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PCU3|2002: Eric
A Klein, MD
Edited comments by Dr Klein
Cleveland Clinic prostate cancer database
We developed a localized prostate cancer database in which we
have almost 5,000 patients treated in the PSA era for localized
prostate cancer with either external beam radiation therapy or surgery.
We have been able to demonstrate in a prospective fashion that
the biochemical failure rates between those two treatments are equal
at about ten years. My gut feeling is that well-selected patients
will respond favorably to either therapy and that the differences
in outcome and quality of life are relatively minor.
| Equivalent efficacy
of radical prostatectomy and external beam radiation therapy
for localized prostate cancer in the PSA era |
"Eight-year
biochemical failure rates were identical between RT and RP
in any subgroup. Outcome is determined mainly by pretreatment
PSA levels, bGS, clinical T stage and, for RT patients, radiation
dose. . . .”
. . . One major criticism of comparisons
between radiation and surgery for localized prostate cancer
has been the use of two different end point definitions. Using
the more stringent definition of reaching and maintaining
a PSA level < 0.5 ng/mL in both RP and RT patients did
not change the ultimate conclusion that there were no differences
in outcome between the two modalities that could not be accounted
for by differences in patient selection." |
| EXCERPT FROM: Kupelian PAet al. Comparison
of the efficacy of local therapies for localized prostate cancer
in the prostate-specific antigen era: A large single-institution
experience with radical prostatectomy and external-beam radiotherapy.
J Clin Oncol 2002;20:3376-3385. Abstract
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Prostate cancer treatment decisions
There are a couple of pieces of information I share with every
patient. First, they will have some side effects irrespective of
the therapy they choose, although the side effects will be specific
for each treatment. Second, based upon our observations, they cannot
make a wrong choice — any therapy is likely to give them good
cancer cure for the first ten years.
The real anxiety for both the physician and the patient is associated
with the younger men with prostate cancer, who are more difficult
in some ways and easier in others. Preservation of potency and continence
is an important issue postprostatectomy. In all major series, younger
patients have a better chance of having their potency and continence
preserved.
The main reason urologists limit the use of radiation therapy
in younger patients is the theoretical possibility that the local
failure rate will be higher with anything that preserves the primary
organ. If you look at other tumors, both urologic and nonurologic,
that is probably correct. However, in our localized prostate cancer
database, the local recurrence rate is the same at ten years for
surgery and radiation therapy.
For the youngest patients (40 to 50 years old), I think radical
prostatectomy is the preferred treatment option. The reasons are
twofold. First is the theoretical chance of a lower local recurrence
rate. If the prostate is left in place and the patient lives another
20 or 25 years, some of the normal epithelial cells in the prostate
can survive and form a second tumor.
The other incontrovertible advantage to a radical prostatectomy
is the pathology report, which provides powerful prognostic information,
such as the grade of the tumor, the percentage of Gleason 4 cancer
and the presence of extracapsular extension or positive margins.
Since there are patients who are upgraded from a Gleason score
of 6 to 7 based on the surgical pathology, a pathology report is
a better prognosticator than pretreatment characteristics. There
are also occasional patients who clinically have organ-confined
disease, but may actually have seminal vesicle invasion. When prognosticating
for a patient, the pathology report is better than the pretreatment
parameters.
Ongoing adjuvant chemotherapy trials
We are currently enrolling patients in two adjuvant chemotherapy
trials. The first study is a phase III Southwest Oncology Group
(SWOG-9921) trial, which is evaluating combined androgen blockade
for two years with or without mitoxantrone/prednisone for six months.
The second study, a phase II feasibility trial, is evaluating docetaxel
alone for up to six months.
Counseling node-positive prostate cancer
patients about adjuvant therapy
In counseling patients, I tell them, “Mr. Jones, you have
an aggressive cancer. And our experience over the last decade has
taught us that you’re not likely to be cured by a single treatment.
I don’t really know what the best treatment is, whether that’s
radiation or surgery or a combination of radiation and hormones
or chemotherapy and surgery, but I am absolutely convinced that
you need more than one treatment.” Then, I present all the
options. Ultimately, I let the patient decide what appeals to him
the most. Probably half of my patients with node-positive prostate
cancer who are not eligible for a clinical trial decide to go on
adjuvant hormonal therapy. Two factors drive that decision. First,
patients have a morbid fear of having positive lymph nodes —
they know it is a bad thing. Second, the Messing trial received
a lot of press, and patients specifically ask about it.
Prostate Cancer Journal Club
Validation study of the accuracy of a postoperative
nomogram for recurrence after radical prostatectomy for localized
prostate cancer.
Graefen M et al. J Clin Oncol 2002;20(4):951-6. Abstract
Mike Kattan, a statistician first at Baylor and then at Memorial
Sloan- Kettering, developed a series of nomograms for predicting
the likelihood of cure after treatment with surgery, radiation therapy
or brachytherapy. They are an evolution from the prior nomograms,
particularly the Partin tables, which actually predict for pathologic
stage and extracapsular extension as a surrogate for cure.
Kattan retrospectively reviewed large databases of prostate cancer
patients treated with surgery, radiation therapy or brachytherapy.
He then determined the likelihood of biochemical failure at a given
time point, either five or seven years after therapy.
There are preoperative, postoperative, preradiation therapy and
prebrachytherapy nomograms. These nomograms are available in a software
package that can be downloaded onto a hand-held PDA.
The nomogram in this paper by Graefen et al is a postoperative
nomogram. In patients electing prostatectomy because of favorable
preoperative characteristics, the nomogram can predict the likelihood
of being disease-free seven years postprostatectomy. Based on that
prediction, a decision can be made as to whether or not adjuvant
therapy might be appropriate.
This paper was based on the worldwide experience of almost 3,000
patients who underwent radical prostatectomy. The original nomogram
was based on a single surgeon’s series, Peter Scardino, from
Baylor and Memorial Sloan- Kettering.
To order prostate nomograms:
http://www.mskcc.org/mskcc/html/5796.cfm
CASE 3:
48-year-old man with a family history of prostate cancer |
History
This man had a normal rectal exam, and his first PSA was
2.6 ng/mL. Since his father was diagnosed with prostate cancer
at age 62, he sought advice about whether to undergo a prostate
biopsy.
Follow-up
He had a prostate biopsy that was positive for prostate
cancer. He was treated with radical prostatectomy, which revealed
organ-confined disease.
Case discussion
Based on the early screening studies, a prostate biopsy
would not have been indicated until the PSA reached a level
of 4 ng/mL, despite this patient’s positive family history.
Recently, Catalona and others have reported a 20% incidence
of prostate cancer when the PSA is between 2.5 and 4 ng/mL.
Given the relatively low morbidity associated with a prostate
biopsy and a 20% chance of having prostate cancer, I recommended
a prostate biopsy for this individual. There is data, which
has not always been interpreted in a uniform fashion, suggesting
that the lower the PSA at diagnosis, the greater likelihood
of having organconfined disease. This is not true in every
case. For example, some very high-grade tumors (Gleason of
8 to 10) do not produce much PSA.
But for lower-grade tumors, there is a linear relationship
between PSA at diagnosis and the likelihood of having organ-confined
disease. If one accepts that early treatment is going to lower
the mortality rate for prostate cancer, again recognizing
the controversy, it makes sense to biopsy younger men with
PSAs below 4 ng/mL.
In 1995, Phil Gann published in JAMA a follow-up to the
Physicians Health Study in which he looked at the risk of
developing prostate cancer based on a bank of serum PSAs.
He found that PSA predicted the likelihood of developing a
clinically significant Gleason = 7 prostate cancer with about
5.5 years of lead time. Even those men with a PSA below 4
ng/mL, but above 1 ng/mL, had a greater likelihood of having
prostate cancer than those with a PSA below 1 ng/mL.
Even within the “normal” range, PSA stratifies
risk. That was another reason to consider a biopsy in this
gentleman. Furthermore, even though it is unlikely this man
has a true hereditary form of prostate cancer, a positive
family history in a first-degree relative doubles the risk
of being diagnosed with prostate cancer. |
Prostate Cancer Prevention Trial (PCPT)
In 1993, the Prostate Cancer Prevention Trial (PCPT) was initiated
on the basis of the hypothesis that cumulative androgen exposure
increases the risk of prostate cancer.
The PCPT randomized 18,000 men to either placebo or finasteride
for seven years. At the end of seven years, a prostate biopsy will
be performed and the rates of prostate cancer will be compared in
the placebo and finasteride groups. The last biopsies will be done
in 2003. Therefore, we ought to have some data by late 2003 or early
2004.
CASE 4:
52-year-old man with high-grade prostatic intraepithelial neoplasia
(PIN) |
History
This man had a normal rectal exam, a PSA of 5.1 ng/mL and
a sextant biopsy that revealed high-grade prostatic intraepithelial
neoplasia (PIN).
Follow-up
This patient had another biopsy, which was negative for
both cancer and high-grade PIN. He is being followed at six-month
intervals with a PSA level and a DRE. He has not been rebiopsied.
Case discussion
PIN is considered a precancerous condition that has a 10%
to 30% chance of ultimately becoming prostate cancer.
In a man with a normal rectal exam and PSA between 4 and
10 ng/mL, the likelihood of finding cancer with six biopsies
is probably about 20%. If you do a second set of six biopsies,
the likelihood rises to around 35%. It is now possible to
combine the second set of sextant biopsies with the first
set. The use of local anesthesia in the office has aided our
ability to do more biopsies.
Obtaining 8 to 12 biopsies in the first sitting, one can
detect all of the cancers that used to require two sets of
sextant biopsies. Initially, this patient did not have an
adequate biopsy sampling. Currently, the standard recommendation
for high-grade PIN is to rebiopsy the prostate to make sure
a cancer was not overlooked because of sampling error.
There is no standard recommendation for patients who do
not have PIN or cancer on rebiopsy. Generally, I follow those
patients with a rectal exam and a PSA level at six-month intervals.
When either changes in some significant fashion, a rebiopsy
is indicated.
The Southwest Oncology Group (SWOG-9917) is studying patients
who have had two sets of biopsies, in which at least one demonstrates
high-grade PIN. The SWOG trial is a randomized comparison
of placebo and selenium taken daily for three years followed
by a repeat biopsy. I try to encourage these patients to enter
this SWOG trial. |
Selenium and Vitamin E Cancer Prevention Trial
(SELECT)
The hypotheses behind SELECT are two separate epidemiologic observations.
First, the Clark trial — designed to determine whether selenium
prevented nonmelanoma skin cancer in 1,300 men — found a marked
reduction in the incidence of prostate cancer in those who took
selenium.
Second, the ATBC trial evaluated whether beta-carotene or vitamin
E (alone or in combination) in 29,000 Finish smokers could reduce
the risk of lung cancer. There was a marked reduction both in the
incidence and mortality due to prostate cancer associated with vitamin
E.
The primary objective of SELECT is to determine whether selenium
or vitamin E, alone or in combination, can prevent prostate cancer.
It is a four-arm trial randomizing 32,400 men to vitamin E plus
a placebo, selenium plus placebo, vitamin E plus selenium or two
different placebos.
We need long-term exposure to these agents that are hypothesized
to act as antioxidants. There will be five years of accrual, and
the trial will end seven years after the last participant is enrolled.
Therefore, the first individual enrolled will be on therapy for
12 years, and the last individual enrolled will be on therapy for
seven years. The average exposure to treatment will be a little
over eight and a half years.
An end-of-study prostate biopsy is not required. The end point
will be the clinical diagnosis of prostate cancer as discovered
by routine clinical care (i.e., an annual rectal exam and PSA level).
If you look at ATBC and the Clark trial, the risk reductions were
pretty marked, 40% better. SELECT was powered with more conservative
risk reduction estimates of 25% for each agent alone and about 44%
for both together.
Select publications
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