Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers.[1] The cancer cells may metastasize (spread) from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.
Rates of detection of prostate cancers vary widely across the world, with South and East Asia detecting less frequently than in Europe, and especially the United States.[2] Prostate cancer tends to develop in men over the age of fifty and although it is one of the most prevalent types of cancer in men, many never have symptoms, undergo no therapy, and eventually die of other causes. This is because cancer of the prostate is, in most cases, slow-growing, symptom-free, and since men with the condition are older they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers, or old age. About two-thirds of cases are slow growing, the other third more aggressive and fast developing.[3]
Many factors, including genetics and diet, have been implicated in the development of prostate cancer. The presence of prostate cancer may be indicated by symptoms, physical examination, prostate-specific antigen (PSA), or biopsy. The PSA test increases cancer detection but does not decrease mortality.[4] Suspected prostate cancer is typically confirmed by taking a biopsy of the prostate and examining it under a microscope. Further tests, such as CT scans and bone scans, may be performed to determine whether prostate cancer has spread.
Treatment options for prostate cancer with intent to cure are primarily surgery, radiation therapy, stereotactic radiosurgery, and proton therapy. Other treatments, such as hormonal therapy, chemotherapy, cryosurgery, and high intensity focused ultrasound (HIFU) also exist, although not FDA approved, depending on the clinical scenario and desired outcome.
The age and underlying health of the man, the extent of metastasis, appearance under the microscope, and response of the cancer to initial treatment are important in determining the outcome of the disease. The decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a patient trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.
The prostate is a part of the male reproductive system that helps make and store seminal fluid. In adult men, a typical prostate is about three centimeters long and weighs about twenty grams.[5] It is located in the pelvis, under the urinary bladder and in front of the rectum. The prostate surrounds part of the urethra, the tube that carries urine from the bladder during urination and semen during ejaculation.[6] Because of its location, prostate diseases often affect urination, ejaculation, and rarely defecation. The prostate contains many small glands which make about twenty percent of the fluid constituting semen.[7] In prostate cancer, the cells of these prostate glands mutate into cancer cells. The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testes; dehydroepiandrosterone, made in the adrenal glands; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass.
[edit] Classification
Main article: Prostate cancer staging
An important part of evaluating prostate cancer is determining the stage, or how far the cancer has spread. Knowing the stage helps define prognosis and is useful when selecting therapies. The most common system is the four-stage TNM system (abbreviated from Tumor/Nodes/Metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases.[8]
The most important distinction made by any staging system is whether or not the cancer is still confined to the prostate. In the TNM system, clinical T1 and T2 cancers are found only in the prostate, while T3 and T4 cancers have spread elsewhere. Several tests can be used to look for evidence of spread. These include computed tomography to evaluate spread within the pelvis, bone scans to look for spread to the bones, and endorectal coil magnetic resonance imaging to closely evaluate the prostatic capsule and the seminal vesicles. Bone scans should reveal osteoblastic appearance due to increased bone density in the areas of bone metastasis—opposite to what is found in many other cancers that metastasize.
After a prostate biopsy, a pathologist looks at the samples under a microscope. If cancer is present, the pathologist reports the grade of the tumor. The grade tells how much the tumor tissue differs from normal prostate tissue and suggests how fast the tumor is likely to grow. The Gleason system is used to grade prostate tumors from 2 to 10, where a Gleason score of 10 indicates the most abnormalities. The pathologist assigns a number from 1 to 5 for the most common pattern observed under the microscope, then does the same for the second-most-common pattern. The sum of these two numbers is the Gleason score. The Whitmore-Jewett stage is another method sometimes used.
[edit] Signs and symptoms
Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for an elevated PSA noticed during a routine checkup.
Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination).
Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra. Changes within the gland, therefore, directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate gland itself are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.[9]
Advanced prostate cancer can spread to other parts of the body, possibly causing additional symptoms. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis, or ribs. Spread of cancer into other bones such as the femur is usually to the proximal part of the bone. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.[10]
[edit] Causes
The specific causes of prostate cancer remain unknown.[11] The primary risk factors are age and family history. Prostate cancer is very uncommon in men younger than 45, but becomes more common with advancing age. The average age at the time of diagnosis is 70.[12] However, many men never know they have prostate cancer. Autopsy studies of Chinese, German, Israeli, Jamaican, Swedish, and Ugandan men who died of other causes have found prostate cancer in thirty percent of men in their 50s, and in eighty percent of men in their 70s.[13] Men who have first-degree family members with prostate cancer appear to have double the risk of getting the disease compared to men without prostate cancer in the family.[14] This risk appears to be greater for men with an affected brother than for men with an affected father. In the United States in 2005, there were an estimated 230,000 new cases of prostate cancer and 30,000 deaths due to prostate cancer.[15] Men with high blood pressure are more likely to develop prostate cancer.[16] A 2010 study found that prostate basal cells were the most common site of origin for prostate cancers.[17]
[edit] Genetic
Genetic background may contribute to prostate cancer risk, as suggested by associations with race, family, and specific gene variants. Men who have a first-degree relative (father or brother) with prostate cancer have twice the risk of developing prostate cancer, and those with two first-degree relatives affected have a fivefold greater risk compared with men with no family history.[18] In the United States, prostate cancer more commonly affects black men than white or Hispanic men, and is also more deadly in black men.[19] [20] In contrast, the incidence and mortality rates for Hispanic men are one third lower than for non-Hispanic whites. Studies of twins in Scandinavia suggest that forty percent of prostate cancer risk can be explained by inherited factors.[21]
No single gene is responsible for prostate cancer; many different genes have been implicated. Mutations in BRCA1 and BRCA2, important risk factors for ovarian cancer and breast cancer in women, have also been implicated in prostate cancer.[22] Other linked genes include the Hereditary Prostate cancer gene 1 (HPC1), the androgen receptor, and the vitamin D receptor.[19] TMPRSS2-ETS gene family fusion, specifically TMPRSS2-ERG or TMPRSS2-ETV1/4 promotes cancer cell growth.[23]
Loss of cancer suppressor genes, early in the prostatic carcinogenesis, have been localized to chromosomes 8p, 10q, 13q,and 16q. P53 mutations in the primary prostate cancer are relatively low and are more frequently seen in metastatic settings, hence, p53 mutations are late event in pathology of prostate cancer. Other tumor suppressor genes that are thought to play a role in prostate cancer include PTEN (gene) and KAI1. "Up to 70 percent of men with prostate cancer have lost one copy of the PTEN gene at the time of diagnosis"[24] Relative frequency of loss of E-cadherin and CD44 has also been observed.
[edit] Dietary
While a number of dietary factors have been linked to prostate cancer the evidence is still tentative.[25] Evidence supports little role for dietary fruits and vegetables in prostate cancer occurrence.[26] Red meat and processed meat also appear to have little effect.[27] Lower blood levels of vitamin D may increase the risk of developing prostate cancer.[28] This may be linked to lower exposure to ultraviolet (UV) light, since UV light exposure can increase vitamin D in the body.[29]
Green tea may be protective (due to its catechins content),[30] although the most comprehensive clinical study indicates that it has no protective effect.[31] Other holistic methods are also studied.[32]
Taking multivitamins more than seven times a week may increase the risks of contracting the disease.[33][34] This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label.
Folic acid supplements have recently been linked to an increase in risk of developing prostate cancer.[35] A ten-year research study led by University of Southern California researchers showed that men who took daily folic acid supplements of 1 mg were three times more likely to be diagnosed with prostate cancer than men who took a placebo.[35]
High alcohol intake may increase the risk of prostate cancer and interfere with folate metabolism.[36] Low folate intake and high alcohol intake may increase the risk of prostate cancer to a greater extent than the sole effect of either one by itself.[36] A case control study consisting of 137 veterans addressed this hypothesis and the results were that high folate intake was related to a 79% lower risk of developing prostate cancer and there was no association between alcohol consumption by itself and prostate cancer risk.[36] Folate's effect however was only significant when coupled with low alcohol intake.[36] There is a significant decrease in risk of prostate cancer with increasing dietary folate intake but this association only remains in individuals with low levels of alcohol consumption.[36] There was no association found in this study between folic acid supplements and risk of prostate cancer.[36]
[edit] Medication exposure
There are also some links between prostate cancer and medications, medical procedures, and medical conditions.[37] Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk.[38]
Infection or inflammation of the prostate (prostatitis) may increase the chance for prostate cancer while another study shows infection may help prevent prostate cancer by increasing blood to the area. In particular, infection with the sexually transmitted infections chlamydia, gonorrhea, or syphilis seems to increase risk.[39] Finally, obesity[40] and elevated blood levels of testosterone[41] may increase the risk for prostate cancer. There is an association between vasectomy and prostate cancer however more research is needed to determine if this is a causative relationship.[42]
Research released in May 2007, found that US war veterans who had been exposed to Agent Orange had a 48% increased risk of prostate cancer recurrence following surgery.[43]
[edit] Viral
In 2006, researchers associated a previously unknown retrovirus, Xenotropic MuLV-related virus or XMRV, with human prostate tumors.[44] Subsequent reports on the virus have been contradictory. A group of US researchers found XMRV protein expression in human prostate tumors,[45] while German scientists failed to find XMRV-specific antibodies or XMRV-specific nucleic acid sequences in prostate cancer samples.[46]
Pathophysiology
When normal cells are damaged beyond repair, they are eliminated by
apoptosis. Cancer cells avoid apoptosis and continue to multiply in an unregulated manner.
Prostate cancer is classified as an
adenocarcinoma,
or glandular cancer, that begins when normal semen-secreting prostate
gland cells mutate into cancer cells. The region of prostate gland where
the adenocarcinoma is most common is the peripheral zone. Initially,
small clumps of cancer cells remain confined to otherwise normal
prostate glands, a condition known as
carcinoma in situ or
prostatic intraepithelial neoplasia (PIN). Although there is no proof that PIN is a cancer precursor, it is
closely associated with cancer. Over time, these cancer cells begin to
multiply and spread to the surrounding prostate tissue (the
stroma) forming a
tumor. Eventually, the tumor may grow large enough to invade nearby organs such as the
seminal vesicles or the
rectum, or the tumor cells may develop the ability to travel in the
bloodstream and
lymphatic system. Prostate cancer is considered a
malignant tumor because it is a mass of cells that can invade other parts of the body. This invasion of other organs is called
metastasis. Prostate cancer most commonly metastasizes to the
bones,
lymph nodes, and may invade rectum,
bladder and lower ureters after local progression. The route of metastasis to bone is thought to be venous as the
prostatic venous plexus draining the prostate connects with the vertebral veins.
[47]The prostate is a zinc accumulating,
citrate producing organ. The protein
ZIP1 is responsible for the active transport of zinc into prostate cells.
One of zinc's important roles is to change the metabolism of the cell in
order to produce citrate, an important component of semen. The process
of zinc accumulation, alteration of metabolism, and citrate production
is energy inefficient, and prostate cells sacrifice enormous amounts of
energy (ATP) in order to accomplish this task. Prostate cancer cells are
generally devoid of zinc. This allows prostate cancer cells to save
energy not making citrate, and utilize the new abundance of energy to
grow and spread. The absence of zinc is thought to occur via a silencing
of the gene that produces the transporter protein ZIP1. ZIP1 is now
called a tumor suppressor gene product for the gene
SLC39A1.
The cause of the epigenetic silencing is unknown. Strategies which
transport zinc into transformed prostate cells effectively eliminate
these cells in animals. Zinc inhibits
NF-κB pathways, is anti-proliferative, and induces apoptosis in abnormal
cells. Unfortunately, oral ingestion of zinc is ineffective since high
concentrations of zinc into prostate cells is not possible without the
active transporter, ZIP1.
[48]RUNX2 is a transcription factor that prevents cancer cells from undergoing
apoptosis thereby contributing to the development of prostate cancer.
[49]The
PI3k/Akt signaling cascade works with the transforming growth factor beta/SMAD signaling cascade
to ensure prostate cancer cell survival and protection against
apoptosis.
[50] X-linked inhibitor of apoptosis (XIAP) is hypothesized to promote
prostate cancer cell survival and growth and is a target of research
because if this inhibitor can be shut down then the apoptosis cascade
can carry on its function in preventing cancer cell proliferation.
[51] Macrophage inhibitory cytokine-1 (MIC-1) stimulates the
focal adhesion kinase (FAK) signaling pathway which leads to prostate cancer cell growth and survival.
[52]The
androgen receptor helps prostate cancer cells to survive and is a target for many anti
cancer research studies; so far, inhibiting the androgen receptor has
only proven to be effective in mouse studies.
[53] Prostate specific membrane antigen (PSMA) stimulates the development of
prostate cancer by increasing folate levels for the cancer cells to use
to survive and grow; PSMA increases available folates for use by
hydrolyzing glutamated folates.
[54][edit] DiagnosisThe only test that can fully confirm the diagnosis of prostate cancer is a
biopsy,
the removal of small pieces of the prostate for microscopic
examination. However, prior to a biopsy, several other tools may be used
to gather more information about the prostate and the urinary tract.
Digital
rectal examination (DRE) may allow a doctor to detect prostate abnormalities.
Cystoscopy shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down the
urethra.
Transrectal ultrasonography creates a picture of the prostate using sound waves from a probe in the rectum.
[edit] BiopsyMain article:
Prostate biopsy
Micrograph showing a prostate cancer (conventional adenocarcinoma) with
perineural invasion.
H&E stain.
If cancer is suspected, a biopsy is offered expediently. During a biopsy a
urologist or
radiologist obtains tissue samples from the prostate via the rectum. A biopsy gun
inserts and removes special hollow-core needles (usually three to six on
each side of the prostate) in less than a second. Prostate biopsies are
routinely done on an outpatient basis and rarely require
hospitalization. Fifty-five percent of men report discomfort during
prostate biopsy.
[55][edit] Gleason scoreMain article:
Gleason scoreThe tissue samples are then examined under a microscope to determine
whether cancer cells are present, and to evaluate the microscopic
features (or
Gleason score) of any cancer found.
Prostate specific membrane antigen is a
transmembrane carboxypeptidase and exhibits
folate hydrolase activity.
[35] This
protein is overexpressed in prostate cancer
tissues and is associated with a higher
Gleason score.
[35][edit] Tumor markersTissue samples can be stained for the presence of PSA and other
tumor markers in order to determine the origin of malignant cells that have metastasized.
[56]Small cell carcinoma is a very rare (1%
[57]) type of prostate cancer that cannot be diagnosed using the PSA.
[57][58] As of 2009
researchers are trying to determine the best way to screen for this
type of prostate cancer because it is a relatively unknown and rare type
of prostate cancer but very serious and quick to spread to other parts
of the body.
[58] Possible methods include chromatographic separation methods by mass
spectrometry, or protein capturing by immunoassays or immunized
antibodies. The test method will involve quantifying the amount of the
biomarker
PCI, with reference to the
Gleason Score.
Not only is this test quick, it is also sensitive. It can detect
patients in the diagnostic grey zone, particularly those with a serum
free to total
Prostate Specific Antigen ratio of 10-20%.
[59]The oncoprotein
BCL-2,
has been associated with the development of androgen-independent
prostate cancer due to its high levels of expression in
androgen-independent tumours in advanced stages of the pathology. The
upregulation of BCL-2 after androgen ablation in prostate carcinoma cell
lines and in a castrated-male rat model further established a
connection between BCL-2 expression and prostate cancer progression.
[60]The expression of Ki-67 by immunohistochemistry may be a significant predictor of patient outcome for men with prostate cancer.
[61]ERK5 is a protein that may be used as a marker. ERK5 is present in
abnormally high levels of prostate cancer, including invasive cancer
which has spread to other parts of the body. It is also present in
relapsed cancer following previous hormone therapy. Research shows that
reducing the amount of ERK5 found in cancerous cells reduces their
invasiveness.
[62][edit] ScreeningMain article:
Prostate cancer screeningProstate cancer
screening is an attempt to find unsuspected cancers, and may lead to more specific follow-up tests such as a
biopsy, with cell samples taken for closer study. Options include the
digital rectal exam (DRE) and the
prostate-specific antigen (PSA) blood test. A 2010 analysis concluded that routine screening with
either a DRE or PSA is not supported by the evidence as there is no
mortality benefit from screening.
[4]Modern screening tests have found cancers that might never have
developed into serious disease, and that "the slight reduction of risk
by surgically removing the prostate or treating it with radiation may
not outweigh the substantial side effects of these treatments," an
opinion also shared by the
CDC.
[63][64][edit] PreventionThere is a significant relation between lifestyle (including food consumption) and cancer prevention.
[65] Exercise and diet may help prevent prostate cancer to the same extent
as may medications such as alpha-blockers and 5-alpha-reductase
inhibitors.
[edit] MedicationsTwo medications which block the conversion of
testosterone to
dihydrotestosterone,
finasteride[66] and
dutasteride,
[67] have also shown some promise. The use of these medications for primary
prevention is still in the testing phase, and they are not widely used
for this purpose. A 2008 study found that finasteride reduces the
incidence of prostate cancer by 30%, without any increase in the risk of
High-Grade prostate cancer.
[68] In the original study it turns out that the smaller prostate caused by
finasteride means that a doctor is more likely to hit upon cancer nests
and more likely to find aggressive-looking cells.
[68]Compared to placebo treatment, taking 5-alpha-reductase inhibitors
(5-ARIs) can reduce a man’s risk of being diagnosed with prostate cancer
from around 5–9% to around 4-6% during up to 7 years of treatment,
according to a Cochrane Review of studies.
[69][edit] Ejaculation frequencyMore frequent ejaculation also may decrease a man's risk of prostate
cancer. One study showed that men who ejaculated 3-5 times a week at the
age of 15-19 had a decreased rate of prostate cancer when they are old,
though other studies have shown no benefit.
[70][71] The results contradict those of previous studies, which have suggested
that having had many sexual partners, or a high frequency of sexual
activity, increases the risk of prostate cancer by up to 40 percent. A
key difference may be that these earlier studies defined sexual activity
as sexual intercourse, whereas this study focused on the number of
ejaculations, whether or not intercourse was involved.
[72] Another study completed in 2004 reported that "Most categories of
ejaculation frequency were unrelated to risk of prostate cancer.
However, high ejaculation frequency was related to decreased risk of
total prostate cancer." The report abstract concluded, "Our results
suggest that ejaculation frequency is not related to increased risk of
prostate cancer."
[73][edit] DietConsuming fish appears to lower prostate cancer deaths but not the occurrence of prostate cancer.
[74] Omega-3 fatty acids are unlikely to prevent prostate cancer.
[75] There is no evidence that
vitamin supplements affect risk.
[76] Trans fats may be associated with an increased risk of cancer but the evidence is still limited.
[77] The American Dietetic Association and Dieticians of Canada report a
decreased incidence of prostate cancer for those following a vegetarian
diet.
[78][edit] ManagementMain article:
Management of prostate cancerTreatment for prostate cancer may involve
active surveillance (monitoring for tumor progress or symptoms),
surgery (i.e. radical prostatectomy),
radiation therapy including
brachytherapy (
prostate brachytherapy) and external beam radiation therapy,
High-intensity focused ultrasound (HIFU),
chemotherapy, oral chemotherapeutic drugs (Temozolomide/TMZ),
cryosurgery,
hormonal therapy, or some combination.
[79][80][81] William J. Catalona, MD: regarding Active Surveillance, "Watchful
Waiting or for some patients, Wishful Waiting: Can delay prompt
treatment of life-threatening tumors, it would require repeated biopsies
that often make subsequent nerve-sparing surgery more difficult and it
causes many patients anxiety about living with untreated cancer, thus
diminishing their quality of life." These men may have already been
chemically castrated and impotent.
Which option is best depends on the stage of the disease, the Gleason
score, and the PSA level. Other important factors are age, general
health, and patient views about potential treatments and their possible
side-effects. Because all treatments can have significant
side-effects,
such as erectile dysfunction and urinary incontinence, treatment
discussions often focus on balancing the goals of therapy with the risks
of lifestyle alterations. Prostate cancer patients are strongly
recommended to work closely with their physicians and use a combination
of the treatment options when managing their prostate cancer.
[82][83][84]Although the widespread use of prostate specific antigen (PSA)
screening in the USA has resulted in diagnosis at earlier age and cancer
stage, the vast majority of cases are still diagnosed in men older than
65 years, and approximately 25% of cases are diagnosed in men older
than 75 years.
[85] Though US National Comprehensive Cancer Network guidelines
[86] recommend using life expectancy greater than or less than 10 years to
help make treatment decisions, in practice, many elderly patients are
not offered curative treatment options such as radical prostatectomy
(RP) or radiation therapy and are instead treated with hormonal therapy
or watchful waiting. This pattern can be attributed to factors such as
medical co-morbidity and patient preferences is regard to quality of
life in addition to prostate cancer specific risk factors such as
pretreatment PSA, Gleason score and clinical stage. As the average life
expectancy increases due to advances in treatment of cardiovascular,
pulmonary and other chronic disease, it is likely that more elderly
patients will be living long enough to suffer the consequences of their
prostate cancer. Therefore, there is currently much interest in the role
of aggressive prostate cancer treatment modalities such as with surgery
or radiation in the elderly population who have localized disease. The
results of one randomized controlled trial published by the Scandinavian
Prostate Cancer Group 4
[87] evaluated cancer-specific mortality in patients treated with RP
compared with watchful waiting. The patients receiving radical
prostatectomy had a relative risk reduction of 30.7% [95% confidence
interval 2.5%-50.7%], but an absolute risk reduction of 6% [95%
confidence interval 0.5%-11.5%]. The number needed to treat was
calculated to be 16. This means that, over the median follow up period
of approximately 10 years, 16 patients with localized prostate cancer
would need to receive radical prostatectomy rather than watchful waiting
in order to prevent one death due to prostate cancer. Further subset
analysis revealed that this benefit did not apply to all ages equally.
In men younger than 65 years, patients randomized to receive radical
prostatectomy actually had a 10-18% absolute risk reduction in
cancer-specific mortality compared to those randomized to watchful
waiting. However, in men older than 65, there was no statistically
significant risk reduction even when adjusted for PSA level, Gleason
score and tumor stage. Randomized, controlled trials comparing radical
prostatectomy, radiation therapy, hormonal therapy and watchful waiting
would provide the best evidence for how to best treat elderly patients.
Such trials are urgently needed, as the elderly population is rapidly
growing and is expected to continue to do so. Study results in 2011
suggest
active surveillance is the best choice for older 'low-risk' patients.
[88]The selection of treatment options may be a complex decision
involving many factors. For example, radical prostatectomy after primary
radiation failure is a very technically challenging surgery and may not
be an option, while salvage radiation therapy after surgical failure
may have many complications.
[89] This may enter into the treatment decision.
If the cancer has spread beyond the prostate, treatment options
significantly change, so most doctors that treat prostate cancer use a
variety of
nomograms to predict the probability of spread. Treatment by watchful
waiting/active surveillance, external beam radiation therapy,
brachytherapy, cryosurgery, HIFU, and surgery are, in general, offered
to men whose cancer remains within the prostate.
Hormonal therapy and chemotherapy are often reserved for disease that has spread beyond
the prostate. However, there are exceptions: radiation therapy may be
used for some advanced tumors, and
hormonal therapy is used for some early stage tumors.
Cryotherapy (the process of freezing the tumor),
hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.
[90][edit] Castration-resistant prostate cancerMost hormone dependent cancers become refractory after one to three
years and resume growth despite hormone therapy. Previously considered
"hormone-refractory prostate cancer" or "androgen-independent prostate
cancer", the term castration-resistant has replaced "hormone refractory"
because while they are no longer responsive to castration treatment
(reduction of available
androgen/
testosterone/
DHT by chemical or surgical means), these cancers still show reliance upon hormones for
androgen receptor activation.
[91] Before 2004, all treatments for castration-resistant prostate cancer (CRPC) were considered
[who?] palliative and not shown to prolong survival.
[citation needed] However, there are now several treatments available to treat CRPC that improve survival.
The
cancer chemotherapic docetaxel, has been used as treatment for (CRPC) with a median survival benefit of 2 to 3 months.
[92][93] Docetaxel's FDA approval in 2004 was significant as it was the first
treatment proven to prolong survival in CRPC. In 2010, the FDA approved a
second-line chemotherapy treatment known as
cabazitaxel.
[94]Off-label use of the oral drug,
Ketoconazole,
is sometimes used as a way to further manipulate hormones with a
therapeutic effect in CRPC. However, many side effects are possible with
this drug and
abiraterone is likely to supplant usage since it has a similar mechanism of action with less toxic side effects.
A combination of
bevacizumab (Avastin), docetaxel (
taxotere),
thalidomide and
prednisone appears effective in the treatment of CRPC.
[95]The immunotherapy treatment,
sipuleucel-T, is also effective in the treatment of CRPC with a median survival benefit of 4 months.
[96]The second line hormonal therapy,
abiraterone,
completed a phase 3 trial for CRPC patients who have failed
chemotherapy in 2010. Results were positive. Overall survival increased
by 4.6 months when compared to placebo. On April 28, 2011, the U.S. Food
and Drug Administration approved abiraterone acetate in combination
with
prednisone to treat patients with late-stage (metastatic) castration-resistant prostate cancer who have received prior
docetaxel (chemotherapy).
[citation needed]Alpharadin completed a phase 3 trial for CRPC patients with bone metastasis. A
pre-planned interim analysis showed improved survival and quality of
life. The study was stopped for ethical reasons to give the placebo
group the same treatment. Apharadin uses bone targeted Radium-223
isotopes to kill cancer cells by alpha radiation. Alpharadin is an
investigational agent and is not approved for marketing by the European
Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), or
any other health authorities.
[97]There are also several treatments currently in clinical trials to
treat CRPC. These include the 2nd generation hormonal therapies
MDV3100 and
orteronel (TAK-700), the immunotherapy PROSTVAC, and the bone metastasis-targeting
cabozantinib (XL-184).
[edit] PrognosisProstate cancer rates are higher and prognosis poorer in developed
countries than the rest of the world. Many of the risk factors for
prostate cancer are more prevalent in the
developed world,
including longer life expectancy and diets high in red meat. (People
who consume larger amounts of meat and dairy also tend to consume fewer
portions of fruits and vegetables. It is not currently clear whether
both of these factors, or just one of them, contribute to the occurrence
of prostate cancer.
[98])
Also, where there is more access to screening programs, there is a
higher detection rate. Prostate cancer is the ninth-most-common cancer
in the world, but is the number-one non-skin cancer in men from the
United States. Prostate cancer affected eighteen percent of American men
and caused death in three percent in 2005.
[99] In
Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and
Europe in the 1990s.
[100] In
India in the 1990s, half of the people with prostate cancer confined to the prostate died within ten years.
[101] African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in
Shanghai,
China.
[102] In
Nigeria, two percent of men develop prostate cancer, and 64% of them are dead after two years.
[103]In patients who undergo treatment, the most important clinical
prognostic indicators of disease outcome are stage, pre-therapy PSA
level, and Gleason score. In general, the higher the grade and the
stage, the poorer the prognosis.
Nomograms can be used to calculate the estimated risk of the individual patient.
The predictions are based on the experience of large groups of patients
suffering from cancers at various stages.
[104]In 1941,
Charles Huggins reported that androgen ablation therapy causes regression of primary and metastatic androgen-dependent prostate cancer.
[105] He was awarded the 1966
Nobel Prize for Physiology or Medicine for this discovery. Androgen ablation therapy causes remission in
80-90% of patients undergoing therapy, resulting in a median
progression-free survival of 12 to 33 months. After remission, an
androgen-independent phenotype typically emerges, wherein the median
overall survival is 23–37 months from the time of initiation of androgen
ablation therapy.
[106] The actual mechanism contributes to the progression of prostate cancer
is not clear and may vary between individual patient. A few possible
mechanisms have been proposed.
[107][edit] Classification systemsMany prostate cancers are not destined to be lethal, and most men
will ultimately die from causes other than of the disease. Decisions
about treatment type and timing may, therefore, be informed by an
estimation of the risk that the tumor will ultimately recur after
treatment and/or progress to metastases and mortality. Several tools are
available to help predict outcomes, such as pathologic stage and
recurrence after surgery or radiation therapy. Most combine stage,
grade, and PSA level, and some also add the number or percent of biopsy
cores positive, age, and/or other information.
- The D'Amico classification stratifies men by low,
intermediate, or high risk based on stage, grade, and PSA. It is used
widely in clinical practice and research settings. The major downside to
the 3-level system is that it does not account for multiple adverse
parameters (e.g., high Gleason score and high PSA) in stratifying patients.
- The Partin tables
predict pathologic outcomes (margin status, extraprostatic extension,
and seminal vesicle invasion) based on the same three variables and are
published as lookup tables.
- The Kattan nomograms predict recurrence after surgery and/or
radiation therapy, based on data available either at time of diagnosis
or after surgery. The nomograms can be calculated using paper graphs or
software available on a website or for handheld computers. The Kattan
score represents the likelihood of remaining free of disease at a given
time interval following treatment.
- The UCSF Cancer of the Prostate Risk Assessment (CAPRA) score
predicts both pathologic status and recurrence after surgery. It offers
comparable accuracy as the Kattan preoperative nomogram, and can be
calculated without paper tables or a calculator. Points are assigned
based on PSA, Grade, stage, age, and percent of cores positive; the sum
yields a 0–10 score, with every 2 points representing roughly a doubling
of risk of recurrence. The CAPRA score was derived from community-based
data in the CaPSURE database. It has been validated among over 10,000 prostatectomy patients, including patients from CaPSURE;[108] the SEARCH registry, representing data from several Veterans Administration and active military medical centers;[109] a multi-institutional cohort in Germany;[110] and the prostatectomy cohort at Johns Hopkins University.[111]
More recently, it has been shown to predict metastasis and mortality
following prostatectomy, radiation therapy, watchful waiting, or
androgen deprivation therapy.[112]
[edit] Epidemiology
Age-standardized death from prostate cancer per 100,000 inhabitants in 2004.
[113] no data
less than 4
4-8
8-12
12-16
16-20
20-24
24-28
28-32
32-36
36-40
40-44
more than 44
Rates of prostate cancer vary widely across the world. Although the
rates vary widely between countries, it is least common in South and
East Asia, more common in Europe, and most common in the United States.
[2] According to the
American Cancer Society, prostate cancer is least common among Asian men and most common among black men, with figures for white men in between.
[114][115] The average annual incidence rate of prostate cancer between 1988 and
1992 among Chinese men in the United States was 15 times higher than
that of their counterparts living in Shanghai and Tianjin.
[114][115][116] However, these high rates may be affected by increasing rates of detection.
[117] Many suggest that prostate cancer may be under reported, yet
BPH incidence in China and Japan is similar to rates in Western countries.,
[118][119]Prostate cancer develops primarily in men over fifty. It is the most
common type of cancer in men in the United States, with 186,000 new
cases in 2008 and 28,600 deaths.
[120] It is the second leading cause of cancer death in U.S. men after
lung cancer.
In the United Kingdom it is also the second most common cause of cancer
death after lung cancer, where around 35,000 cases are diagnosed every
year and of which around 10,000 die of it. Many factors, including
genetics and
diet, have been implicated in the development of prostate cancer. The Prostate Cancer Prevention Trial found that
finasteride reduces the incidence of prostate cancer by 30%. There had been a
controversy about this also increasing the risk of more aggressive
cancers, but more recent research showed this may not be the case.
[68][121]More than 80% of men will develop prostate cancer by the age of 80.
[122] However, in the majority of cases, it will be slow-growing and harmless. In such men, diagnosing prostate cancer is
overdiagnosis—the
needless identification of a technically aberrant condition that will
never harm the patient—and treatment in such men exposes them to all of
the adverse effects, with no possibility of extending their lives.
[123]
Mer Aoû 17, 2011 7:54 am
