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Prostate Cancer in the Older Man

Prostate Cancer in the Older Man

ABSTRACT: Most men diagnosed with prostate cancer are more than 65 years of age. Therefore, a discussion of the issues surrounding the diagnosis, prevention, and treatment of prostate cancer in older men is, in many ways, a review of prostate cancer in general. Nonetheless, older patients with prostate cancer are often faced with a different set of problems than younger patients. For instance, if preventive strategies prove useful, they will have important implications for older men. Even a significant delay in diagnosis could greatly benefit the elderly population. Prostate-specific antigen (PSA) screening is controversial for men of any age but, for older men, screening may impart a risk to quality of life that may outweigh the potential advantages of diagnosis and treatment. Results of a large follow-up study of patients treated with radical prostatectomy suggest that even men with rising PSA values after surgery can have a relatively benign and protracted course. The survival rates noted in this study, however, were only for a select population of surgical patients, and, in fact, higher prostate cancer death rates have been observed for patients adopting the watchful waiting approach. Older men who request some form of primary therapy are increasingly being treated with brachytherapy, despite the lack of randomized trials demonstrating efficacy compared to external-beam radiation therapy, surgery, or watchful waiting. Contrary to an often-held view, older prostate cancer patients may have more morbidity from long-term testosterone suppression than younger patients. On the other hand, chemotherapy seems to be as well tolerated overall in older patients as in younger patients. [ONCOLOGY 15:1113-1131, 2001]

Prostate cancer is the second leading cause of cancer death in US
males. In older men, it represents a significant cause of morbidity and
mortality, since more than 75% of all prostate cancer is diagnosed in men who
are more than 65 years of age.[1] The lifetime cumulative risk of prostate
cancer is 1 in 6, but the risk increases dramatically with increasing age. For
instance, men aged 40 to 59 years have only a 1 in 100 chance of being diagnosed
with prostate cancer, compared with the 1 in 8 risk for men aged 60 to 79
years.[2] The median age of prostate cancer death is 78 years in whites and 76
years in blacks.[1] Given the increasing expected life span of North American
men, it is obvious that any issues regarding prevention, screening, and
treatment of prostate cancer will include their effects on the elderly.

Both patients and providers are aware of the lack of definitive standards of
care for many aspects of prostate cancer diagnosis and treatment. New insights
into the natural history of prostate cancer and its risk factors, as well as
some newly-appreciated side effects of long-term androgen ablation therapy, can
help guide the prevention and management of prostate cancer in the elderly.

Indolent Prostate Cancer in Older Men

An enigma of prostate cancer biology is that a high (> 70%) proportion of
men over age 80 will have histologic evidence of prostate cancer on autopsy
examination, although far fewer will ever manifest clinically evident
disease.[3] It is unclear why this specific cancer, unlike colorectal or lung
cancers, seems so prevalent in an indolent form in the aging male. The
prevailing view is that the incidence of occult or indolent disease is similar
worldwide, despite dramatic differences in clinically evident prostate cancer.
For example, the incidence of prostatic intraepithelial neoplasia (PIN)—a
lesion believed to be a precursor of prostate cancer—does not differ between
the high- and low-risk groups in the United States.[4]

Prevention Strategies

In addition to genetic influences, environmental factors also likely play a
role in prostate cancer pathogenesis. Hypotheses regarding potential
environmental risks form the basis of preventive strategies to modify the risk
of prostate cancer or, at least, the risk of progression from an indolent to a
clinically important form of the disease. For older men, the appeal of effective
preventive strategies is that they may delay the onset of clinical disease
beyond their otherwise expected life span, although there is no effective
strategy yet for men of any age. There are several preventive initiatives and
strategies, however, that are either being discussed or being studied formally
in clinical trials.

Androgens and Prostate Cancer Risk—Although high serum androgen levels
have generally been implicated as a risk factor for prostate cancer,[5] their
role in the elderly remains less defined. Men exhibit a modest but steady
decline in serum androgen levels with age,[6] making the value of decreasing
prostate exposure to androgenic stimuli less obvious as a preventive strategy.
In fact, a more common issue facing elderly men is the potential need for
exogenous testosterone replacement therapy. A relatively frequent medical
problem in older men is erectile dysfunction, which in some cases can be
attributed to decreased serum androgens. Some clinicians recommend that men have
a routine prostate biopsy before embarking on replacement therapy. However, the
long-term effects and cancer risk of restoring testosterone levels to normal in
hypogonadal men are not known.

There are no feasible methods of long-term testosterone depletion without
undesirable side effects. However, an alternative strategy is currently being
studied. Finasteride (Proscar) is an inhibitor of 5-alpha-reductase, an
intracellular enzyme responsible for converting testosterone to
dihydrotestosterone, a potentially more potent agonist of androgen receptors. A
continuing Southwest Oncology Group trial (SWOG 9217) is comparing rates of
prostate cancer in healthy men treated with finasteride or placebo.
Approximately 18,000 men have been randomized to this trial, which began in 1993
and was closed to accrual in 1997. The final analysis is expected sometime in
2004.

Vitamin E and Selenium for Prevention—The Southwest Oncology Group
recently initiated an Intergroup study to determine the efficacy of vitamin E
and selenium supplementation, either alone or in combination, in the prevention
of prostate cancer. This randomized, four-armed, placebo-controlled study will
continue for 12 years. Importantly, this study has no upper age limit on
eligibility, allowing enrollment of elderly men.

The rationale behind this large trial is derived from the epidemiologic
studies that have correlated intake of both vitamin E and selenium with lower
prostate cancer mortality. For instance, a randomized trial of 29,000 smokers
testing the effects of alpha-tocopherol (a form of vitamin E) and beta-carotene
in prevention demonstrated that men receiving vitamin E had a 40% decrease in
stage B prostate cancer and a 32% overall reduction in prostate cancer.
Selenium, at a dose of 200 µg/d, has also been associated with a significant
reduction in mortality from prostate, lung, and colon cancers.[7] Furthermore,
in a case-control study by Giovannucci and colleagues, reduced selenium intake,
as measured in toenail clippings, was associated with a greater risk of advanced
prostate cancer.[8]

Can an elderly man hope to lower his risk of prostate cancer by taking
vitamin E and selenium later in life? It will be more than a decade before the
SWOG study will be able to answer this question. In the interim, there has been
no obvious deleterious effect from vitamin E or selenium at the doses being used
in the national study.

Role of Dietary Fat and Soy—Several descriptive[9,10] and case-control
studies[11,12] have demonstrated a positive correlation between intake of animal fat and the risk of
prostate cancer. In one review, 10 of 13 studies reported a positive correlation
between fat intake and prostate cancer risk.[13] Dietary fat intake may increase
the risk of prostate cancer through an effect on the hormonal environment. For
instance, high-fat diets have been found to be associated with higher serum
androgen levels.[14-16]

In addition to case-control studies, population-based analyses have shown
that dietary intake might affect prostate cancer risk. Japan has a low death
rate from prostate cancer, for instance, and the average Japanese man consumes
18% of dietary calories in fat, compared with the typical 40% intake in the
traditional Western diet.[9] It is difficult to establish causality, however, as
there are many confounding factors. Intake of soy is also very high in Japan,
which could contribute to the lower prostate cancer risk. Soy contains
phytoestrogens, which have hormonal, and perhaps, antioxidant properties. Levels
of genistein, a key phytoestrogen, are drastically lower in men from Finland,
where there is a much higher rate of prostate cancer than in Japan.[17]

The American Health Foundation is testing the effects of both soy
supplementation and a low-fat diet on prostate cancer progression in an ongoing
trial. In the interim, our group performed a pilot study of a low-fat and a
low-fat/high-soy diet combined with vitamin E (400 IU/d) and selenium (200
µg/d) supplements in stage D0 patients with biochemical progression (as
measured by prostate-specific antigen [PSA] levels) after primary therapy. We
used a sequential design strategy to determine whether the effects of soy are
additive to the benefits of a low-fat diet. Patients were started on a low-fat
diet and then given soy powder (40 g/d) when their PSA values increased by 25%
or more over baseline. On enrollment and to date, the median age at study entry
is 72 years. Therefore, the findings will be relevant to the older patient.

Neither low-fat intake alone, nor the combination of low-fat and high-soy in
the diet, has effected a PSA reduction greater than 50% in any patient in this
study. However, 6 of 17 patients on the low-fat diet and 5 of 13 patients on the
low-fat/high-soy combination demonstrated a delay in PSA progression (defined as
less than a 25% increase in PSA over baseline values for at least 6 months)
(see
Table 1).

The importance of this observation about the natural history of prostate
cancer progression is undefined in these patients. Nor is it clear whether these
results can be extrapolated to men interested in prevention rather than in
delaying disease progression after PSA relapse. However, a reduction in dietary
fat may possess other potential health benefits, such as preventing
atherosclerotic disease.

Epidemiologic studies have implicated other dietary factors, including green
tea and tomato products, in the prevention of prostate cancer. It is readily
apparent that an older man who hopes to reduce his prostate cancer risk faces a
myriad of choices for dietary modification. Yet there is a paucity of studies
that have rigorously examined these factors.

Screening in Older Men

Prostate cancer screening by PSA testing for the general population remains
controversial in both medical and public forums. No randomized study has
demonstrated a clear survival benefit from such screening. There is some consensus
among screening experts that PSA screening should be limited to patients under
the age of 65 or to those with life expectancies exceeding 10 years or more. For
example, the Prostate, Lung, Colorectal, and Ovarian (PLCO) randomized screening
trial sponsored by the National Cancer Institute limits enrollment to people
under 75 years of age. The decision to limit PSA screening in older men is
based, in part, on the relatively long natural history of untreated prostate
cancer.

Other experts believe that, regardless of their age, patients should be
offered a choice about prostate cancer screening, with an explanation
emphasizing the associated risks and benefits. In one study, use of a 3-minute
scripted informational intervention targeted to primary care patients was
associated with significantly reduced interest in PSA screening among elderly
participants.[18] Importantly, older patients have been shown to be more likely
to focus on quality, rather than quantity of life, and may be less willing to
trade possible increased longevity for potential treatment side effects.[19]

In older men who do undergo PSA screening, the use of age-specific reference
ranges has been advocated to enhance diagnostic accuracy (see Table
2
). These
age-specific ranges demonstrate that serum PSA levels correlate with prostatic
volume, which, in turn, is strongly correlated with age.[20]

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