Diagnosis and Treatment of Genitourinary Malignancies

268 Pages·1997·33.268 MB·English

by  Ronald K. Ross (auth.), Kenneth J. Pienta (eds.)

DIAGNOSIS AND TREATMENT OF
GENITOURINARY MALIGNANCIES
Diagnosis and Treatment of
Genitourinary Malignancies
edited by
KENNETH J. PIENTA
Department of Internal Medicine
Division of Hematology/Oncology
University of Michigan
Ann Arbor, MI48109-0680
ISBN 978-1-4613-7913-3 ISBN 978-1-4615-6343-3 (eBook)
DOI 10.1007/978-1-4615-6343-3
Contents
DIAGNOSTIC Advances: The Use of Molecular Medicine in the
Diagnosis and Prognosis of Genitourinary Malignancies
1. Epidemiology of prostate cancer and bladder cancer:
An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
RONALD K. ROSS
2. Von Hippel-Lindau syndrome: hereditary cancer arising from
Inherited mutations of the VHL tumor suppressor gene. . . . . . . . . 13
JEFFREY S. HUMPHREY, RICHARD D. KLAUSNER,
and W. MARSTON LINEHAN
3. New pathologic techniques for diagnosing genitourinary
Malignancies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
KIRK J. WOJNO
4. Reverse transcriptase-polymerase chain reaction (RT-PCR) to
detect prostate cancer micrometastasis in the blood. . . . . . . . . . . . . 77
KAI-LING YAO, MARY JOSEPHINE PILAT,
and KENNETH J. PIENTA
5. Successful separation between benign prostatic hyperplasia
and prostate cancer by measurement of free
and complexed PSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
HANS LILJA and ULF-HAKAN STENMAN
Surgical and Radiation Advances
6. Retroperitoneal lymphadenectomy in staging and treatment
of clinical stage I and II nonseminomatous testis cancer
(NSGCT): the development of nerve-sparing techniques ........ 105
J.P. DONOHUE
v
7. Current therapy for invasive bladder cancer. . . . . . . . . . . . . . . . . .. 121
JAMES E. MONTIE
8. Beyond the nerve-sparing radical prostatectomy. . . . . . . . . . . . . . .. 129
ROBERT C. SMITH, GARY D. STEINBERG,
and CHARLES B. BERNDLER
9. Three-dimensional conformal therapy (3D-CRT)
for prostate cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 147
PAUL J. CHUBA, ARTHUR T. PORTER, and
JEFFREY D. FORMAN
10. Cryosurgical ablation of the prostate: treatment alternative
for localized prostate cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 167
JEFFREY K. COHEN, GINA M. ROOKER,
RALPH J. MILLER, JR., and LORI MERLOTTI
Medical Advances
11. The chemoprevention of prostate cancer and the prostate
cancer prevention trial ..................................... 189
OTIS W. BRAWLEY and IAN M. THOMPSON
12. Total androgen blockade for prostate cancer: the end does not
justify the means. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201
MILIND JAV LE and DEREK RAGHAV AN
13. Therapy for hormone-resistant prostate cancer no longer
a myth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 211
DANIEL P. PETRYLAK and BASSAM ABI-RASHID
14. Renal, bladder, and prostate cancers: gene therapy. . . . . . . . . . . .. 219
MICHAEL A. CARDUCCI and JONATHAN W. SIMONS
15. The role of immunotherapy in urologic malignancies .......... 235
YOUSIF A. ABUBAKR and BRUCE G. REDMAN
16. Assessing health-related quality of life in patients with
genitourinary malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 249
MARK S. LITWIN
INDEX ....................................................... 265
vi
DIAGNOSIS AND TREATMENT OF
GENITOURINARY MALIGNANCIES
1. Epidemiology of prostate cancer and bladder
cancer: an overVieW
Ronald K. Ross
The category of genitourinary cancer potentially includes a large number of
cancers with diverse epidemiology and etiology. We limit discussion in this
chapter to an update of recent activity in the areas of prostate cancer and
bladder cancer epidemiology, since these are far and away the most common
genitourinary malignancies. Since each of these topics is extensive in its own
right and both have been recently reviewed in some detail [1,2], we only briefly
summarize historical risk factor data for each of these cancers and then pro
vide an overview of current and, from our perspective, likely future foci of
research into the epidemiology of these malignancies.
Prostate cancer
Prostate cancer is now the most commonly diagnosed cancer in the United
States. An estimated 200,000 men were diagnosed in 1994, and an estimated
38,000 men died of prostate cancer, making it the second leading cause of
cancer deaths in men (exceeded only by lung cancer) [3]. Prostate cancer rates
exploded in the U.S. beginning in the late 1980s. In most segments of the U.S.
population, prostate cancer incidence rates approximately doubled between
1988 and 1992 [1]. This rapid increase in incidence was not accompanied by a
change in mortality and is likely due almost entirely to increased utilization of
serologic assays for prostate-specific antigen to detect subclinical disease in
otherwise healthy men.
The two most important known risk factors for prostate cancer are demo
graphic - age and race-ethnicity (or international variation) [4]. Prostate
cancer is the most age-related of all epithelial cancers - rare prior to age 40
and increasing at the 8th-9th power of age thereafter. African-American men
have long been known to have the highest prostate cancer rates in the world.
Japanese and Chinese men native to those countries and probably other Asian
ethnicities such as Koreans have the lowest. The difference in risk between
these high-and low-risk extremes has been reported to be as much as 50-fold,
although a substantial part of this difference may be due to differences in
detection strategies among populations [5].
Pienta, KJ., (ed.), DIAGNOSIS AND TREATMENT OF GENITOURINARY MALIGNANCIES. Copyright
© 1996. Kluwer Academic Publishers, Boston. All rights reserved.
There has been interest in the role of dietary factors in prostate cancer
etiology for at least two decades. Dietary fat has been the most studied of
many dietary components evaluated over these years. Both case-control and
cohort studies, which have attempted either to estimate individual fat con
sumption or have simply looked at foods rich in fat, have rather consistently
shown that men who develop prostate cancer consume more fat than men who
do not. These studies have been conducted in target populations varying
widely in age, underlying risk of prostate cancer, and socioeconomic status [1].
Nonetheless, this relationship cannot be considered totally established as a
causal one, since these studies have varied considerably in quality; some have
suffered from incompleteness in their dietary histories or from questionable
reliability and/or validity of their dietary instruments; the case-control studies
(which constitute the majority of these studies) suffer from the very real
possibility that men who have been diagnosed with prostate cancer may
change their diets or, more importantly, may report their dietary histories
differently (Le., provide invalid results due to 'recall bias'). Finally, many of
these studies, even the better-designed ones, while finding an overall relation
ship between dietary fat and prostate cancer risk, nevertheless find incon
sistencies in dose-response relationships or in subgroup analyses. These
inconsistencies raise doubts regarding the causal nature of these associations.
The recently reported Health Professionals Follow-Up prospective study of
dietary fat and prostate cancer illustrates the latter problem [6]. This ongoing
study involves 47,855 men aged 40-75 years who completed a comprehensive
131-item food-frequency questionnaire at baseline (Le., at study entry). After
four years of follow-up, 300 men had developed prostate cancer. After exclud
ing stage A (largely occult) lesions, there was a modest association between
prostate cancer risk and increasing quintile of fat consumption (RRs of 1.0
(low), 1.2, 1.1, 1.1, and 1.4 (high)) - a relationship that, however, did not
achieve statistical significance. When the analysis was limited to more ad
vanced disease (stages C and D), the association strengthened (RRs of 1.0
(low), 1.2, 1.3, 1.3, and 1.6), and approached statistical significance (p = .08).
The other major focus of dietary research on prostate cancer over the past
decade has been the possible protective role of vitamin A or its precursor
molecule, beta-carotene. The former compound is of interest principally due
to its role in inducing differentiation of epithelial cells, whereas the latter
serves as a potent antioxidant, binding free radicals that can damage DNA.
The large series of observational studies that have tested this hypothesis have,
as a group, offered no strong evidence that these compounds play any impor
tant role in modifying prostate cancer risk [1].
Two relatively recent dietary hypotheses concerning prostate cancer de
serve mention. The active form of vitamin D, 1,25-dihydroxyvitamin D, can
induce differentiation and reduce proliferation of both healthy and malignant
prostatic epithelium [7]. A recent prospective serologic study suggested that
men with high circulating levels of this compound have a much reduced risk of
prostate cancer [8]. Phytoestrogens, such as isoflavonoids found in soy prod-
2
ucts, are weak estrogens that have been hypothesized to compete with andro
gens at receptor sites or at a more central level, and thereby mildly reduce
androgen activity in the prostate [9]. There have been no epidemiologic stud
ies directly testing whether these compounds reduce prostate cancer risk.
Growth of both normal and, at least in the early stages of malignancy,
malignant prostatic epithelium is dependent on androgens. This finding has
resulted in longstanding interest in the possible role of androgens in the
pathogenesis of prostate cancer. This concept is supported by experimental
evidence; although it has proven difficult to produce adenocarcinomas of the
prostate in animal models by any means, all the currently established, repro
ducible experimental models have an androgen requirement for tumor devel
opment [10]. The main circulating human androgen, testosterone, diffuses
freely into prostate cells, where it is rapidly and irreversibly converted to its
metabolically active reduced form, dihydrotestosterone, through the activity
of the enzyme 5-alpha reductase. Dihydrotestosterone binds to the androgen
receptor, and this complex activates androgen-responsive genes involved in
the growth and proliferation of prostate epithelium.
There have been many attempts to compare circulating androgen levels in
men with and without prostate cancer, with little consistency in results [1].
Such studies are problematic given the strong possibility that either the pres
ence of the disease itself or the treatment for it can alter androgen secretion or
metabolism. More informative have been studies comparing androgen profiles
in healthy men at varying risk of prostate cancer, especially with regard to
racial-ethnic and international variation in risk. Such studies have demon
strated that high-risk African-American men have higher circulating testoster
one levels than lower-risk Asian or U.S. white men [11,12] and that low-risk
Asian men have altered intraprostatic metabolism of testosterone compared
to U.S. whites and blacks [13,14]. These differences in androgenic profiles
among racial-ethnic groups appear sufficiently large when extended over a
lifetime to fully explain the underlying differences in prostate cancer incidence
among these populations [11]. Asian men native to China or Japan do not have
low levels of testosterone, as might be predicted from this hypothesis, but do
have substantially reduced levels of two 5-alpha androgens, androstanediol
and androsterone, that are thought to indicate reduced 5-alpha reductase
expression in the prostate. Thus, the racial-ethnic variation in prostate cancer
incidence might be explicable, in part, by differences in testosterone secretion
on the one hand and intraprostatic metabolism of testosterone on the other.
The reasons for these underlying hormonal differences among populations
at varying risk of prostate cancer are unknown, but are likely due to a combi
nation of environmental (e.g., diet) and genetic differences among these popu
lations. A number of genes are involved in the production and metabolism of
testosterone. Table 1-1 lists and describes the function of several of these.
Although some preliminary data suggest, directly or indirectly, that at least
some of these genes might affect prostate cancer risk, none have to date
undergone serious epidemiologic investigation.
3
Table 1-1. 'Candidate' genes for prostate cancer: genes involved in testosterone metabolism
Candidate gene Prostate function
Androgen receptor Translates androgen effects
5-alpha reductase type II Converts testosterone to dihydrotestosterone
CYP17 Catalyzes rate limiting steps in testosterone biosynthesis
HSD3B2 Deactivates dihydrotestosterone
The 5-alpha reductase type 2 gene, for example, like all four of the genes
listed, has been shown to be polymorphic, providing opportunities to compare
sequence variations in the gene among populations at varying risk of prostate
cancer and.among individuals with and without prostate cancer. The polymor
phism that has been described is a dinucleotide (TA) microsatellite in the 3'
UTR of the gene [15]. Although most individuals possess a single allelotype,
being TAo homozygotes, between 15 % and 25 % of the population, depending
on race-ethnicity, carry a variant allele. African-American men, in fact, pos
sess a series of alleles (T A1s-T Azz) that appear to be unique to this population
and, based on preliminary data, appear to convey an p.xcess risk of prostate
cancer [15]. Asian populations have a low frequency of variant alleles, based
on this polymorphism. If these results are confirmed through more definitive
epidemiologic studies, an important additional issue will be to determine the
functional significance of this polymorphism; polymorphic microsatellites in
the UTRs of other genes have been shown themselves to have functional
significance.
The androgen receptor gene encodes the androgen receptor, which serves
multiple functions related to androgen activity in the prostate. It binds
dihydrotestosterone in the cytosol of prostatic epithelium, translocates
dihydrotestosterone to the nucleus for DNA binding, and participates in the
transactivation of androgen-responsive genes [16]. The androgen receptor
gene is located on the X-chromosome, so men carry only a single copy. There
have been two polymorphic trinucleotide repeat microsatellites described in
the gene, both located in exon 1, the transcription modulatory domain. In
healthy men, one of these microsatellites, a CAG repeat sequence, is approxi
mately normally distributed with a range of some 8 to 31 repeats. Several
observations have suggested that the length of this microsatellite correlates
with androgen function. A rare adult-onset motor-neuron, X-chromosome
linked disorder, namely, Kennedy's disease, is caused by an expansion of this
microsatellite, so men with this disease have a minimum of 40 repeats and a
reduced ability to transactivate androgen-responsive genes [17]. Experimental
results utilizing transfection assays suggest that, within the normal range of
repeats, there are also differences in activation of reporter genes: the greater
the number of repeats, the less activation [18]. This finding has led to the
hypotheses that a low number of repeats results in a more 'supercharged'
androgen receptor than does a high number of repeats, and as a result, carries
with it a higher risk of prostate cancer [19]. Based on their respective incidence
4