Home:
PCU2|2002: Anthony
V D’Amico, MD, PhD
Edited Comments by Dr D'Amico
Brachytherapy
If quality-assured, brachytherapy offers low-risk patients the
opportunity to escalate the radiation dose and spare much of the
toxicity. Acutely, patients have more urethral symptoms. Long term,
impotence is no better, but radiation proctitis may be improved
with brachytherapy compared to external beam radiation. The quality
assurance for brachytherapy should include CT-based postimplantation
dosimetry. For intermediate-risk patients, many believe brachytherapy
should be combined with external beam radiation. Only the Seattle
group believes implants alone can be used in intermediate-risk patients.
We use MRI-based implants, which are a little more precise. For
the most part, ultrasound-based implants are fine as long as there
is quality assurance afterwards.
Adjuvant hormonal therapy
For T3-4 disease, there is no argument that the standard of care
should include long-term hormonal blockade. RTOG and EORTC consider
two and three years of hormonal therapy, respectively, to be long-term.
Two years is most commonly used.
In localized disease, I would recommend the addition of hormonal
therapy for a high-risk patient or an intermediate-risk patient
who has unfavorable features (i.e., Gleason score = 4+3 or PSA >
10 ng/mL and more than half of the biopsy cores positive). These
patients are more likely to have a systemic, as opposed to a local-only,
pattern of failure. I would use six months of hormonal therapy —
two months before, two months during and two months after radiation
therapy.
Higher radiation doses
Since men receiving hormonal therapy are also at risk for local
failure, do they need higher radiation doses? This question remains
unanswered. I am conducting a clinical trial at our institution
using a higher radiation dose in combination with six months of
hormonal therapy. We protect the rectum by using a 3-D conformal
technique and inserting an intrarectal balloon for either the first
or the last three weeks of radiation. I obtain a lateral port film
to see the balloon, set my posterior border so the rectum is almost
completely excluded and then treat. That is the only way I feel
comfortable using highdose radiation and hormones.
I am convinced that rectal toxicity is lower with 3-D conformal
radiation therapy, as suggested by a number of phase II studies.
I think 3-D conformal radiation therapy is key from a quality-of-life
perspective. A Foley catheter and a rectal tube should no longer
be used to locate the prostate. A CT-based simulation or at least
a CT scan to transfer onto bony anatomy should define our target.
Dose-escalations beyond 72 Gy without a conformal approach are dangerous,
because one does not know the location of the rectum. The conformal
technique is a technical advance with quality-of-life improvements.
The Surgical Prostatectomy versus Interstitial
Radiation Intervention Trial (SPIRIT)
The SPIRIT trial, conducted by the American College of Surgeons,
will compare two treatment modalities in patients with low-risk
prostate cancer. Patients will be randomized to either radical prostatectomy
or brachytherapy. This trial is particularly important because it
will help to define both quality of life and cancer control outcomes
in a disease state — low-risk prostate cancer — that
has become the most prevalent as a result of PSA-based screening.
Hormonal therapy in combination with radiation therapy
There have been a number of studies, conducted primarily by the
RTOG and the Europeans, evaluating the role of hormonal therapy
in combination with radiation therapy. The main study, published
by Bolla in the New England Journal of Medicine in 1997, was the
EORTC trial. This trial, which changed practice patterns, added
three years of hormonal therapy both during and following radiation
therapy in patients with locally advanced prostate cancer. Since
that trial was published, the standard of care for patients with
T3-4 prostate cancer has become radiation and hormonal therapy.
In patients with localized prostate cancer, three trials have
been completed and await follow-up. RTOG 9408 compared four months
of hormonal therapy (two months prior and two months during radiation
therapy) to radiation therapy alone in patients with T1-2 disease,
PSA < 20 ng/mL and any Gleason score. A second trial, conducted
at Dana-Farber Cancer Institute, randomized patients with intermediate-
and high-risk prostate cancer to radiation with or without six months
of hormonal therapy (two months prior, two months during and two
months after radiation therapy). The final study, by the Europeans,
also compares six months of hormonal therapy to no hormonal therapy
in radiation-managed patients with localized prostate cancer.
These studies will determine whether the addition of hormonal
therapy can improve survival in patients with localized disease
who are treated with radiation therapy. Currently, most radiation
oncologists in the United States are adding hormonal therapy to
radiation therapy in patients with localized prostate cancer and
a PSA > 10 ng/mL or a Gleason score = 7. The regimen is short
term, usually anywhere from four to six months. However, we are
awaiting these trial results to answer this localized prostate cancer
question definitively.
Standard hormonal therapy consists of complete androgen blockade
with an LHRH agonist and a nonsteroidal antiandrogen. A study is
currently being planned to compare bicalutamide 150 milligrams to
complete androgen blockade. Until results from that trial are available,
we have not moved to using high-dose bicalutamide alone. However,
instead of using no hormonal therapy in patients refusing an LHRH
agonist — maybe because of qualityof- life issues —
we may offer them high-dose bicalutamide monotherapy.
Patients with low-risk prostate cancer
In patients with low-risk prostate cancer, current radiation doses
may be inadequate. An abstract presented at the AUA meeting, suggests
that conventional radiation therapy doses (70 Gy) are not as effective
as radical prostatectomy after eight years of follow-up in low-risk
or low-volume, intermediate-risk patients. Radiation therapy is
less effective than radical prostatectomy in otherwise low-risk
prostate cancer patients, because the radiation doses used are ineffective
to sterilize one or two cubic centimeters of adenocarcinoma. There
are no other sites in the body where we can completely sterilize
two cubic centimeters of adenocarcinoma with radiation doses of
70 to 85 Gy. The exceptions are head and neck or gynecologic cancers,
but those are predominantly squamous cell.
According to the Bolla trial, hormonal therapy in combination
with radiation therapy provides some synergy that seems to improve
patient outcomes. RTOG 9413 asked, “Is hormonal therapy better
when given before and during than after radiation therapy?”
Radiation therapy given concurrently with hormonal therapy was the
superior regimen in that study in terms of progression-free survival
— overall survival cannot be determined yet. RTOG 9413 and
the Bolla trial indicate that some type of synergy occurs in terms
of tumor cell kill when radiation and hormonal therapy are combined
synchronously. In patients with low-risk prostate cancer, there
are two approaches: one is to increase the radiation dose, and the
other is to add hormonal therapy to the standard radiation dose.
Managing PSA recurrence after radiation therapy
A retrospective study that will be published this summer shows
that when hormonal therapy is started before the bone scan becomes
positive in the postradiation therapy setting, the duration of response
and survival is longer. It is a retrospective study, so it is not
randomized. Therefore, it is not a conclusion, but a hypothesis.
However, based on this data, my policy has been to not wait much
beyond a PSA of 10 ng/mL to treat the patient. Around a PSA level
of 10 ng/mL, bone scans start to become positive. In several hundred
patients with a rising PSA after radiation that had not yet reached
10 ng/mL, we did not find a single positive bone scan. Once the
PSA got above 10 ng/mL, bone scans started to become positive. Above
20 ng/mL, then most of the bone scans were positive.
Early versus delayed hormonal therapy
Three studies in the literature support early, rather than delayed,
hormonal therapy. The Bolla trial essentially compares adjuvant
and delayed hormonal therapy in patients with T3-4 disease. The
Messing trial compares immediate and delayed hormonal therapy in
node-positive patients treated by radical prostatectomy. The Medical
Research Council trial compares early and delayed hormonal therapy
in patients with metastatic or T3-4 disease. All of those trials
can be criticized for various reasons, but they all, as a group,
support the concept of early hormonal therapy.
Initiating hormonal therapy at PSA recurrence
I either offer patients with PSA elevation a clinical trial or
immediate hormonal therapy, if they wish. If they do not want treatment,
I say, “Okay. I’m comfortable waiting until your PSA
is 10 ng/mL, not beyond that because of the positive bone scan issue.”
Bicalutamide monotherapy may be more appealing to a patient with
a biochemical relapse who does not want to be treated with castration.
But, we do not know whether combined hormonal blockade and high-dose
bicalutamide are equally effective. Some patients have accepted
high-dose bicalutamide as an alternative. Since they are getting
some therapy, but not experiencing the full repertoire of side effects,
many of them are happy with it as a compromise. In terms of the
quality of life for bicalutamide monotherapy compared to an LHRH
agonist, patients need prophylactic irradiation up front for the
gynecomastia; they do not get as anemic and are not as fatigued;
they do not have the same degree of hot flashes; and they maintain
their libido. Overall, for a man in his fifties or sixties, it definitely
provides an improvement in quality of life. But, we do not know
the cancercontrol outcome.
Bone mineral density is also decreased with hormonal therapy.
A recent New England Journal of Medicine article by Matthew Smith
suggests that the bone density loss can be reversed by the addition
of a bisphosphonate during hormonal therapy. While there is no proven
cancer-control benefit, it may very well be down the road. Bisphosphonates
appear, in terms of bone density, likely to impact on the risk of
developing a pathologic fracture in the future.
PSA doubling time as a predictor of survival
There are six studies in the literature — three in surgical
and three in radiation therapy patients — which have evaluated
a number of parameters in terms of their ability to predict the
time to bone scan progression and death from prostate cancer after
the initiation of hormonal therapy. All six studies have one factor
in common — the rate at which the PSA rises following local
therapy. If the PSA doubles within 6 to 12 months after local therapy,
the patient is likely to develop a positive bone scan and subsequently
die of the disease sooner.
In a group of 381 men managed with 70 Gy of radiation for T1-2
disease, we looked at prostate cancer-specific and overall survival.
On a multivariate analysis, a PSA doubling time of less than a year
was the most important predictor of time to prostate cancer death
following the PSA failure. When we plotted cancer-specific survival
and overall survival and stratified by PSA doubling time, we found
that cancer-specific survival and overall survival for patients
whose PSA doubling time was less than a year was essentially equal.
This meant that if a man with a PSA doubling time less than a
year following radiation died, he died of prostate cancer. Possibly,
a doubling time of less than year may be a surrogate for prostate
cancer-specific death. Since the median age at diagnosis was 73
and the men had comorbid illnesses, these results are particularly
intriguing.
In patients with a PSA doubling time greater than a year, cancer-specific
survival five years following PSA failure was 95%. Our results mimic
the Pound paper from Johns Hopkins, which found that it took on
average eight years to go from PSA failure to distant failure and
another five years to die — a total of 13 years until death.
This indicates that the Johns Hopkins group is well selected for
low- to intermediate-risk patients. Therefore, they do not have
patients with a fast PSA doubling time. In our study, the patients
with a PSA doubling time of less than a year had a five-year median
survival from PSA failure to death.
I am looking at larger databases to validate whether or not a
PSA doubling time less than a year is a surrogate for cancer-specific
survival. If it is, this may have an enormous impact on clinical
trial design. If we had a surrogate end point for cancer-specific
survival (i.e., PSA doubling time less than a year), the number
of patients required to answer a question in a phase III trial would
decrease markedly, the follow-up period would also decrease markedly
and answers would be available more quickly.
Select publications
|
