MARK SCHOLZ, MD
The largest oncology
market in the world is the early-stage prostate cancer market. Every year, 80,000
men undergo surgery. Even greater numbers are treated with IMRT, seed implants,
cyberknife and proton therapy.
What about Hormones?
Hormone therapy is
another popular treatment approach, especially for older men. For example, the
Capsure database indicates that hormone blockade is used more commonly than
radioactive seeds. Randomized clinical
trials also indicate that intermittent
hormone therapy is feasible: Men who stop
hormone therapy and take “treatment holidays” have identical survival rates to
men who stay on continuous treatment.
Standard Treatment is Deplorable
Since PSA screening
started in the early 1990s, surgery and radiation have been all the rage. Aggressive treatment has succeeded in reducing
annual prostate cancer mortality by half a percent. Now “only” 2.5% of men die
of prostate cancer. Previously, prior to the advent of PSA screening, 3% of men
died from prostate cancer. The “cost” of achieving this mortality reduction,
however, should be measured in terms of diminished quality-of-life. The
frequency of serious side effects is typically under-appreciated. For example,
at the highest quality treatment centers only 5% of men recover sexual function
similar to what they enjoyed prior to treatment. 7% of men are grossly incontinent;
50% have stress incontinence and 20% chronically ejaculate urine.
The reason for such a
minuscule impact of local treatment on survival is obvious: Surgery and
radiation are only effective when implemented prior to metastases. Ironically,
until metastases occur, local treatment is unnecessary. After metastases, local
treatment is ineffective. Logically, early
therapy with an anticancer agent with both local and systemic effects will
result in better cancer control.
Active Surveillance is Now Mainstream
It is now known that Low-Risk disease (Gleason 6, PSA <
10, Stage T1c or T2a) can safely be monitored with active surveillance. At worst,
active surveillance has the positive effect of delaying treatment and postponing treatment-related side effects
like impotence and incontinence. With delayed local treatment, men benefit from
the fact that medical technology is continually improving. The best case scenario of active surveillance
is when cancer never progresses and men are able to avoid treatment
active surveillance methodology relies on periodic random 12-core needle
biopsies. Now encouraging studies are
reporting that 3T multiparametric MRI detects high-grade disease more
accurately than biopsy. Also, new
computerized imaging technology enables doctors to record the exact location of
the cancer within the prostate gland so that areas of known disease can accurately
be resampled with targeted biopsies.
Hormone Therapy Causes
Remission of Localized High-Risk Disease
with Reversible Side-Effects
study using a six-month induction course of abiraterone (Zytiga) shows complete
pathologic remission or close to complete remission in a third of men with High-Risk disease. Logic predicts that
complete response rates will be substantially better in men with Intermediate-Risk prostate cancer.
the most part, side effects of hormone therapy are reversible or preventable—hot
flashes, breast enlargement, osteoporosis, and erectile dysfunction respond to
DepoProvera, Femara, Prolia and Viagra respectively. Muscle atrophy can be
counteracted with strength training. Low libido dissipates after therapy is stopped.
Careful diet averts weight gain.
the reversibility of hormone therapy depends on the resumption of normal testosterone
production after treatment is stopped. Unfortunately, LHRH agonists, the
traditional hormone medications employed, often induce lingering low
testosterone levels. Some men, particularly those over 70, are saddled with permanently
Xtandi is Well-Suited
to Intermittent Administration
has several potential advantages over LHRH agonists. First, it is more potent. Studies show that Xtandi has notable activity
even after cancer had developed resistance
to LHRH agonists. Second, Xtandi blocks
testosterone activity rather than suppressing testicular production. Therefore
the risk of delayed testosterone recovery or long-term testicular atrophy is
circumvented. Third, though perhaps this
is a relatively small issue, most men would rather take a pill than a shot.
An Observational Trial of Intermittent Xtandi Could
Laurence Klotz, M.D.
prospectively accrued men with Low-Risk
(and some Intermediate-Risk) prostate
cancer to a simple observational trial starting in the mid-1990s. By simply reporting a very favorable ten-year
mortality rate he brought about a total change in clinical practice patterns in
the United States and throughout the world.
Intermittent hormone therapy as primary treatment is
certainly feasible for localized prostate cancer. Active surveillance methodology has been
refined with improved imaging. New
genetic tests can estimate cancer aggressiveness with more accuracy. The animus
to delay treatment, even for a few years, is increasing as the pace of
technological innovation accelerates and the hope for the discovery of less
toxic treatment increases. Now, with the recent FDA approval of this more
potent, more convenient oral agent that is free of lingering effects, the
impetus for men to embark on a six-month induction course of Xtandi followed by
active surveillance will be even greater.
Meaningful Endpoint for an Observational Clinical Trial
Published studies already document excellent survival with
primary hormone therapy (see attached). Hence, the most meaningful clinical
outcome measure of Xtandi efficacy would be its capacity to forestall or delay local
treatment. The objective endpoint, therefore, should measure the number of
months or years before local therapy is required, starting from the date of
initiating Xtandi and ending when (and if) local therapy is ultimately
While complete avoidance of local treatment may be a
frequent occurrence (in the men who show durable responses to a single cycle of
Xtandi) it can be anticipated that men who have locally recurrent disease and whose
initial experience with Xtandi was tolerable, may elect to use repeated cycles
of Xtandi at the time of recurrence rather than risking the potentially
irreversible side effects of local therapy. Conversely, the men most likely to
select local therapy are those who experience a particularly short treatment
holiday or suffer more severe hormone-related side effects.
A six-month course of Xtandi can also function as a
“disease-related stress test.” Men in the subgroup manifesting either high PSA
nadir or rapid disease recrudescence after treatment are those most likely to
harbor an aggressive prostate cancer variant. Thus, this initial “test” using Xtandi
will help ensure that men referred for radical local therapy are those who actually