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PCU 4|2002: Leonard
G Gomella, MD, FACS
Edited comments by Dr Gomella
CASE 1:
58-year-old man presenting with a neck mass and PSA over 500
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History
In 1991, this man noticed a kiwi-sized mass in his neck
while shaving. He went to the doctor, and his PSA exceeded
500 ng/ml. Biopsy of a left supraclavicular lymph node revealed
metastatic adenocarcinoma, consistent with prostate cancer.
The prostate was nodular on physical exam, and biopsy showed
Gleason 8/9 prostate cancer throughout the gland. Abdominal
CAT scan and bone scan were negative.
Follow-up
At that time, we were participating in a trial led by Paul
Schellhammer evaluating combined androgen blockade —
a prospective double-blind trial randomizing patients to either
bicalutamide (50 mg) or flutamide combined with either goserelin
or leuprolide. We entered this patient in the trial, and his
PSA subsequently became undetectable. His neck mass completely
disappeared, he felt fine, had no evidence of metastases and
continued in the study. His PSA remained undetectable for
almost eight years.
We later found out that he had been randomized to goserelin
and bicalutamide, which was continued even after the trial
was over. In 1999, his PSA started to bump up. It went to
.5, then to 1, and then to 1.5.
We stopped the bicalutamide, and his PSA gradually came
back down again. To this day, almost two years since the bicalutamide
withdrawal, this man is in remission with an undetectable
PSA on goserelin alone.
Case discussion
We would not have expected this man to live this long, yet
he is doing very well. His PSA did not drop precipitously
when we stopped the bicalutamide, but it gradually came down
almost the same way it went up. We reported this case in the
literature as one of the earliest cases of bicalutamide withdrawal.
Interestingly, it was a durable response that has now lasted
several years.
We know surprisingly little about the mechanism of antiandrogen
withdrawal. Flutamide withdrawal has potentially been traced
to a specific genetic alteration in the androgen receptor,
causing flutamide to act as a receptor agonist, rather than
a receptor blocker. The mechanism of bicalutamide withdrawal
is not understood, but the withdrawal phenomenon has now been
seen with all of the antiandrogens.
Most patients, however, do not have a durable response to
antiandrogen withdrawal — it usually only lasts six
to eight months. You can rotate antiandrogens with some patients
and obtain some long-term PSA responses, putting them on and
taking them off flutamide, bicalutamide or nilutamide. The
medical oncologist at our center uses high-dose bicalutamide
before committing to chemotherapy in patients who continue
to progress after several antiandrogens.
If and when this man progresses again, we will probably
try a different antiandrogen. But currently, he is stable.
El-Gabry EA, Strup SE, Gomella LG. Undetectable
prostate-specific antigen response with bicalutamide withdrawal
phenomenon. Tech Urol 2000;6(3):221-2. Abstract |
Is combined
androgen blockade more effective than castration?
Cochrane Collaborative Review Group
on Prostate Diseases Analysis of 20 major randomized trials
with 6,320 patients |
Conclusion:
“We find that there is a 5% improvement in the percentage
of men surviving at 5 years (30% vs 25%) with combined androgen
blockade with nonsteroidal antiandrogens as well as improvements
in progression-free survival at 1 year. Appropriate patients
with metastatic prostate cancer should be informed of the
potential benefits, toxicities, and out-of-pocket expenditures.” |
| EXCERPT FROM : Schmitt
B et al. Combined androgen blockade with nonsteroidal
antiandrogens for advanced prostate cancer: A systematic review.
Urology 2001;57(4):727-32. Abstract |
Prostate Cancer Journal Club
Feasibility Study: Watchful waiting for localized low-
to intermediate-grade prostate carcinoma with selective delayed
intervention based on prostate specific antigen, histological and/or
clinical progression
Choo R et al. J Urol 2002;167:1664-69. Abstract
The benefit of treating low- and intermediate-risk patients with
observation alone is uncertain. Unfortunately, no randomized clinical
trial data exist to support this approach. This paper reports a
prospective cohort study of watchful waiting in patients with favorable
clinical parameters — stage T1b to T2b N0M0 disease, Gleason’s
score of 7 or less and PSA 15 ng/ml or less.
Patients were followed with PSAs, digital rectal exams and periodic
imaging studies every three months for the first two years, and
every six months thereafter. They also underwent repeat biopsy 18
months after randomization.
Patients were considered to have progressed based on histological
change on repeat biopsy, physical change in the digital rectal exam,
or a change in symptoms. The investigators also looked at the PSA-doubling
times.
Results are reported in 206 patients with a mean follow-up time
of 29 months. About two-thirds (137) remained on the surveillance
protocol with no evidence of disease progression, while the other
third (69) were withdrawn for various reasons — clinical progression,
PSA progression, higher Gleason scores on repeat biopsy, death from
other causes, and request to be treated more actively.
The estimated actuarial probability of remaining on the surveillance
protocol was 67 percent at two years and 48 percent at four years.
The probability of a patient remaining progression-free was 81 percent
at two years and 67 percent at four years.
This paper begins to give us parameters to follow patients with
low- to intermediate-risk prostate cancer. In addition, as reported
in this study, patients may then receive treatment upon clinical,
PSA or histological progression, without adverse effects on outcome.
We do not have any prospective, observational, longitudinal trial
information specifically looking at observation in patients with
prostate cancer. This is one of the first papers to begin to define
parameters for this strategy.
In an editorial comment, Dr. Peter Albertsen, from the University
of Connecticut, notes that this will be an important paper to begin
to establish how patients may be followed optimally by observation.
Prospective evaluation of prostate cancer detected on biopsies
1, 2, 3 and 4: When should we stop?
Djavan B et al. J Urol 2001;166:1679-83. Abstract
This prospective trial evaluated 1,051 men with PSAs between four
and ten. The authors evaluated biochemical parameters, pathologic
features and biopsy-related morbidity on a series of four transrectal
biopsies.
If the first biopsy was negative, patients had a second biopsy
six weeks later. If the second biopsy was negative, they had a third
biopsy eight weeks later. If the third was negative, biopsy four
was performed eight weeks later.
Patients in the study had more complications with biopsies three
and four than with biopsies one and two. In addition, the cancers
discovered on biopsies three and four tended to have very favorable
characteristics — low Gleason scores and organ-confined disease.
These results suggest that the yield after two negative sextant
biopsies is fairly low in men with mildly elevated screening PSA.
The authors concluded that without a high suspicion of cancer and/or
poor prognostic factors on first or second biopsy, the third and
fourth biopsies do not usually yield much additional information.
According to this study, if the PSA rises again, you can do another
biopsy, and any cancer found is likely to be a very favorable cancer.
This study used a very aggressive biopsy schema — performing
biopsies every six to eight weeks. In the United States, most people
wait three to six months after a negative biopsy before repeating
it.
I generally just follow most men with two completely negative
biopsies within a three- to six-month period. This study gives me
more confidence in that approach. These results should help ease
the minds of patients with elevated but stable PSAs.
| Authors' conclusions |
"Prostate
cancer on biopsy 2 is not an uncommon finding and will be
encountered in 10% of cases. In contrast, cancer detection
on biopsies 3 (5%) and 4 (4%) is rare. Despite differences
in location and multifocality, pathological and biochemical
features of cancer detected on biopsies 1 and 2 were similar,
suggesting comparable biological behaviors. However, cancer
detected on biopsies 3 and 4 had a lower grade, stage and
volume compared with biopsies 1 and 2. Therefore, biopsy 2
in all cases of a negative finding on biopsy 1 appears justified.
However, biopsies 3 and 4 should only be obtained in select
patients with a high suspicion of cancer and/or poor prognostic
factors on biopsy 1 or 2." |
| EXCERPT FROM: Djavan
B et al. J Urol 2001;166:1679-83. Abstract |
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