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PCU3|2002: Adam
P Dicker, MD, PhD
Edited comments by Dr Dicker
CASE 1:
64-year-old man with a T1c Gleason 7 (3+4) prostate cancer |
History
This man, employed as a cabinetmaker, was in a very stable
marriage and had adult children. His previous PSA had been
within the age-adjusted normal range, but during the current
evaluation his PSA was 12 ng/mL. A prostate biopsy revealed
a Gleason 7 (3+4) prostate cancer in two cores on the left
and one core on the right, with 20-40% involvement in each
core.
Follow-up
He elected a combination of external beam radiation therapy
with brachytherapy. Towards the end of the external beam radiation,
he experienced more frequent bowel movements, indicating rectal
irritation. As he was healing from that, we did a permanent
radioactive seed implant. He developed a lot of annoying urinary
side effects.
Six months after the implant, his PSA is 0.5 ng/mL, and
it has been dropping very steadily. His urinary symptoms have
persisted, and he wakes up two to three times a night to urinate,
despite being on an alpha-blocker.
Case discussion
A Gleason 3+4 prostate cancer clearly behaves differently
than lower grade prostate cancer. In surgical or radiation
series where those patients were treated with a single modality,
there was an inferior outcome in terms of cure. How to improve
the cure rate for these patients is a subject of much investigation.
From the urology perspective, it is a question of whether
neoadjuvant hormonal therapy or postoperative radiation therapy
might be of benefit. In the radiation oncology community,
the questions have centered on escalating the radiation dose,
combining external beam radiation therapy with brachytherapy
or the use of adjuvant hormonal therapy.
I am very uncomfortable — at least intellectually
— about what the right answer is for this type of patient.
Although I am biased toward brachytherapy and I actually think
external beam radiation therapy with brachytherapy is a way
to increase the dose to the prostate, no data suggests that
external beam radiation therapy plus brachytherapy is superior
to external beam radiation therapy alone.
This patient was interested in brachytherapy. He did not,
however, appreciate that Gleason 7 prostate cancer is more
aggressive than favorable-risk prostate cancer. I had the
unpleasant task of informing him that he would not be an appropriate
candidate for brachytherapy alone. It is not the standard
of care to treat an intermediate-risk prostate cancer patient
(PSA = 12 ng/mL, Gleason score = 7) with brachytherapy alone.
Urologists who counsel patients with intermediate-risk prostate
cancer must caution them about their increased risk of positive
margins, and they should also discuss the available treatment
options for positive margins or extracapsular extension. Had
he elected surgery, his chance of having positive margins
was 40% to 50%. Positive margins do not always equal a death
sentence. Clearly, there are patients with positive margins
who do not have a PSA recurrence. There is also considerable
controversy about who should receive adjuvant therapy in this
situation.
Adjuvant hormonal therapy
There are very few adjuvant hormonal therapy trials in prostate
cancer. In patients with node-positive disease, studies have
demonstrated a benefit for adjuvant hormonal therapy. There
is also a large trial — the Early Prostate Cancer (EPC)
trial — that looked at prostate cancer patients with
localized disease, locally advanced disease and those undergoing
watchful waiting.
In the EPC trial, patients were randomized to adjuvant bicalutamide
150 mg or placebo. Clearly, patients with intermediate-risk
and locally advanced disease benefited from adjuvant therapy.
For the patients with favorable-risk prostate cancer, the
follow-up in the EPC trial is not long enough to know whether
adjuvant therapy is beneficial.
I think there are a group of patients with intermediate-risk
disease — a very broad category — who would benefit
from adjuvant therapy, and a group who would not. It also
depends on the local therapy utilized and whether there are
subsequent local therapies. In the United States, bicalutamide
150 mg is not FDA-approved, and it is not part of my armamentarium.
The role for adjuvant LHRH therapy is also not yet defined
in patients with intermediate-risk prostate cancer. |
Re-implantation of radioisotope seeds for
a suboptimal implant
Earlier in my career, I had two patients in whom I was not satisfied
with the results of the postoperative CT scan, and they required
re-implantation. In those days, I did the postoperative CT scan
on the day of the implant, so I knew immediately whether the seed
distribution was adequate. The patients were re-implanted one month
later, and both have been fine.
It is very complicated to re-implant the prostate, both technically
and from a medical physics standpoint. We are actually writing up
these cases for publication. Re-implantation is not addressed in
the literature, because it is a very difficult situation to manage.
“PSA bounce” after radioactive
seed implant
It has been observed that one and a half to two years after an
implant, patients may suddenly have their PSA double or triple from
its nadir of less than 1 ng/mL. After another few weeks, the PSA
can go up to 5, 10 or even as high as 12 ng/mL. PSA bounce may also
occur three or four years after an implant and is not limited to
the year and a half window, although that is the most common time
period.
It occurs in as many as 20% of patients treated with brachytherapy.
Many of these patients have urinary symptoms, which are reminiscent
of the first month or two after the implant.
At first, it was thought that it might be caused by a urinary
tract infection, but that did not pan out. I believe “PSA
bounce” is related to some nonspecific inflammatory event
in the prostate, which we do not understand, but provides a great
deal of anxiety to the patient and the doctor.
It is difficult to differentiate a “PSA bounce” from
tumor recurrence. In a favorable-risk patient, however, tumor recurrence
does not usually occur a year and a half after external beam radiation
therapy or brachytherapy. Usually, patients with favorable-risk
prostate cancer fail about two to three years, or sometimes later,
after treatment. Patients with intermediate-risk and locally advanced
disease fail earlier. During these PSA bounces, patients require
considerable reassurance.
Commentary on the update of the Bolla trial
A paper, recently published in The Lancet, substantiates the 1997
report in the New England Journal of Medicine of the benefit of
hormonal therapy in patients receiving radiation. The long-term
cure rates are significantly improved with hormonal therapy, and
patients with the worse disease are the ones who benefit the most
from hormonal therapy added to radiation therapy.
It is not yet known whether three years of hormonal therapy is
required. The EORTC is currently comparing six months to three years
of total androgen blockade.
A major criticism of the trial is whether the radiation therapy
is actually necessary. Some of these patients may have been cured
by hormonal therapy alone. However, it is very difficult to compare
hormonal therapy alone to radiation therapy alone and hormonal therapy
plus radiation therapy. From a patient’s perspective, all
the arms are not equally balanced.
CASE 2:
65-year-old man with Gleason 8, cT2a prostate cancer |
History
This very active attorney had been getting his PSA checked
about every other year. His PSA was generally in the 3.5 to
4 ng/mL range. For reasons that were unclear, he missed his
physical exam. When it was finally rescheduled, his PSA was
15 ng/mL and he had an abnormal rectal exam with induration
on the right.
A transrectal ultrasound-guided biopsy revealed Gleason
4+4 prostate cancer in 70% of two cores on the right. A bone
and CAT scan did not reveal any evidence of osseous disease
or lymphadenopathy.
Follow-up
He opted for a combination of hormonal therapy and radiation
therapy. Because his gland was somewhat bulky, he was treated
with three to four months of hormonal therapy before the radiation
therapy. He continued on hormonal therapy during the radiation
therapy, and he has been on it now for two and a half years.
My goal is for him to receive three years of hormonal therapy.
Then, he will continue to be monitored.
After three weeks on hormonal therapy, he noticed a loss
of libido. He was not happy about it, but he was in a stable
relationship and his wife was extremely supportive. After
a couple of months, he started experiencing hot flashes, which
he did not find too bad. Then after about a year and a half,
he noticed a 10-pound weight gain around his midsection that,
despite all attempts to exercise and diet, still remains.
Case discussion
Although this may appear to be a very simple case, it is
not necessarily straightforward. Had the patient opted for
surgery, his probability of having positive margins was high.
Some physicians believe that it is best to debulk the prostate
by removing it and then follow with postoperative radiation
therapy. Another group of doctors believes that if the patient
will have positive margins, the probability of failing is
high and some other forms of local therapy, such as radiation
therapy, might provide similar benefits without removing the
prostate.
Based on a number of studies from the Radiation Therapy
Oncology Group (RTOG) and the EORTC, hormonal therapy plus
radiation therapy is superior to radiation therapy alone in
patients with locally advanced disease. Although the EORTC
trial, with three years of hormonal therapy, is the only one
demonstrating a survival benefit, it is the best data we have
now.
My philosophy is that this man had a systemic element to
his disease. Although local control is important, it is not
sufficient for a cure. Some physicians would order a ProstaScint®
scan in this group of patients. If it showed disease in the
supraclavicular fossa, that could make an impact on the selection
of therapy. Others may use the ProstaScint® scan to decide
whether to treat the pelvis with radiation. In a younger patient,
some physicians might recommend a laparoscopic node dissection.
If the nodes were positive, then the patient might get radiation
or hormonal therapy. The hormonal therapy would be given indefinitely,
similar to the Messing trial.
For this patient, I recommended long-term androgen suppression
and radiation therapy. I felt that was the standard of care.
If the patient wanted to try to do something beyond radiation
therapy with hormonal therapy, it would be in the context
of a clinical trial evaluating the role of chemotherapy in
addition to hormonal therapy and radiation therapy. This patient,
however, felt that the potential benefits of chemotherapy
did not outweigh the potential toxicity, and he did not want
to pursue that avenue.
Without hormonal therapy, this man’s chance of relapse
was 50% to 60%. The risk of recurrence would probably be reduced
by 15% to 20% with the addition of hormonal therapy. He reluctantly
accepted the hormonal therapy.
He was not thrilled to hear that hormonal therapy would
result in decreased libido and erectile dysfunction —
effects that can persist even after the hormonal therapy is
discontinued. With two or three years of hormonal therapy,
there is a 5% to 10% chance that libido and sexual function
may never return.
Had bicalutamide 150 mg been available, he might have been
more interested in that option. Bicalutamide 150 mg does not
have the same negative impact on muscle mass, libido and erectile
function. The patient would have had to balance the side-effect
profile of bicalutamide relative to an LHRH agonist. I am
in favor of patients having more, not less, options.
The EPC trial evaluated the role of bicalutamide 150 mg
in the truly adjuvant setting. On the other hand, the Bolla
study and the RTOG studies gave concurrent and continued hormonal
therapy. We need trials comparing the positive arm of the
Bolla trial to bicalutamide 150 mg. It is important to counsel
patients who will be on hormonal therapy for a long period
of time about the potential side effects, including hot flashes
and weight gain. They should also be informed that what they
experience in the first few months of hormonal therapy might
not be the same as after two years. They should feel free
to bring up these side effects on their visits.
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