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PCU 4|2002: A
Oliver Sartor, BA, MD
Edited comments by Dr Sartor
Prostate Cancer Journal Club
Extended pelvic lymphadenectomy in patients undergoing
radical prostatectomy: High incidence of lymph node metastasis
Heidenreich A et al. J Urol 2002;167(4):1681-6. Abstract
The definition of advanced disease in prostate cancer has changed
over the last decade. Today, a diagnosis of Stage D-1 disease has
very clear therapeutic implications, because the data from Messing
and colleagues show a survival benefit for treating patients with
Stage D-1 disease with early or immediate hormonal therapy. Therefore,
accurate staging is critical.
This study, in the Journal of Urology, demonstrates that patients
receiving standard lymphadenectomy are probably being understaged
and physicians may be missing opportunities for early treatment.
Currently, standard lymph node dissection during radical prostatectomy
includes the external iliac and obturator nodes, with an average
yield of ten lymph nodes. This paper compares 100 patients undergoing
standard lymphadenectomy to 103 patients undergoing extended lymphadenectomy
in which the internal iliacs, common iliacs and presacrals are also
dissected. The two patient series were very similar with regard
to Gleason scores, PSAs and patients’ ages.
The results showed a doubling in the incidence of node-positive
disease in the extended lymphadenectomy group. Only 12% of the patients
had nodepositive disease in the standard dissection group, whereas
26% had nodepositive disease in the extended dissection group. The
toxicities were essentially the same with no excess morbidity in
the extended dissection group.
Careful cataloging of the location of the lymph node metastases
revealed that 42% in the extended procedure were outside of the
regions of the standard pelvic lymphadenectomy. There were at least
six patients who had internal iliac metastases that would have been
missed if this area had not been dissected. Researchers found no
value in presacral dissection. Only one patient had presacral involvement,
and that patient had involvement in other areas as well. They concluded
that pelvic lymphadenectomy should include dissection of the internal
iliac, external iliac and obturators fossa groups. This paper is
also interesting as it relates to a variety of studies with the
ProstaScint Monoclonal Antibody Scan. Patients who had a positive
scan and a negative dissection were classified as “false positives.”
The findings of this article suggest that the standard lymph node
dissection may be inadequate for proper staging.
Improved staging methods are needed to ensure staging accuracy.
Until we know the extent of the patient’s disease, we will
continue to subject patients to treatments that may fail.
Osteoporosis in men treated with androgen deprivation
therapy for prostate cancer
Ross RW, Small EJ. J Urol 2002 May;167(5):1952-6. Abstract
This review paper notes that androgen deprivation leads to an
increased risk of osteoporosis, and discusses the implications of
this as we subject men to androgen deprivation earlier in the treatment
of prostate cancer.
Bone mineral density peaks relatively early in life and bone loss
begins at about age 30. In quantifying bone loss over time, one
can then expect about a one percent bone mineral density loss per
year. Androgen deprivation increases that loss to about four percent
during the first couple of years and then it drops to two percent
around years three and four.
Clearly, bone loss becomes more serious as the duration of deprivation
increases. If we treat younger men earlier, they may be living with
androgen deprivation for decades.
This raises several interesting questions: How much osteopenia
and osteoporosis has a clinically meaningful endpoint? What is a
reliable laboratory measurement? What translates into a fracture
rate? The author cites four different studies, and the percentage
of osteoporotic fracture varies from four to 50 percent —
a wide variance. Part of the variance is due to a variation in follow-up.
In addition, the analyses were predominantly retrospective. It is
fairly clear that if you follow people for a period of time, the
fracture rate goes up as a function of time.
One of the important points made in this article is that, if we
are going to treat patients with hormonal therapy, particularly
in clinical trials, we need to improve our monitoring of osteoporosis
and fracture rates.
Other interesting questions are, how often should you measure
bone loss, and when should you intervene? Men start with a higher
bone mass density than women, so men can lose more bone mass, and
it may not be clinically relevant. There are very poor data with
regards to how much bone mass men need to lose before the osteoporotic
risk increases. This article recommends a baseline measurement before
androgen deprivation therapy begins, and another one year later.
Other than exercise, calcium and Vitamin D, which are all relatively
benign, it is not clear whether or not we should use other aggressive
interventions.
There are data that show bisphosphonates can either diminish bone
loss or actually restore bone. Analogous to the breast cancer literature
with pamidronate, zoledronate has been associated with fewer skeletal-related
events. Pamidronate was very equivocal in the prostate studies,
but zoledronate was not. Zoledronate is now FDA-approved and commercially
available for patients with hormone-refractory disease and skeletal
metastases. While some people advocate treating patients with prophylactic
bisphosphonates, I think we need more data.
In addition to the bisphosphonate question, one could question
estrogen therapy. We can use estradiol, the estrogen patches or
low-dose DES. The role of estrogens in treating this complication
is unknown, as we do not have the data.
In summary, it is unequivocal that androgen deprivation leads
to an acceleration of bone loss, and it probably increases the osteoporotic
fracture rate. More data are needed, however, particularly on reversal
of osteoporosis in terms of what agents to use and the timing of
intervention. Vitamin D, calcium and exercise are all reasonable,
and patients should be counseled about smoking and excessive alcohol
use, which contribute to osteoporosis. Whether or not we treat with
bisphosphonates needs to be answered in clinical trials designed
with relevant end points.
Relationship between obesity and race in predicting adverse
pathologic variables in patients undergoing radical prostatectomy
Amling CL et al. Urology 2001;58(5):723-8. Abstract
This paper describes a study in which 860 prostate cancer patients
undergoing radical prostatectomy were categorized by body mass index
into three groups: obese, overweight and normal. Each group was
then compared in terms of age, race, PSA, Gleason score, and pathologic
stage.
The initial uni-variant analysis showed a relationship between
obesity and poor prognostic factors. Obese patients presented at
a younger age, had a higher Gleason score on average, had a greater
percentage of high-grade Gleason scores, and were less likely to
have organ-confined disease. They also found a higher percentage
of African-American patients in the obese group.
Race was an interesting finding because African-Americans present
with prostate cancer at a younger age, and with higher Gleason scores.
The findings indicate that obesity may, at least in part, account
for the ethnic variability related to the poorer prognostic factors.
On multi-variate analysis, body mass index was the only factor that
predicted the Gleason score and the stage after radical prostatectomy.
The bottom line on this study is that obesity is associated with
an early onset of prostate cancer, as well as a higher Gleason score
and a higher percentage of nonorgan-confined disease. Even though
we already knew that we should not be obese, we now have one more
reason to avoid it.
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