There is a “conventional wisdom” that active surveillance
(AS) is only for older men, and that younger men are better off having
immediate radical treatment, typically prostatectomy (RP). By “better off” we
mean that there is a better chance at cancer control, or that the side effects
of treatment, particularly incontinence and impotence, will be milder if
treated earlier. Let’s turn a spotlight on that conventional wisdom, and see if
it holds up under scrutiny.
The screening protocol for men under 50 years of age that is
advocated by Memorial Sloan Kettering (see this link and this one), and recently discussed here,
has important implications for active surveillance. Autopsy studies have
demonstrated prostate cancer incidence of 20-30% in men under 50, mostly low
grade and indolent. With increased screening of this young cohort, there will
be an increase in the current incidence rate (now at about 10%). These men will
increasingly be urged by their urologists to seek radical treatment, primarily
surgery. If their screening protocol is widely adopted, there is great danger
of over-treatment for this age group.
Oncological
Control
With up to 20 years of follow-up, the Klotz Active Surveillance Trial has demonstrated the safety of that protocol. Klotz reported that of
the 993 patients, there were only 15 deaths (1.5%) due to prostate cancer. When
he pooled together several active surveillance studies, he found that the
combined disease-specific survival rate was 99.7%. A Gleason score of 8-10 on
confirmatory biopsy and a PSA doubling time of less than 3 years were
associated with mortality, indicating the importance of close monitoring and
follow-up biopsies on any active surveillance protocol.
It is worth noting how long men entering the Klotz study
were able to stay on active surveillance before their progression
characteristics indicated that radical treatment was required. Most of the
progression was found in the first 5 years after entering the program, and
reached a plateau by 15 years.
Time on AS
|
Percent for whom no
treatment was recommended
|
5 years
|
75.7%
|
10 years
|
63.5%
|
15 years
|
55.0%
|
20 years
|
55.0%
|
Age was not a risk factor for prostate cancer mortality.
Klotz said, “Younger patients were not at increased risk of prostate
cancer mortality.” In fact, in younger men, the risk of non-prostate cancer
mortality was almost six times higher than the rate of prostate cancer
mortality.
It’s important to understand how slowly low-risk prostate
cancer typically progresses in young men, even without active surveillance;
that is, even without an intention to treat if
the cancer progresses. Based on the Memorial Sloan Kettering Nomogram, we can see that for a 45 year-old man in
excellent health diagnosed with a Gleason score of 3+3, PSA of 4 ng/ml, and
nothing felt on a digital rectal exam, he has a zero chance of dying of
prostate cancer in the next ten years, and a 4% chance of dying of something
else. Even if he lets it go for 15 years, he only has a 3% chance of dying of
prostate cancer, and an 8% chance of dying of something else.
It has been observed that there are rare and virulent forms
of prostate cancer that are more prevalent in men under 50, and particularly
among younger African-American men (see this link and this link). This is irrelevant to the discussion of active surveillance because those men will seldom be good candidates for active surveillance from
the outset. And if they do get in, clinical progression will be noticed in any
active surveillance protocol at a very early time. Still, it is a reasonable
precaution to screen men under 50 for genetic markers when there is a family
history of early prostate cancer; for example, Oncotype Dx, Prolaris,
TMPRSS2-ERG fusion, PTEN loss, or BRCA2 mutations.
Advancing age at the time of diagnosis is associated with a
worse prognosis. In an analysis of 205,551 cases in the SEER database (see this link),
15-year prostate cancer mortality rates increased steadily with age at
diagnosis.
Age Group
|
15-year PC mortality
|
≤50
|
2.3%
|
51-60
|
3.4%
|
61-70
|
4.6%
|
≥71
|
6.3%
|
Once again, this observation is irrelevant to a discussion
of active surveillance. Age was not found to be a prognostic factor after
accounting for Gleason score, tumor stage and PSA. The higher risk older men
would probably not meet the entry criteria for active surveillance (although,
depending on co-morbidities, they may be good candidates for watchful waiting).
Those older men with more virulent disease that do get into an AS program would
most likely be soon found to progress and be safely treated in time.
Based on oncological prognosis, younger age should not be
used to decide between active surveillance and radical therapy.
Continence
An argument for treatment for younger men has been that
there is a higher chance of continence preservation after surgery among younger
men who already have better continence. Let’s see what the real-world numbers
look like.
Continence naturally declines with age. Population-based
continence statistics on younger men is scarce, but we can reasonably assume
that moderate to severe incontinence is a rare occurrence in a 45 year-old man,
and for our purposes, let us suppose that a 45 year old, just diagnosed with
low-risk prostate cancer, is fully continent. What decision maximizes his
lifetime expected continence?
Age
|
A. No natural moderate
or severe incontinence
|
B. Expected lasting
continence for men treated at that age
|
C. Percent losing
continence due to RP at that age
|
D. Probability of
staying on AS if started at 45
|
E. Expected loss of
continence due to decision to initially have RP rather than AS
|
F. Life expectancy
(years)
|
45
|
100%
|
80%
|
20%
|
100%
|
20%
|
34
|
50
|
92%*
|
79%
|
13%
|
76%
|
10%
|
30
|
55
|
84%
|
74%
|
10%
|
64%
|
6%
|
25
|
60
|
81%
|
70%*
|
11%
|
55%
|
6%
|
21
|
65
|
79%
|
66%
|
13%
|
55%
|
7%
|
18
|
70
|
74%
|
63%
|
11%
|
55%*
|
6%
|
14
|
75
|
74%*
|
59%
|
15%
|
55%*
|
8%
|
11
|
Sources:
B.
Younger cohort is from Johns Hopkins
prostatectomy patients, older cohort is from University of Chicago: http://www.jurology.com/article/S0022-5347(06)01930-6/abstract
http://www.jurology.com/article/S0022-5347(10)00017-0/abstract
C.
Column A – Column B
D.
Klotz, assuming plateau continues
E.
Column C x Column D
F.
Social Security actuarial tables
* extrapolated figures
Our fully continent 45 year-old man has about an 80% chance
of retaining his continence if he has an immediate RP. So, about 20% of 45 year-old men will
lose continence if they decide for RP rather than AS. Those 20% will live with
that loss of continence for 34 years.
If he chooses AS instead of RP, what happens in the next 5
years? He has some small natural deterioration of continence, roughly an 8%
expected loss. If he has an RP 5 years from now, his expected continence is
about the same at 79%. Therefore, his net expected loss of continence will be
13% if he remains on AS for the full 5 years. But he has only a 76% chance of
staying on AS for the first 5 years. Therefore, his expected loss of continence
due to the decision to go on AS at 45 and get treated at 50 is 10% - only half
as much as if he had the RP at 45. And he will expect to live with that
incontinence for fewer years.
If he chooses AS at 45 and manages to stay on it for the next
25 years without treatment (a 55% probability), his expected loss of continence
(incorporating the probability of being able to go that long without treatment)
is minimized, at only 6%. And he will only have to suffer the loss for 14
years.
With respect to preserving continence, the 45 year old man
is better off going on AS and staying on it as long as he can. What’s more, it
can be easily shown with a similar continence analysis that a man diagnosed
with low risk prostate cancer at any age, is better off choosing AS
over immediate treatment.
We have ignored the stress incontinence that persists even
after “full” continence is restored. 34 years is a long time to worry about
leakage every time a man coughs, sneezes, laughs or plays sports.
Potency Preservation
Potency is better preserved by prostatectomy while the
patient is younger and fully potent. Is our 45-year old man, newly diagnosed
with low risk prostate cancer and fully potent, better off having a
prostatectomy immediately, or choosing AS? Let’s run the numbers.
Age
|
A. Expected potency
without prostatectomy
|
B. Expected lasting
potency for men treated at that age
|
C. Percent losing potency
due to RP at that age
|
D. Probability of
staying on AS if started at 45
|
E. Loss of potency
due to decision to initially have RP rather than start with AS
|
F. Life expectancy
(years)
|
45
|
100%
|
55%
|
45%
|
100%
|
45%
|
34
|
50
|
94%*
|
49%*
|
45%
|
76%
|
34%
|
30
|
55
|
87%
|
43%
|
44%
|
64%
|
28%
|
25
|
60
|
82%
|
35%*
|
47%
|
55%
|
26%
|
21
|
65
|
74%
|
27%
|
47%
|
55%
|
26%
|
18
|
70
|
60%
|
18%*
|
42%
|
55%*
|
23%
|
14
|
75
|
45%
|
8%
|
37%
|
55%*
|
20%
|
11
|
Sources:
B.
http://jama.jamanetwork.com/article.aspx?articleid=1104401
Supplemental content: eTable3 (97% had nerve-sparing surgery)
C.
Column A – Column B
D.
Klotz, assuming plateau continues
E.
Column C x Column D
F.
Social Security actuarial tables
* extrapolated figures
Our fully potent 45 year-old man has a 55% chance of retaining
his potency if he has an immediate RP.
So, about 45% of 45 year-old men will lose potency if they decide for RP
rather than AS. Those 45% will live with that impotence for 34 years.
If he chooses AS instead of RP, what happens in the next 5
years? He has some small natural deterioration of potency, roughly a 6% expected
loss. If he has an RP 5 years from now, his expected potency will be a less too,
at 49%. Therefore, his expected loss of potency nets out exactly the same (at 45%)
if he remains on AS for the full 5 years. But he has only a 76% chance of
staying on AS for the first 5 years. Therefore, his expected loss of potency due
to the decision to go on AS at 45 and get treated at 50 is 34% - 11 percentage
points less than if he had the RP at
45. And he will expect to live with that impotence for fewer years.
If he chooses AS at 45 and manages to stay on it for the
next 25 years without treatment (a 55% probability), his expected loss of potency
(incorporating the probability of being able to go that long without treatment)
is only half of the expected loss due to immediate treatment, at only 23%. And
he will only have to suffer the loss for 14 years.
With respect to preserving potency, the 45 year-old man is
better off going on AS and staying on it as long as he can. What’s more, it can
be easily shown with a similar potency analysis that a man diagnosed with low-risk
prostate cancer at any age, is better off choosing AS over immediate treatment.
This analysis ignores other important sexual side effects
that would certainly weigh against immediate prostatectomy. Those sexual side
effects include loss of penile length and girth, climacturia, Peyronie’s,
venous leak, dry orgasms, anorgasmia, and dysorgasmia. Baseline erectile
function is seldom restored fully. Loss of libido and psychologically induced
loss of erectile function and depression are common results of all the
aforementioned. Even when erectile function can be induced chemically, there is
significant cost attached to 34 years of ED medicines or injections.
Radiation
The choice is not nearly as clear when the decision is
between AS and radiation therapy (either external beam or brachytherapy) for young
low-risk patients. Incontinence is a very low probability side effect of
radiation, and potency preservation is much better within every age group,
chronic side effects of any kind are rare with modern technology. It is often
argued that we don’t know how cancer control will change with 25+ years of
follow-up after dose-escalated radiation. As we have seen (see this link), recurrence rates did not reach a plateau for RP or IMRT;
however, if we were to examine low-risk patients only, it is likely that
long-term results would be more stable for both surgery and radiation.
It is worth mentioning that there is another bit of “conventional
wisdom” that does not hold up under scrutiny of the medical evidence. Many
urologists incorrectly state or imply that the side effects of radiation are
progressive and won’t show up for many years. Under that scenario, a 45
year-old man treated with radical radiation would eventually wind up with
impotence 10 years later, as well as urinary and rectal problems. The PROSTQA
study (see this link) of men treated in 1999 showed that most of the radiation-induced
toxicity showed up early, and that much of the “late-term toxicity” observed
may actually have been attributable to age, diabetes, and comorbidities (see this link).
The percent experiencing grade 2 or higher urinary
toxicities (excluding incontinence) by 5 years, 8 years, and 10 years after
treatment was:
- · IMRT: 8.6% at 5 years, 11.2% at 8 years, and 10 years (76% of 10-year total by 5 years)
- · BT: 4.3% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
- · RP: 3.1% at 5 years, 3.7% at 8 years, and 5.5% at 10 years (56% of 10-year total by 5 years)
Ironically, we would conclude (erroneously) from the above that it is prostatectomy, rather
than radiation, that has cumulative urinary side effects that progress most over
time.
The percent experiencing grade 2 or higher rectal toxicities
by 5 years, 8 years, and 10 years after treatment was:
- · IMRT: 7.8% at 5 years, 8 and 10 years (100% of 10-year total by 5 years)
- · BT: 1.7% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
- · RP: 0% at 5 years, 8 years, and 10 years (100% of 10-year total by 5 years)
We have seen in a previous commentary that erectile dysfunction due to radiation was lower than
for RP within every age group, that it occurred within the first 9 months
following treatment, and that half of the observed deterioration over time was
due to the normal aging process.
The case for active surveillance and against radical
treatment at a younger age is less convincing if radiation is the treatment of
choice. It is for currently mostly a moot point because younger low-risk
patients are seldom offered radiation therapy.
Conclusions
I have been personally influenced by the testimony of a 45 year-old man in my prostate cancer support group who was inconsolable and under
treatment for suicidal ideation after the loss of continence and potency.
Younger men who are single and suddenly find themselves to be impotent and
incontinent often despair of finding a mate, and younger men who are married
sometimes find their marriages on shaky ground.
It is also important to remember that the longer one is able
to stay on AS, the higher the probability a cure will emerge from all the
research now in the field. Already it seems that 5ARis (Proscar or Avodart) may delay or even reverse progression in low risk PC.
There are a number of hormonal medicines and immunotherapies already being
tested that might prove to be even more potent.
AS protocols are already improving, and will continue to be
safer. Many institutional protocols now dictate that the first follow-up biopsy
should be multiparametric MRI-targeted and/or targeted using a transperineal
mapping biopsy. To avoid the danger of excessive biopsies in younger men, many
institutions have moved off of the original protocol of annual biopsies. After the
first follow-up biopsy, what happens next depends on what happened before. If
there were no signs of any progression, the next biopsy can be two years later;
after that, maybe 4 years with just an imaging study in between, etc. I know
that even Johns Hopkins, which had the strictest AS protocol, relaxed their position
on annual biopsies.
We have now seen that starting with AS is a more rational
decision than starting with RP for all low risk men. However, the decision is
often not a rational one, but is based on fear, traditional “baggage” carried
over from other cancers, and the influence of loved ones, relatives and
friends. In the end, the young patient must decide what he is most comfortable
doing. Maybe it will be AS, maybe SBRT or brachytherapy, maybe surgery. What I
am uncomfortable with is his doctor making those life-changing decisions for the
patient, and ruling out any options without evidence. The low-risk patient
certainly has plenty of time to investigate all options thoroughly for himself
before coming to a decision. Taking one’s time often allows one to put emotions
in perspective. Leaving all options open until one
is ready to decide is the best stance to take. I have only seen treatment
regret in men who didn't take the time to do that.
