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Prostate Cancer

Etiology:

- 2nd most frequent cause of cancer in men


- alteration of genes on chromosome 1 and the X chromosome have been found in some
patients with a family history of prostate cancer. Genetic studies suggest that a strong
familial predisposition amy be responsible for as many as 10% of prostate cancer cases.
- African Americans have a higher incidence and more aggressive prostate cancer than white
men, who have a higher incidence than men of Asian origin. Young African men have
testosterone levels 15% higher than young white men, also 5-alpha reductase may be more
active in African Americans than in whites, implying that hormonal differences may play a
role.
- A high fat diet may also lead to increased risks, while a diet rich in soy may be protective.
Omega-6 fatty acids are positive stimulants of prostate cancer cell growth, while omega-3
fatty acids are negative stimuli.
- Vitamin E may have some protective effects, vitamin D deficiency may be a risk factor.
- Hormonal causes have been implicated due to the fact that Eunuchs do not develop
adenocarcinoma of the prostate. However, a study done by Hsing found no difference in
testosterone, DHT, prolactin, FSH, or estrone.

- most prostate cancers are adenocarcinomas (95%).


- 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the
transitional zone.
- Most prostate cancers are multifocal with synchronous involvement of multiple zones of the
prostate, which may be due to clonal and noncolonal tumors.
- The mechanism for distant metastasis is poorly understood. There is early spread to bone,
occasionally without significant lymphadenopathy. 2 theorys: (1) mechanical—involves
direct spread through the lymphatics and venous spaces into the lower lumbar spine, (2)
‘seed and soil’—theory states that there must be tissue factors that allow for preferential
growth in certain tissues, such as the bone. Specific tissue growth factors and extracellular
matrices are possible examples.
Staging:
T – primary tumor
T1 – clinical inapparent tumor not palpable or visible by imaging.
T2 – tumor confined within prostate
T3 – tumor extending beyond prostatic capsule.
T4 – tumor fixed or invading adjacent structures other than the seminal vesicles.
N1 – metastasis in regional lymph or nodes
M1 – distant metastasis
- within each staging are several sub-classifications.

Signs & Symptoms:

- many symptoms stem from obstruction of the urethra and gradual loss of bladder
function, which results in incomplete emptying of the bladder.
o A hesitant, interrupted, weak stream.
o Urgency and leaking or dribbling.
o More frequent urination, especially at night.
- Size of prostate does not correlate with severity of obstruction.
- Acute urinary retention may occur inability to urinate, it may be triggered by taking
over-the-counter cold or allergy medicines.
- When a partial obstruction is present, urinary retention also can be grought on by
alcohol, cold temperatures, or a long period of immobility.
- Urine retention and strain on the bladder can lead to urinary tract infections, bladder or
kidney damage, bladder stones, and incontinence.
- Some may have hematuria or impotence. These two findings are usually uncommon in
early stages and may be seen only in advanced cases.
- If the cancer as metastasized then there may be complaints of back and hip pain, as well
as symptoms of fatigue, malaise, and weight loss.
Prostate-specific antigen PSA is a serine protease that is produced by both nonmalignant and
malignant epithelial cells. PSA is prostate specific but not prostate cancer specific and is measure
most commonly by radioimmunoassay. The normal range is 0 to 4 ng/mL; ~30% of men with a
PSA in the range of 4 to 10 ng/mL and 50% of those with a PSA > 10 ng/mL will have cancer.
Percent-free PSA athe measurement of bound and free PSA can help discriminate between
patients with mildly elevated PSA from cancer and those with BPH. The lower the ratio of free-to-
total PSA, the higher the likelihood of cancer. Free PSA is reported as a percentage. Using 25% as
the cut-off detected 95% of cancers in both African Americans and whites.

Refer to info on BPH to supplement.

Lab Studies:

• Hematological workup should include a CBC count and a chemistry profile, including serum
creatinine, liver function tests, serum PSA, free-to-total PSA ratio, and acid and alkaline
phosphatase. Further studies may be ordered if any of these test results demonstrate
abnormalities.
• Urinalysis should be performed. If results are abnormal, ie, indicating the presence of an
infection, urinalysis should be followed by a urine culture, especially if the patient is
symptomatic.
• Certain molecular markers, such as E-cadherin, p53 and p21, DNA ploidy analysis, human
kallikrein 2, and microvessel density (histologic marker of tumor angiogenesis) also are
being evaluated to help characterize disease progression.
• Note that elevated PSA levels are not always present in a relatively higher-grade prostate
cancer, nor are they always observed in disease progression.

Imaging Studies:

• Bone scan: Activity in the bone scan may not be observed until 5 years after micrometastasis
has occurred; therefore, a bone scan with negative results does not prove the absence of
metastasis. In a biochemical failure, follow-up bone scan usually has no value until the PSA
level rises higher than 30 ng/mL.
• Radiological imaging of suspicious areas should be performed if indicated.
• A chest radiograph can be used as a baseline study or to help detect rare pulmonary
metastases in selected cases.
• Computed axial tomography (CAT) scan of the abdomen and pelvis or an MRI in patients
suggested to have locally advanced disease may give an indication of extracapsular
extension, seminal vesical involvement, pelvic lymph node enlargement, liver metastases,
and hydronephrosis as a result of distal ureteral obstruction.

o Because a rising PSA level may not always indicate an absence of disease
progression, repeat CAT scan or an MRI may help determine treatment response.
o These studies also may be helpful in patients suggested to have locally advanced
disease, based on their Gleason score and PSA level, where local treatment is
otherwise being considered.

• ProstaScint scan: Immunoscintigraphy is used to detect extraprostatic spread (ie, localized


recurrence or lymphatic spread). The false-negative rate for ProstaScint scans is high.

• At initial presentation with prostate cancer, the value of a bone scan is limited in patients
with a Gleason score of less than 7 and a PSA value of 20-30 ng/mL or less.

o A bone scan may be performed in patients at high risk of having bony metastatic
disease as a baseline to indicate treatment response and later presence of recurrent
metastatic disease.
o Regardless of these guidelines, a bone scan is indicated in patients with prostate
cancer who have symptoms suggesting bony metastases.

Other Tests:

Transrectal ultrasound–guided needle biopsy of the prostate certainly is indicated for tissue
diagnosis in patients presenting with advanced prostate cancer. It should be repeated, if indicated, to
determine local recurrence.

Treatment:

Radical Prostatectomy:

- surgical procedure is indicated for cancer that is limited to the prostate and hasnot
invaded any other nearby structures such as the bladder and seminal vesicle.
- Surgeon removes entire prostate, seminal vesicles, and ampulla of vas deferens while
connecting the bladder to the membranous urethra.

Radiation Therapy:

- an external-beam radiation therapy to treat localized prostate cancer. Survival rates


similar to radical prostatectomy when there is no distant involvement. It is also used
with localized spread of cancer outside the prostate.
Hormonal Therapy:

- used in cases in which the cancer has spread to distant regions. The purpose is to lower
testosterone levels or to antagonize it because prostate cancer is stimulated by male
hormones.
- The initial response is usually good, however, the cancer may progress over time.
- Surgical castration—removes the hormonal stimulation of the cancer from the testes.
- Medical castration (preferred)—administration of a luteinizing hormone releasing
hormone (LHRH) agonist such as leuprolide and goserelin stops the production of
testosterone.

Chemotherapy:

- the last treatment method to be employed against prostate cancer. Has not shown to
increase survival.

Cryotherapy:

- insertion of a probe through a small skin incision and freezing areas of cancer in the
prostate.
- Reserved for cancer that is localized to within the prostate.
- Long-term effectiveness is unknown.

Brachytherapy:

- variation of radiation therapy where small, radioactive pellets are implanted into the
prostate.
- Effected for localized cancer.
- Provides radiation to a limited area.

Treatment with metastatic considerations:

Medical Care: Historically, systemic therapy for metastatic and advanced prostate cancer has
involved androgenic suppression. In metastatic disease, this palliative therapy has produced a
median progression-free survival of 18-20 months and an overall survival of 24-36 months.
However, virtually all patients develop hormone-refractory disease. Although hormone therapy is
associated with significant responses, its curative potential is limited due to the inherent
heterogeneity of prostate cancer and due to the inability of hormones to eradicate all prostate cancer
clones, the androgen-dependent and androgen-independent components.

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and
microscopic lymph node metastasis from 20% in the 1970s to 3.4% in the 1990s, the risk of
extraprostatic disease in patients with clinically localized disease remains high, at 30-60%.
Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately
50% of patients with clinically localized prostate cancer are estimated to progress despite definite
local therapy.
• Metastatic prostate cancer
o Management of metastatic prostate cancer is similar to that of locally advanced
prostate cancer, except that palliative radiation should be instituted at painful
metastatic sites and to the bony lesions with impending fractures. These lesions also
may need orthopedic stabilization.
o Flare with LHRH agonists is more common in this group of patients; therefore,
pretreatment with antiandrogens is necessary.
o Treatment-related hypercalcemia might result from eradication of bony metastasis
and can require emergency management.
o Other supportive measures include treatment of anemia and bleeding, management
of disseminated intravascular coagulation (if it occurs), opioids for pain control,
ureteral stenting or diversion for ureteral obstruction, and management of
osteoporosis using bisphosphonates and adjuvant therapy.

 Combination therapy with finasteride and flutamide: This treatment currently


is being studied in an effort to improve the quality of life and to reduce
disease progression. Finasteride (5alpha-reductase inhibitor) at 5 mg PO bid
is used with flutamide at 125 mg PO bid. However, recognize that the action
of finasteride depends on the presence of prostatic epithelial cells.

o Short-term palliative response and improved quality of life in patients with hormone-
refractory prostate cancer is achieved presently by single or multimodal therapies,
which may include second-line hormone manipulations, megestrol, addition of
antiandrogens, corticosteroids, ketoconazole, radiation therapy, chemotherapeutic
agents, mitoxantrone, estramustine, taxanes, bisphosphonates, suramin,
chemohormonal therapy, and some investigational modalities (eg, gene therapy;
vaccine therapy; antiangiogenesis drugs such as thalidomide, telomerase inhibitors,
matrix metalloproteinase inhibitors, and signal transduction inhibitors).

• Antiandrogen addition
o If patients are receiving an LHRH agonist alone, PSA response of more than 50%
and other subjective responses have been observed in 15-80% of the patients when
an antiandrogen is added.
o The median duration of response is only 4 months. Survival benefits are unclear.
• Bisphosphonates
o Bisphosphonates, which are stable analogs of calcium pyrophosphate, inhibit
osteoclastic activity in bone, relieving bone pain. In addition, they also may have a
beneficial effect on the progression of prostate cancer. They also are being studied
for the treatment of osteoporosis induced by androgens.
o Zoledronic acid (Zometa) has shown some promising results.
• Radiation therapy
o External beam radiation therapy is used to palliate painful isolated bone metastasis in
patients with hormone-refractory prostate cancer and in patients with impending
spinal cord compression.
o Certain radiopharmaceutical agents, such as strontium chloride 89 and samarium
153, relieve pain by delivering beta ray irradiation at new bone formation sites.
• Suramin
o Suramin acts via growth factor inhibition. Suramin is an active drug in patients with
hormone-refractory prostate cancer and can be used in combination with other
agents.
o Adverse effects include edema, leukopenia, infection, hyperglycemia, anemia,
anorexia, dyspnea, platelet abnormalities, elevated creatinine, malaise, arrhythmias,
and prothrombin abnormalities.

• Chemohormonal therapy
o The rationale behind chemohormonal regimens for hormone-naïve advanced disease
is based on exposing prostate cancer cells to cytotoxic chemotherapy earlier, before
clonal expansion of androgen independent cells or constitutive overexpression of cell
survival genes becomes established and before patients develop hormone-refractory
prostate cancer.
o No such active well-tolerated cytotoxic agent has been identified that has shown
significant survival advantage without affecting quality of life.

Surgical Care: Bilateral orchiectomy has been the criterion standard initial treatment for patients
with advanced prostate cancer; however, since the inception of LHRH agonist hormonal therapy, it
has become a less popular option.

• Spinal cord decompression for patients with spinal cord compression must be performed
immediately.

Similarly, pinning/plating of weight-bearing bones involved in pathological fractures is mandatory.

Nutrition:

Selenium

Selenium is an essential trace nutrient that is critical for the activity of glutathione peroxidase,
which protects DNA and other cellular molecules against oxidative damage. High levels have been
shown to be protective against some carcinogens in animal models.

Selenium is found in vegetables and garlic grown in selenium-rich soil. Lower age-specific death
rates from some types of cancer are noted in areas with higher soil selenium levels.

A prospective study by Clark et al demonstrated a 50% decrease in cancer mortality and in the
incidence of prostate cancer in men who took 200 mcg of selenium daily versus a placebo. A study
examining the role of selenium in skin cancer found that a daily dose of 200 mcg of selenium did
not affect the incidence of skin cancer, but there were fewer occurrences of prostate and breast
cancer.

Yoshizawa et al investigated the association between the risk of prostate cancer and selenium levels
using toenails as an indicator of long-term selenium intake. When they analyzed case control data,
higher selenium levels were associated with a significantly reduced risk of developing advanced
prostate cancer (odds ratio = 0.49 with selenium compared to a risk ratio of 1.0 for those with low
selenium levels). This means that the risk of prostate cancer was cut in half. This association
remained when additional controls were applied, including family history, body mass index,
calcium intake, lycopene intake, saturated fat intake, and geographical region.

Carotinoids

There are more than 500 different carotenoids, which are pigments synthesized by plants. They are
required for normal cellular growth and differentiation and act as antioxidants. They are represented
in the serum by 5 measurable peaks that include alpha-carotene, beta-carotene, beta-cryptoxanthin,
lutein, and lycopene. In tissue culture experiments, a variety of carotenoids, including lycopene,
accumulate in the prostate and inhibit the growth of prostate cancer cells.

Lycopene is the primary carotenoid in the serum and tissues and is the only carotenoid not
converted to vitamin A. Of the major carotenoids, lycopene is the most effective quencher of singlet
oxygen.

Giovannuci et al found that among a variety of carotenoids, only lycopene was associated with a
decreased risk of cancer. Gann et al reported that lycopene was the only carotenoid that was
inversely related to the presence of prostate cancer. This association was particularly apparent for
aggressive cancer and for men not consuming beta-carotene supplements. For men with low
lycopene levels, beta-carotene supplements produced risk reductions comparable to those observed
in men with high lycopene levels.

The major dietary source of lycopene is cooked and processed tomatoes.

Vitamin E

Vitamin E is a potent antioxidant that has the ability to inhibit malignant transformation. This fat-
soluble vitamin has a potent effect on the immune system.

The most biologically active and common source of vitamin E is alpha-tocopherol, one of 8
naturally occurring forms. This vitamin has been shown to have a substantial protective effect
against prostate cancer. Heininen et al reported a 32% decrease in the incidence of prostate cancer
in men receiving 50 mg of alpha-tocopherol daily. This reduction was noted for clinical cancer but
not for latent cancer. Mortality from prostate cancer was reduced by 41% in the alpha-tocopherol
group, but there was no apparent effect on the time interval between diagnosis and death.

Vitamin D

Vitamin D is involved in calcium metabolism and in the control of cell growth and apoptosis.
Dietary vitamin D can be ingested from plant sterols (ergosterol), milk, and foods supplemented
with this vitamin. It also is produced by the action of ultraviolet radiation on the skin.

Animal experiments have demonstrated that vitamin D (1,25-dihydroxyvitamin D3) inhibits the
growth and invasiveness of prostate cancer cells. Xue et al studied the effects of added dietary
vitamin D and calcium on mice fed a western-style diet. They found epithelial cell
hyperproliferation in mice deficient in these compounds. They demonstrated that the typical western
diet, which is low in both calcium and vitamin D, produces epithelial cell changes that can be
prevented by supplying increased levels of these agents.

Fiber

Numerous epidemiologic and laboratory studies have indicated a role for dietary fiber during the
development and progression of prostate cancer. An inverse relationship has been described
between circulating estrogens and dietary fiber, and a similar relationship has been found for serum
prostate-specific antigen. Dietary intake of fiber has been compared among lactovegetarian and
nonvegetarian males who are Seventh-day Adventists and males who are not Seventh-day
Adventists. Fat consumption was the same for all 3 groups, but the vegetarians consumed
significantly more crude and dietary fiber. Plasma testosterone and estradiol levels in the
vegetarians were lower than those in the other 2 groups and were inversely correlated with dietary
fiber intake. These epidemiologic studies suggest that the amount of dietary fiber intake could affect
prostate cancer by influencing sex steroid production.

Hebert et al conducted a study to identify the major predictors of prostate cancer mortality using
data collected from 59 countries. The specific food-related results indicated that fiber from grains,
cereals, and nuts were protective against prostate cancer.

In the laboratory, Pienta et al examined the role of fiber by studying the effect of modified citrus
pectin, a soluble component of plant fiber derived from citrus fruit, on a rat model. Modified citrus
pectin (MCP) is a complex polysaccharide rich in galactosyl residues, which are cell surface
carbohydrate-binding proteins. Citrus pectin is modified by adjusting the pH, which results in the
creation of smaller, nonbranched carbohydrate chains that appear to be nontoxic. An anticancer
effect has been shown in the B-16 melanoma. This is due to the effects of carbohydrate binding on
the cell surface, which influences cell-to-cell interactions and motility.

Pienta et al used a subline of the Dunning rat prostate cancer, MAT-LyLu, which is a fast-growing,
poorly differentiated cell line that causes death from cancer within 25 days following injection of 1
million cells into the thigh. In this experiment, 4 groups of rats were given 0.0%, 0.01%, 0.1%, or
1.0% of MCP continuously in their drinking water beginning 4 days after tumor inoculation. The
number of lung metastases were counted on day 30, or sooner if the animal had died. Compared
with 15/16 control rats with lung metastases, 7/14 rats in the 0.1%-MCP group and 9/16 rats in the
1%-MCP group had significantly fewer lung metastases, although the primary tumor was not
affected. The authors concluded that MCP acted as a potent inhibitor of prostate cancer pulmonary
metastasis in this particular experiment.

Soy protein

Epidemiologic studies have demonstrated a wide disparity in the incidence of prostate cancer
around the world. While Asian men are just as likely as American men of developing histologic
cancer, they are much less likely to develop clinical cancer. Investigators have linked this difference
to the variation in soy protein consumption, which is high in Asian countries. Soy protein
consumption is estimated to average 50 g per day in Asian countries compared to less than 2-3 g per
day in western diets. In Taiwan, the intake of isoflavones has been shown to be as high as 100 mg
per day.
Many beneficial effects have been attributed to the isoflavones genistein and daidzein. These
particular isoflavones and their beta-glucoside conjugates are present in soybeans in concentrations
of up to 3 mg/g.

Experiments have shown that genistein has a broad variety of actions including inhibiting the
growth of androgen-dependent and independent cell lines. Genistein is a potent modulator of
various tyrosine kinase receptors such as epidermal growth factor, insulin, insulin growth factor-1,
and platelet-derived growth factor. This isoflavone influences signal transduction, apoptosis, and
can inhibit angiogenesis.

Herbal products

Herbal therapies have been utilized for centuries in the treatment of many disorders including
cancer. One particular preparation that shows promise in the treatment of patients with prostate
cancer is PC-SPES. PC-SPES consists of 8 herbs that affect specific biochemical targets. They
include the following:

• Reishi (Ganoderma lucidum Karst) - Immunomodulatory effects


• Baikal skullcap (Scutellaria baicalensis Georgi) - Contains baicalin, which inhibits
lipoxygenase and alters DNA topoisomerase activity.
• Rabdosia (Rabdosia rubescens Hara)
• Dyers woad (Isatis indigotica Fort)
• Mum (Dendranthema morifolium Tzvel)
• Saw palmetto (Serenoa repens Small) - A phytoestrogen, which lowers estrogen levels and
affects the binding of ligands to the androgen receptor
• San-Qi ginseng (Panax notoginseng Burk) - Anticarcinogenic effects on spontaneous and
carcinogen-induced in animal tumor model systems and inhibits metastases
• Chinese licorice (Glycyrrhiza uralensis Fisch) - Reverses mutations

Dietary Recommendations:

In spite of conflicting reports in the epidemiologic literature and with the understanding that
laboratory studies investigating single nutrients may not relate to humans, there seems to be a
consensus regarding dietary recommendations for prostate cancer patients.

These dietary principles include an increased intake of fruits, vegetables, cereals, and grains in a
nutrient-rich diet that is low in fat and high in fiber. Multivitamins and other supplements should be
used to augment, not replace, natural foods.

Pharmacologically manufactured nutrients may not have the same value as those found in nature.
As an example, beta-carotene may be more effective when our bodies extract this nutrient from
natural foods rather than from synthetic sources. During their preparation or storage, dietary
supplements may be subjected to influences, such as artificial light, which can affect their properties
and render them ineffective.
There is no evidence that a single nutrient or single whole food can confer greater cancer protection
than any other. A variety of fruits and vegetables are necessary. Cohen et al evaluated the effects of
fruit and vegetable consumption and the risk of prostate cancer. Of the nutrients they studied, only
the association between lutein (a carotenoid found in high concentrations in cruciferous and green
leafy vegetables) and zeaxanthin (another carotenoid) and prostate cancer risk was even close to
showing a statistical significance.

When total vegetable intake was computed, men who consumed more than 28 servings of
vegetables weekly had a 35% decreased risk for prostate cancer compared to men eating fewer than
14 servings per week. There was a 41% decreased risk for men eating 3 or more cruciferous
vegetables weekly compared to those eating less than 1 serving per week. The authors concluded
that increasing the consumption of cruciferous vegetables while maintaining a constant intake of
total vegetables significantly reduces prostate cancer risk.

The protective effect for cruciferous vegetables may be related to their influence on glutathione S-
transferase (GST). One group of GST isoenzymes is GST pi, which is in high concentration in the
prostate and inactivates carcinogenic electrophiles and organic hydroperoxides and protects cells
from DNA damage. Indoles and isothiocyanates are products of the hydrolysis of glucosinolates,
which are found in cruciferous vegetables. They inhibit tumorigenesis by inducing GST pi
isoenzymes. These GST pi isoenzymes, which are the most abundant GST isoenzyme in the
prostate, are absent in 95% of prostate cancers. Patients should be advised as follows:

• Limit the percentage of dietary fat to 15-20% of total energy intake.


• Eat more than 5 servings of fruits and vegetables daily.
• Consume 25-35 g of dietary fiber daily.
• Consume 40 g of soy protein per day.
• Balance caloric intake to energy output.

Whether these dietary recommendations can prevent or delay the onset of clinical prostate cancer
remains to be proven. The authors have no evidence to indicate that adopting such measures can
influence the progression of an established cancer. Nor do the authors know at what age individuals
should begin this dietary program in order to deter or influence cancer. Evidence indicates that these
dietary principles are more likely to lead to a healthier life than the current western diet.