Home: PCU
1|2003: Frank A Vicini, MD
Edited comments by Dr Vicini
William Beaumont Hospital brachytherapy dose-escalation
trial
We have evaluated high-dose brachytherapy as a means of dose escalation
for prostate cancer in a series of Phase II dose escalation trials
starting in 1992. The patients had to have a tumor stage of T2b
or greater, PSA of 10 ng/mL or greater, or a Gleason score of 7
or greater. The dose-limiting structure is the rectum, but we’ve
reached the highest planned dose level and not seen serious rectal
complications. The real question is how much dose you need, and
it appears that optimal biochemical local control may peak between
950 and 1050 Rad.
During this trial, studies have been published suggesting that
in these locally advanced patients, some of the subsets benefit
from adjuvant androgen deprivation therapy, and so the trial was
set-up to allow patients to receive endocrine therapy.
Currently, we treat these patients with either 3D conformal therapy
or on our high-dose brachytherapy boost protocol, where instead
of eight weeks of external beam treatment they receive five weeks
of therapy, but they have the two implants interdigitated during
the five weeks of treatment. These patients also generally receive
hormonal therapy for two years, and my preference is for complete
androgen blockade.
I believe that the reason the radiation therapy trials have demonstrated
a benefit for adjuvant androgen deprivation therapy, whereas most
of the surgical trials have not, is that the radiation trials used
more prolonged treatment.
ASTRO criteria for biochemical relapse after radiation
therapy
This is in the process of being redefined. Through the years,
we have seen problems with the definition of three consecutive rises.
One issue is followup and the intervals of testing. Too short of
a follow-up can give a false impression of the true efficacy of
the therapy. Probably the largest research concern has been the
backdating issue, in that failure is defined as the midpoint between
the nadir and the first of three consecutive rises. Early in a trial,
this gives a false impression that a particular therapy is better
than it really is. In other words, instead of saying the patient
failed when they’ve reached the third PSA increase, you backdate
it and say they failed at the midpoint between the nadir and first
consecutive rise. We’ve also found that it has the opposite
effect as the years go on. In other words, it may overestimate the
benefits of radiation early on, but it underestimates the benefits
later on.
Another issue is the clinical impact. If the PSA is not doubling
very quickly, you may be able to just monitor the patient for many
years. Our group looked at more than 40 different modifications
of the ASTRO Consensus Panel definition, and we found that the definition
of the nadir plus 2 ng/mL is very accurate in defining when a patient
has truly failed, but more importantly, this predicted for clinical
significance. I believe the ASTRO consensus panel will convene again,
taking all of this information into consideration and refine the
definition.
Transient false-positive rises in PSA after radiation
therapy (“PSA bounce”)
This even applies to external beam radiation therapy. Any time
you have a very aggressive therapy, like brachytherapy, you can
see a fairly rapid drop in the PSA of some patients. You can have
something as simple as prostatitis, such as inflammation from riding
an exercise bicycle for an extended period, that in effect massages
the prostate and causes a false blip in the PSA. That is one of
the problems with the biochemical failure definitions — these
spikes in the PSA may have nothing to do with the prostate cancer.
They may just be irritation to the prostate.
Fortunately, these elevations are usually transient, but in some
cases they can last for an extended period of time. Generally if
it’s a very small increase that only lasts about three to
four months, it’s of no practical or clinical
significance, but beyond that, it’s really hard to say what
to do with the PSA rises. Essentially, you need to monitor these
patients, but not assume that they’ve failed treatment because
of a very small increase in the PSA.
Advantages of high-dose-rate brachytherapy
With high-dose-rate brachytherapy, the patient is radioactive
only during the actual time the seeds are temporarily implanted.
Also, by placing the needles directly into the gland under ultrasound
guidance, you can control the dose much more precisely than with
the permanent seed implant. With the permanent seed implant, the
prostate can swell after the implant is performed, and the seeds
can migrate after treatment. With high-dose-rate brachytherapy,
what you implant is what you treat. The gland is impaled, and the
actual radiation dose distribution that is calculated is actually
received by the prostate. If you’re going to dose escalate,
high-dose-rate brachytherapy offers the best means of tailoring
the dose precisely to the gland.
Quality control: Tracking prostate gland movement
during radiation therapy
There are quality control issues with both brachytherapy and 3D-conformal
external beam radiation therapy. With 3D-conformal external beam
radiation therapy, generally you’re treating a static image
of the prostate before a treatment. Unless you monitor the prostate
over the course of treatment and how the patient sets up from day
to day, you may not necessarily be treating the same volume each
day. The radiation therapy has to be adapted to how the prostate
changes over time and how the patient moves over time. The prostate
does change shape even though the patient is immobilized. Subtle
changes in the motion of the prostate gland means changes in the
rectum as well. So you have to be very careful because you’re
right on the edge of the dose tolerance.
At our institution, we do serial CT scans during the first week
of treatment to track the motion and shape of the prostate. We track
how the patient moves on the table, and we are even learning how
the prostate moves upon breathing. This is one of the most interesting
areas of investigation right now.
Surgical Prostatectomy versus Interstitial Radiation
Intervention Trial (SPIRIT)
Accrual to the SPIRIT trial will be challenging. About 90% of
my patients have already decided on their choice of therapy by the
time I see them. It’s the rare patient with early-stage prostate
cancer who will be subjected to randomization between prostatectomy
and brachytherapy.
The trial will give us useful information, but I'm concerned about
interpreting the data. How will we tease out the subtle differences
in the manner in which permanent seed implants are performed and
how prostatectomies are performed? Differences in the quality of
the procedures could "wash out" potential differences
between the actual procedures themselves. These are low-risk patients,
so to detect any differences in outcome will require large numbers
of patients.
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