed carefully to enable early intervention if there is evidence of progression,
it is likely that the majority of men with indolent disease will not suffer from
clinical disease progression or PC death, and the minority with aggressive PC
will still be amenable to cure. Using two different approaches, we estimate that
if all such patients were offered radical prostatectomy compared to this strategy,
the number-needed-to-treat would be approximately 100 for each patient who avoids
a PC death. Thus, the proportion of patients who die of PC is not likely to be
significantly different from the proportion dying in spite of aggressive treatment
of all good risk patients at the time of diagnosis. This approach is currently
being evaluated in a large-scale phase 3 study.
Suggested Algorithm for
Eligibility and Follow-up
= 10 Gleason Score = 6 Stage T1c-T2a Depending on age and co-morbidity:
3 cores involved, < 50% of any one core.
Follow up schedule:
DRE @ 3 months x 2 years, then @ 6 months assuming PSA is stable.
core biopsy at one year, and then every 3-5 years until age 80.
TRUS on alternate visits.
PSA doubling time < 3 years (in most cases, based on at least 8 determinations)
(about 20% of patients)
For Grade progression
to Gleason 7 (4+3) or higher (about 5% of patients)
are guidelines, and should be modified according to patient age and co-morbidity.
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