prostate cancer

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. 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.^[1] 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 men with the condition often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers, or old age. 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. There is controversy about the accuracy of the PSA test and the value of screening. 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 and radiation therapy. Other treatments such as hormonal therapy, chemotherapy, proton therapy, cryosurgery, high intensity focused ultrasound (HIFU) also exist 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.

Prostate

The prostate is a part of the male reproductive organ that helps make and store seminal fluid. In adult men, a typical prostate is about three centimeters long and weighs about twenty grams.^[2] 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.^[3] 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.^[4] 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.

Classification

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.

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.

Computed tomography (CT) and magnetic resonance imaging (MRI) currently do not add any significant information in the assessment of possible lymph node metastases in patients with prostate cancer according to a meta-analysis.^[5] The sensitivity of CT was 42% and specificity of CT was 82%. The sensitivity of MRI was 39% and the specificity of MRI was 82%. For patients at similar risk to those in this study (17% had positive pelvic lymph nodes in the CT studies and 30% had positive pelvic lymph nodes in the MRI studies), this leads to a positive predictive value (PPV) of 32.3% with CT, 48.1% with MRI, and negative predictive value (NPV) of 87.3% with CT, 75.8% with MRI.

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. Proper grading of the tumor is critical, since the grade of the tumor is one of the major factors used to determine the treatment recommendation.^{[citation needed]}

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 hypertrophy. These include frequent urination, increased urination at night, difficulty starting and maintaining a steady stream of urine, blood in the urine, and 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.^[6]

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.^[7]

Causes

The specific causes of prostate cancer remain unknown.^[8] A man's risk of developing prostate cancer is related to his age, genetics, race, diet, lifestyle, medications, and other factors. The primary risk factor is age. Prostate cancer is uncommon in men younger than 45, but becomes more common with advancing age. The average age at the time of diagnosis is 70.^[9] 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.^[10] In the year 2005 in the United States, there were an estimated 230,000 new cases of prostate cancer and 30,000 deaths due to prostate cancer.^[11]

Genetics

A man's genetic background contributes to his risk of developing prostate cancer. This is suggested by an increased incidence of prostate cancer found in certain racial groups, in identical twins of men with prostate cancer, and in men with certain genes. In the United States, prostate cancer more commonly affects black men than white or Hispanic men, and is also more deadly in black men.^[12] Men who have a brother or father with prostate cancer have twice the usual risk of developing prostate cancer.^[13] Studies of twins in Scandinavia suggest that forty percent of prostate cancer risk can be explained by inherited factors.^[14] However, no single gene is responsible for prostate cancer; many different genes have been implicated. Two genes (BRCA1 and BRCA2) that are important risk factors for ovarian cancer and breast cancer in women have also been implicated in prostate cancer.^[15]

Diet

Dietary amounts of certain foods, vitamins, and minerals can contribute to prostate cancer risk. Dietary factors that may increase prostate cancer risk include low intake of vitamin E^{[citation needed]} and the mineral selenium^{[citation needed]}. A study in 2007 cast doubt on the effectiveness of lycopene (found in tomatoes) in reducing the risk of prostate cancer.^[16] Lower blood levels of vitamin D also may increase the risk of developing prostate cancer. This may be linked to lower exposure to ultraviolet (UV) light, since UV light exposure can increase vitamin D in the body.^[17]

A large study has implicated dairy, specifically low-fat milk and other dairy products to which vitamin A palmitate has been added. This form of synthetic vitamin A has been linked to prostate cancer because it reacts with zinc and protein to form an unabsorbable complex.^{[citation needed]}

Medication exposure

There are also some links between prostate cancer and medications, medical procedures, and medical conditions. Daily use of anti-inflammatory medicines such as aspirin, ibuprofen, or naproxen may decrease prostate cancer risk.^[18] Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk.^[19] Infection or inflammation of the prostate (prostatitis) may increase the chance for prostate cancer. In particular, infection with the sexually transmitted infections chlamydia, gonorrhea, or syphilis seems to increase risk.^[20] Finally, obesity^[21] and elevated blood levels of testosterone^[22] may increase the risk for prostate cancer.

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.^[23]

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 remains 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, rectum, and bladder.

Diagnosis

Normal prostate (A) and prostate cancer (B). In prostate cancer, the regular glands of the normal prostate are replaced by irregular glands and clumps of cells, as seen in these pictures taken through a microscope.

When a man has symptoms of prostate cancer, or a screening test indicates an increased risk for cancer, more invasive evaluation is offered.

The 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. 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.

Biopsy

If cancer is suspected, a biopsy is offered. 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. ^[24]

Gleason score

The 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.

Tumor markers

Tissue samples can be stained for the presence of PSA and other tumor markers in order to determine the origin of maligant cells that have metastasized.^[25]

Diagnostic tools under investigation

At Present, an active area of research involves non-invasive methods of prostate tumor detection. Adenoviruses modified to transfect tumor cells with harmless yet distinct genes (such as luciferase) have proven capable of early detection. So far, however, this area of research has been tested only in animal and LNCaP models.^[26]

PCA3

Another potential non-invasive method of early prostate tumor detection is through a molecular test that detects the presence of cell-associated PCA3 mRNA in urine. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. PCA3 is not a replacement for PSA but an additional tool to help decide whether, in men suspected of having prostate cancer, a biopsy is really needed. The higher the expression of PCA3 in urine, the greater the likelihood of a positive biopsy, i.e., the presence of cancer cells in the prostate.

Early prostate cancer

It was reported in April 2007 that a new blood test for early prostate cancer antigen-2 (EPCA-2) that may alert men if they have prostate cancer and how aggressive it will be is being researched.^[27][28]

Prostate mapping

Prostate Mapping is a method of diagnosis that may be accurate in determining the precise location and aggressiveness of cancer. It uses a combination of multi-sequence MRI imaging techniques and a template-guided biopsy system, and involves taking multiple biopsies through the skin that lies in front of the back passage rather than through the back passage. The procedure is carried out under general anaesthetic.^[29]

Prostasomes

Epithelial cells of the prostate secrete prostasomes as well as PSA. Prostasomes are membrane–surrounded, prostate-derived organelles that appear extracellularly, and one of their physiological functions is to protect the sperm from attacks by the female immune system. Cancerous prostate cells continue to synthesize and secrete prostasomes, and may be shielded against immunological attacks by these prostasomes. Research of several aspects of prostasomal involvement in prostate cancer has been performed.^[30]

Prevention

Vitamins and medication

Evidence from epidemiological studies supports protective roles in reducing prostate cancer for dietary selenium, vitamin E, lycopene, and soy foods. High plasma levels of Vitamin D may also have a protective effect.^[31] Estrogens from fermented soybeans and other plant sources (called phytoestrogens) may also help prevent prostate cancer.^[32] The selective estrogen receptor modulator drug toremifene has shown promise in early trials.^[33][34] Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride^[35] and dutasteride,^[36] 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. The initial problem with these medications is that they may preferentially block the development of lower-grade prostate tumors, leading to a relatively greater chance of higher grade cancers, and negating any overall survival improvement. More recent research found that finasteride did not increase the percentage of higher grade cancers. A 2008 study update found that finasteride reduces the incidence of prostate cancer by 30%. In the original study it turns that 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. Most of the men in the study who had cancer — aggressive or not — chose to be treated and many had their prostates removed. A pathologist then carefully examined every one of those 500 prostates and compared the kinds of cancers found at surgery to those initially diagnosed at biopsy. Finasteride did not increase the risk of High-Grade prostate cancer.^[37][38]

Green tea may be protective (due to its polyphenol content),^[39] although the most comprehensive clinical study indicates that it has no protective effect.^[40] A 2006 study of green tea derivatives demonstrated promising prostate cancer prevention in patients at high risk for the disease.^[41] Recent research published in the Journal of the National Cancer Institute suggests that taking multivitamins more than seven times a week can increase the risks of contracting the disease.^[42][43] 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. Scientists recommend a healthy, well balanced diet rich in fiber, and to reduce intake of meat.^{[citation needed]} A 2007 study published in the Journal of the National Cancer Institute found that men eating cauliflower, broccoli, or one of the other cruciferous vegetables, more than once a week were 40% less likely to develop prostate cancer than men who rarely ate those vegetables.^[44][45] The phytochemicals indole-3-carbinol and diindolylmethane, found in cruciferous vegetables, has antiandrogenic and immune modulating properties.^[46][47]

Ejaculation frequency

More frequent ejaculation also may decrease a man's risk of prostate cancer. One study showed that men who ejaculated five times a week in their 20s had a decreased rate of prostate cancer, though other studies have shown no benefit.^[48][49] 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. The key difference is 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.^[50] 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." ^[51] A 2008 study showed that frequent masturbation, of about two to seven times a week, at the ages of 20s and 30s, increases the risk of having prostate cancer. While frequent masturbation, once a week, at the age of 50s decreases the disease risk.^[52]

Oils and fatty acids

In experimental models using mice have been tested, dietary and serum omega-6 polyunsaturated fatty acids (PUFAs) increased prostate tumor growth,and has sped up histopathological progression, and decreased survival, while the omega-3 fatty acids, in the same situation, had the opposite, beneficial effect.^[53]

Men with higher serum levels of the short-chain omega-6 fatty acid linoleic acid have higher rates of prostate cancer.^[54] However, men with high serum linoleic acid, but not palmitic, can reduce the risk of prostate cancer by taking tocopherol supplementation.^[55]

Men with elevated levels of long-chain omega-3 fatty acids (EPA and DHA) had lowered incidence.^[54]

A long-term study reports that "blood levels of trans fatty acids, in particular trans fats resulting from the hydrogenation of vegetable oils, are associated with an increased prostate cancer risk."^[56]

Some researchers have indicated that serum myristic acid^[55][57] and palmitic acid^[57] and dietary myristic^[58] and palmitic^[58] saturated fatty acids and serum palmitic combined with alpha-tocopherol supplementation^[55] are associated with increased risk of prostate cancer in a dose-dependent manner. Serum association of these and other saturated fatty acids was also investigated by another study.^[57]

Prostate cancer risk is decreased in a vegetarian diet.^[59]

Screening

Prostate cancer screening is an attempt to find unsuspected cancers. Screening tests may lead to more specific follow-up tests such as a biopsy, where small cores of the prostate are removed for closer study. Prostate cancer screening options include the digital rectal exam and the prostate-specific antigen (PSA) blood test. Screening for prostate cancer is controversial because it is not clear whether the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments.

Prostate cancer is usually a slow-growing cancer, very common among older men. In fact, most prostate cancers never grow to the point where they cause symptoms, and most men with prostate cancer die of other causes before prostate cancer has an impact on their lives. The PSA screening test may detect these small cancers that would never become life-threatening. Doing the PSA test in these men may lead to overdiagnosis, including additional testing and treatment. Follow-up tests, such as prostate biopsy, may cause pain, bleeding and infection. Prostate cancer treatments may cause urinary incontinence and erectile dysfunction. A large randomized study in which 76,000 men were randomized to receive either PSA screening or conventional care found that more men that underwent PSA screening were diagnosed with prostate cancer, but that there was no difference in mortality between the two groups. ^[60]

The results from two of the largest randomized trials regarding the efficacy of screening have now been published. ^[61] In one of these trials, the death rate from prostate cancer was actually higher in the group that had total screening compared to the control group that had only normal rates of screening. The other showed some benefit from screening, but the reduction in deaths was minor compared to the level of intervention needed to prevent it.

In the European Randomized Study of Screening for Prostate Cancer initiated in the early 1990s, the intention was to evaluate the effect of screening with prostate-specific antigen (PSA) testing on death rates from prostate cancer. The trial involved 182,000 men between the ages of 50 and 74 years in seven European countries randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. During a median follow-up of almost 9 years, the cumulative detected incidence of prostate cancer was 820 per 10,000 in the screening group and 480 per 10,000 in the control group. Deaths from these cancers in this time was much lower. There were 214 prostate cancer deaths in the screening group and 326 in the control group, a difference of 71 men per 10,000 in the tested group compared to the control. The researchers concluded that PSA-based screening did reduce the rate of death from prostate cancer by 20%, but that this was associated with a high risk of overdiagnosis, which means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent just one death from prostate cancer. ^[62]

A US study looked at the general effectiveness of a screening program involving both PSA and DRE methods. This was conducted between 1993 thu 2001, in which 76,693 men at 10 U.S. study centers 38,343 subjects received screening (an annual PSA testing for 6 years and DRE for 4 years) and a control group of 38,350 subjects reveived 'usual care' with subjects and healthcare providers receiving the results and deciding on the type of follow-up evaluation. 'Usual care' means that some in this group would have received some screening, as some organizations have recommended. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2,820 cancers) in the screening group and 95 (2,322 cancers) in the control group. The incidence of death attributed to prostate cancer per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. The researchers concluded that, after 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups.^[63]

Commenting on the findings, the Chief Medical Officer of the American Cancer Society, Otis W. Brawley, MD, said

many experts had anticipated these studies would show a small number of men will benefit from prostate screening, but a large number of men will be treated unnecessarily. And that's what these studies show. However, the question is not as simple as: 'does prostate cancer screening work?' What we need to know is: what are benefits of prostate cancer screening and are they large enough to outweigh the harms associated with it? And, despite the release of this early data, we still cannot say whether the benefits outweigh the risk.^[64]"

His Deputy chief medical officer, Len Lichtenfeld, MD, MACP said

"When one considers all of the problems associated with treatment for prostate cancer -- urine incontinence, impotence, pain and bleeding among others -- that is a lot of men left with a lot of symptoms to save one life."

The American Urological Association said that "The decision to screen is one that a man should make in conjunction with his physician, and should incorporate known prostate cancer risk factors, such as family history of prostate cancer, age, ethnicity/race, and whether or not a man has had a previous negative prostate biopsy. These factors are different for every man and, therefore, the benefits of screening should be considered in the broader perspective."^[65] The organization will review its best practice guidelines later this year.

• In 2002, the U.S. Preventive Services Task Force (USPSTF) concluded that the evidence was insufficient to recommend for or against routine screening for prostate cancer using PSA testing or digital rectal examination (DRE).^[66] The previous 1995 USPSTF recommendation was against routine screening.
• In 1997, American Cancer Society (ACS) guidelines began recommending that beginning at age 50 (age 45 for African-American men and men with a family history of prostate cancer, and since 2001, age 40 for men with a very strong family history of prostate cancer), PSA testing and DRE be offered annually to men who have a life-expectancy of 10 or more years (average life expectancy is 10 years or more for U.S. men under age 76)^[67] along with information on the risks and benefits of screening.^[68] The previous ACS recommendations since 1980 had been for routine screening for prostate cancer with DRE annually beginning at age 40, and since 1992 had been for routine screening with DRE and PSA testing annually beginning at age 50.^[69]
• The 2007 National Comprehensive Cancer Network (NCCN) guideline recommends offering a baseline PSA test and DRE at ages 40 and 45 and annual PSA testing and DRE beginning at age 50 (with annual PSA testing and DRE beginning at age 40 for African-American men, men with a family history of prostate cancer, and men with a PSA ≥ 0.6 ng/mL at age 40 or PSA > 0.6 ng/mL at age 45) through age 80, along with information on the risks and benefits of screening. Biopsy is recommended if DRE is positive or PSA ≥ 4 ng/mL, and biopsy considered if PSA > 2.5 ng/mL or PSA velocity ≥ 0.35 ng/mL/year when PSA ≤ 2.5 ng/mL.^[70]
• Some U.S. radiation oncologists and medical oncologists who specialize in treating prostate cancer recommend obtaining a baseline PSA in all men at age 35^[71] or beginning annual PSA testing in high risk men at age 35.^[72]
• The American Urological Association Patient Guide to Prostate Cancer.^[73]

Since there is no general agreement that the benefits of PSA screening outweigh the harms, the consensus is that clinicians use a process of shared decision-making that includes discussing with patients the risks of prostate cancer, the potential benefits and harms of screening, and involving the patients in the decision.^[74]

However, because PSA screening is widespread in the United States, following the recommendations of major scientific and medical organizations to use shared decision-making is legally perilous in some U.S. states.^[75] In 2003, a Virginia jury found a family practice residency program guilty of malpractice and liable for $1 million for following national guidelines and using shared decision-making, thereby allowing a patient (subsequently found to have a high PSA and incurable advanced prostate cancer) to decline a screening PSA test, instead of routinely ordering without discussion PSA tests in all men ≥ 50 years of age as four local physicians testified was their practice, and was accepted by the jury as the local standard of care.^[76]

An estimated 20 million PSA tests are done per year in North America and possibly 20 million more outside of North America.^[77]

• In 2000, 34.1% of all U.S. men age ≥ 50 had a screening PSA test within the past year and 56.8% reported ever having a PSA test.^[74]
• In 2000, 33.6% of all U.S. men age 50–64 and 51.3% of men age ≥ 65 had a PSA test within the past year.^[78]
• In 2005, 33.5% of all U.S. men age 50–64 had a PSA test in the past year.
  • 37.5% of men with private health insurance, 20.8% of men with Medicaid insurance, 14.0% of currently uninsured men, and 11.5% of men uninsured for > 12 months.^[79]
• In 2000–2001, 34.1% of all Canadian men age ≥ 50 had a screening PSA test within the past year and 47.5% reported ever having a screening PSA test.^[80]
• Canadian men in Ontario were most likely to have had a PSA test within the past year and men in Alberta were least likely to have had a PSA test with the past year or ever.^[81]

Digital rectal examination

Digital rectal examination (DRE) is a procedure where the examiner inserts a gloved, lubricated finger into the rectum to check the size, shape, and texture of the prostate. Areas that are irregular, hard, or lumpy need further evaluation, since they may contain cancer. Although the DRE evaluates only the back of the prostate, 85% of prostate cancers arise in this part of the prostate. Prostate cancer that can be felt on DRE is, in general, more advanced.^[82] The use of DRE has never been shown to prevent prostate cancer deaths when used as the only screening test.^[83]

Prostate specific antigen

The PSA test measures the blood level of prostate-specific antigen, an enzyme produced by the prostate. To be specific, PSA is a serine protease similar to kallikrein. Its normal function is to liquify gelatinous semen after ejaculation, allowing spermatozoa to more easily navigate through the uterine cervix.

The risk of prostate cancer increases with increasing PSA levels.^[84] 4 ng/mL was chosen arbitrarily as a decision level for biopsies in the clinical trial upon which the FDA in 1994 based adding prostate cancer detection in men age 50 and over as an approved indication for the first commercially available PSA test.^[85] 4 ng/mL was used as the biopsy decision level in the PLCO trial, 3 ng/mL was used in the ERSPC and ProtecT trials, and 2.5 ng/mL is used in the 2007 NCCN guideline.

PSA levels can change for many reasons other than cancer. Two common causes of high PSA levels are enlargement of the prostate (benign prostatic hypertrophy (BPH)) and infection in the prostate (prostatitis). It can also be raised for 24 hours after ejaculation and several days after catheterization. PSA levels are lowered in men that use medications used to treat BPH or baldness. These medications, finasteride (marketed as Proscar or Propecia) and dutasteride (marketed as Avodart), may decrease the PSA levels by 50% or more.

Several other ways of evaluating the PSA have been developed to avoid the shortcomings of simple PSA screening. The use of age-specific reference ranges improves the sensitivity and specificity of the test. The rate of rise of the PSA over time, called the PSA velocity, has been used to evaluate men with PSA levels between 4 and 10 ng/ml, but it has not proven to be an effective screening test.^[86] Comparing the PSA level with the size of the prostate, as measured by ultrasound or magnetic resonance imaging, has also been studied. This comparison, called PSA density, is both costly and has not proven to be an effective screening test.^[87] PSA in the blood may either be free or bound to other proteins. Measuring the amount of PSA which is free or bound may provide additional screening information, but questions regarding the usefulness of these measurements limit their widespread use.^[88][89]

Treatment

Treatment for prostate cancer may involve active surveillance, surgery, radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, High-intensity focused ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy, or some combination. Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are the man's age, his general health, and his feelings 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.

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.^[90] 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, HIFU, external beam radiation therapy, brachytherapy, cryosurgery, 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.^[91]

Active surveillance

Active surveillance refers to observation and regular monitoring without invasive treatment. Active surveillance is often used when an early stage, slow-growing prostate cancer is suspected. However, watchful waiting may also be suggested when the risks of surgery, radiation therapy, or hormonal therapy outweigh the possible benefits. Other treatments can be started if symptoms develop, or if there are signs that the cancer growth is accelerating (e.g., rapidly-rising PSA, increase in Gleason score on repeat biopsy, etc.). Approximately one-third of men that choose active surveillance for early stage tumors eventually have signs of tumor progression, and they may need to begin treatment within three years.^[92] Men that choose active surveillance avoid the risks of surgery, radiation, and other treatments. The risk of disease progression and metastasis (spread of the cancer) may be increased, but this increase risk appears to be small if the program of surveillance is followed closely, generally including serial PSA assessments and repeat prostate biopsies every 1–2 years depending on the PSA trends.

For younger men, a trial of active surveillance may not mean avoiding treatment altogether, but may reasonably allow a delay of a few years or more, during which time the quality of life impact of active treatment can be avoided. Published data to date suggest that carefully selected men will not miss a window for cure with this approach. Additional health problems that develop with advancing age during the observation period can also make it harder to undergo surgery and radiation therapy.

Hormonal therapy

Hormonal therapy in prostate cancer. Diagram shows the different organs (purple text), hormones (black text and arrows), and treatments (red text and arrows) important in hormonal therapy.

Hormonal therapy uses medications or surgery to block prostate cancer cells from getting dihydrotestosterone (DHT), a hormone produced in the prostate and required for the growth and spread of most prostate cancer cells. Blocking DHT often causes prostate cancer to stop growing and even shrink. However, hormonal therapy rarely cures prostate cancer because cancers that initially respond to hormonal therapy typically become resistant after one to two years. Hormonal therapy is, therefore, usually used when cancer has spread from the prostate. It may also be given to certain men undergoing radiation therapy or surgery to help prevent return of their cancer.^[93]

Hormonal therapy for prostate cancer targets the pathways the body uses to produce DHT. A feedback loop involving the testicles, the hypothalamus, and the pituitary, adrenal, and prostate glands controls the blood levels of DHT. First, low blood levels of DHT stimulate the hypothalamus to produce gonadotropin-releasing hormone (GnRH). GnRH then stimulates the pituitary gland to produce luteinizing hormone (LH), and LH stimulates the testicles to produce testosterone. Finally, testosterone from the testicles and dehydroepiandrosterone from the adrenal glands stimulate the prostate to produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting this pathway at any point. There are several forms of hormonal therapy:

• Orchiectomy, also called "castration," is surgery to remove the testicles. Because the testicles make most of the body's testosterone, after orchiectomy testosterone levels drop. Now the prostate not only lacks the testosterone stimulus to produce DHT but also does not have enough testosterone to transform into DHT.
• Antiandrogens are medications such as flutamide, bicalutamide, nilutamide, and cyproterone acetate that directly block the actions of testosterone and DHT within prostate cancer cells.
• Medications that block the production of adrenal androgens such as DHEA include ketoconazole and aminoglutethimide. Because the adrenal glands make only about 5% of the body's androgens, these medications are, in general, used only in combination with other methods that can block the 95% of androgens made by the testicles. These combined methods are called total androgen blockade (TAB). TAB can also be achieved using antiandrogens.
• GnRH action can be interrupted in one of two ways. GnRH antagonists suppress the production of LH directly, while GnRH agonists suppress LH through the process of downregulation after an initial stimulation effect. Abarelix is an example of a GnRH antagonist, whereas the GnRH agonists include leuprolide, goserelin, triptorelin, and buserelin. Initially, GnRH agonists increase the production of LH. However, because the constant supply of the medication does not match the body's natural production rhythm, production of both LH and GnRH decreases after a few weeks.^[94]
• A very recent Trial I study (N=21) found that abiraterone acetate caused dramatic reduction in PSA levels and tumor sizes in aggressive end-stage prostate cancer for 70% of patients. This is prostate cancer that resists all other treatments (e.g., castration, other hormones, etc.). Officially the impacts on life-span are not yet known because subjects have not been taking the drug very long. Larger Trial III Clinical Studies are in the works. If successful an approved treatment is hoped for around 2011.^[95][96]

The most successful hormonal treatments are orchiectomy and GnRH agonists. Despite their higher cost, GnRH agonists are often chosen over orchiectomy for cosmetic and emotional reasons. Eventually, total androgen blockade may prove to be better than orchiectomy or GnRH agonists used alone.

Each treatment has disadvantages that limit its use in certain circumstances. Although orchiectomy is a low-risk surgery, the psychological impact of removing the testicles can be significant. The loss of testosterone also causes hot flashes, weight gain, loss of libido, enlargement of the breasts (gynecomastia), impotence, and osteoporosis. GnRH agonists eventually cause the same side-effects as orchiectomy but may cause worse symptoms at the beginning of treatment. When GnRH agonists are first used, testosterone surges can lead to increased bone pain from metastatic cancer, so antiandrogens or abarelix is often added to blunt these side-effects. Estrogens are not commonly used because they increase the risk for cardiovascular disease and blood clots. In general, the antiandrogens do not cause impotence, and usually cause less loss of bone and muscle mass. Ketoconazole can cause liver damage with prolonged use, and aminoglutethimide can cause skin rashes.

Surgery

Surgical removal of the prostate, or prostatectomy, is a common treatment either for early stage prostate cancer or for cancer that has failed to respond to radiation therapy. The most common type is radical retropubic prostatectomy, when the surgeon removes the prostate through an abdominal incision. Another type is radical perineal prostatectomy, when the surgeon removes the prostate through an incision in the perineum, the skin between the scrotum and anus. Radical prostatectomy can also be performed laparoscopically, through a series of small (1 cm) incisions in the abdomen, with or without the assistance of a surgical robot.

Radical prostatectomy

Radical prostatectomy is effective for tumors that have not spread beyond the prostate;^[97] cure rates depend on risk factors such as PSA level and Gleason grade. However, it may cause nerve damage that may significantly alter the quality of life of the prostate cancer survivor.

Radical prostatectomy has traditionally been used alone when the cancer is localized to the prostate. In the event of positive margins or locally advanced disease found on pathology, adjuvant radiation therapy may offer improved survival. Surgery may also be offered when a cancer is not responding to radiation therapy. However, because radiation therapy causes tissue changes, prostatectomy after radiation has higher risks of complications.

Laparoscopic radical prostatectomy, LRP, is a new way to approach the prostate surgically with intent to cure. Contrasted with the open surgical form of prostate cancer surgery, laparoscopic radical prostatectomy requires a smaller incision. Relying on modern technology, such as miniaturization, fiber optics, and the like, laparoscopic radical prostatectomy is a minimally invasive prostate cancer treatment but is technically demanding and seldom done in the USA.

Some believe that in the hands of an experienced surgeon, robotic-assisted laparoscopic prostatectomy (RALP) may reduce positive surgical margins when compared to radical retropubic prostatectomy (RRP) among patients with prostate cancer according to a retrospective study.^[5] The relative risk reduction was 57.7%. For patients at similar risk to those in this study (35.5% of patients had positive surgical margins following RRP), this leads to an absolute risk reduction of 20.5%. 4.9 patients must be treated for one to benefit (number needed to treat = 4.9). Other recent studies have shown RALP to result in a significantly higher rate of positive margins.^[98] Other studies showed no difference of robotic to open surgery.^[99] A recent French study comparing standard laparoscopic to robotic to open prostatectomy showed no difference in margin status or biochemical recurrence at 5 years.^[100] The relative merits of RALP and potential benefit versus open radical prostatectomy is currently an area of intense research and debate in urology. The only proven and accepted advantage to RALP is less intraoperative blood loss. Other suggested advantages beyond this lack definitive data and have not been widely accepted by the broader urological community.

Transurethral resection of the prostate

Transurethral resection of the prostate, commonly called a "TURP," is a surgical procedure performed when the tube from the bladder to the penis (urethra) is blocked by prostate enlargement. In general, TURP is for benign disease and is not meant as definitive treatment for prostate cancer. During a TURP, a small instrument (cystoscope) is placed into the penis and the blocking prostate is cut away.

Orchiectomy

In metastatic disease, where cancer has spread beyond the prostate, removal of the testicles (called orchiectomy) may be done to decrease testosterone levels and control cancer growth. (See hormonal therapy, below).

Cryosurgery

Cryosurgery is another method of treating prostate cancer in which the prostate gland is exposed to freezing temperatures.^[101] It is less invasive than radical prostatectomy, and general anesthesia is less commonly used. Under ultrasound guidance, a method invented by Dr. Gary Onik,^[102] metal rods are inserted through the skin of the perineum into the prostate. Highly-purified argon gas is used to cool the rods, freezing the surrounding tissue at −186 °C (−302 °F). As the water within the prostate cells freezes, the cells die. The urethra is protected from freezing by a catheter filled with warm liquid. In general, cryosurgery causes fewer problems with urinary control than other treatments, but impotence occurs up to ninety percent of the time. When used as the initial treatment for prostate cancer and in the hands of an experienced cryosurgeon, cryosurgery has a 10-year biochemical disease-free rate superior to all other treatments including radical prostatectomy and any form of radiation.^[103] Cryosurgery has also been demonstrated to be superior to radical prostatectomy for recurrent cancer following radiation therapy.

Complications of surgery

The most common serious complications of surgery are loss of urinary control and impotence. Reported rates of both complications vary widely depending on how they are assessed, by whom, and how long after surgery, as well as the setting (e.g., academic series vs. community-based or population-based data). Although penile sensation and the ability to achieve orgasm usually remain intact, erection and ejaculation are often impaired. Medications such as sildenafil (Viagra), tadalafil (Cialis), or vardenafil (Levitra) may restore some degree of potency. For most men with organ-confined disease, a more limited "nerve-sparing" technique may help reduce urinary incontinence and impotence.^[104]

Radiation therapy

Overview

Brachytherapy for prostate cancer is administered using "seeds," small radioactive pellets or ribbons implanted directly into the tumor.

Radiation therapy, also known as radiotherapy, is often used to treat all stages of prostate cancer. It is also often used after surgery if the surgery was not successful at curing the cancer. Radiotherapy uses ionizing radiation to kill prostate cancer cells. When absorbed in tissue, Ionizing radiation such as gamma and x-rays damage the DNA in cancer cells, which increases the probability of apoptosis (cell death). Normal cells are able to repair radiation damage, while cancer cells are not. Radiation therapy exploits this fact to treat cancer. Two different kinds of radiation therapy are used in prostate cancer treatment: external beam radiation therapy and brachytherapy (specifically prostate brachytherapy).

External beam radiation therapy uses a linear accelerator to produce high-energy x-rays that are directed in a beam towards the prostate. A technique called Intensity Modulated Radiation Therapy (IMRT) may be used to adjust the radiation beam to conform with the shape of the tumor, allowing higher doses to be given to the prostate and seminal vesicles with less damage to the bladder and rectum. External beam radiation therapy is generally given over several weeks, with daily visits to a radiation therapy center. New types of radiation therapy such as IMRT have fewer side-effects than traditional treatment. Doctors are also studying proton therapy for prostate cancer, which uses protons rather than X-rays to kill the cancer cells. They are also studying types of stereotactic body radiotherapy (SBRT) to treat prostate cancer. ^[105]

External beam radiation therapy for prostate cancer is delivered by a linear accelerator, such as this one.

Permanent implant brachytherapy is a popular treatment choice for patients with low to intermediate risk features, can be performed on an outpatient basis, and is associated with good 10-year outcomes with relatively low morbidity^[106] It involves the placement of about 100 small "seeds" containing radioactive material (such as iodine-125 or palladium-103) with a needle through the skin of the perineum directly into the tumor while under spinal or general anesthetic. These seeds emit lower-energy X-rays which are only able to travel a short distance. Although the seeds eventually become inert, they remain in the prostate permanently. The risk of exposure to others from men with implanted seeds is generally accepted to be insignificant.^[107]

Uses

Radiation therapy is commonly used in prostate cancer treatment. It may be used instead of surgery or after surgery in early stage prostate cancer (adjuvant radiotherapy). Radiation treatments also can be combined with hormonal therapy for intermediate risk disease, when surgery or radiation therapy alone is less likely to cure the cancer. Some radiation oncologists combine external beam radiation and brachytherapy for intermediate to high-risk situations. Radiation therapy is often used in conjunction with hormone therapy for high-risk patients.^[108] Others use a "triple modality" combination of external beam radiation therapy, brachytherapy, and hormonal therapy. In advanced stages of prostate cancer, radiation is used to treat painful bone metastases or reduce spinal cord compression.

Radiation therapy is also used after radical prostatectomy either for cancer recurrence or if multiple risk factors are found during surgery. Radiation therapy delivered immediately after surgery when risk factors are present (positive surgical margin, extracapsular extension, seminal vessicle involvement) has been demonstrated to reduce cancer recurrence, decrease distant metastasis, and increase overall survival in two separate randomized trials.^[109]

Side-effects

Side-effects of radiation therapy might occur after a few weeks into treatment. Both types of radiation therapy may cause diarrhea and mild rectal bleeding due to radiation proctitis, as well as potential urinary incontinence and impotence. Symptoms tend to improve over time except erections which typically worsen as time progresses.

Comparison to surgery

Multiple retrospective analyses have demonstrated that overall survival and disease-free survival outcomes are similar between radical prostatectomy, external beam radiation therapy, and brachytherapy.^[110] Rates for impotence when comparing radiation to nerve-sparing surgery are similar. Radiation has lower rates of incontinence compared with surgery, but has higher rates of occasional mild rectal bleeding.^[111] Men who have undergone external beam radiation therapy may have a slightly higher risk of later developing colon cancer and bladder cancer.^[112]

High intensity focused ultrasound (HIFU)

HIFU for prostate cancer utilizes high-intensity focused ultrasound to ablate/destroy the tissue of the prostate. During the HIFU procedure, sound waves are used to heat the prostate tissue, thus destroying the cancerous cells. In essence, ultrasonic waves are precisely focused on specific areas of the prostate to eliminate the prostate cancer, with minimal risks of affecting other tissue or organs. Temperatures at the focal point of the sound waves can exceed 100 °C (212 °F).^[113] The ability to focus the ultrasonic waves leads to a relatively low occurrence of both incontinence and impotence. (0.6% and 0-20%, respectively)^[114] According to preliminary international studies, HIFU has a high success rate with a reduced risk of side-effects. Studies using HIFU machine have shown that 94% of patients with a pretreatment PSA (Prostate Specific Antigen) of less than 10 ng/mL were cancer-free after three years.^[114] However, many studies of HIFU were performed by manufacturers of HIFU devices, or members of manufacturers' advisory panels.^[115]

HIFU was first used in the 1940s and 1950s in efforts to destroy tumors in the central nervous system. Since then, HIFU has been shown to be effective at destroying malignant tissue in the brain, prostate, spleen, liver, kidney, breast, and bone.^[113] Today, the HIF procedure for prostate cancer is performed using a transrectal probe. This procedure has been performed for over ten years and is currently approved for use in Japan, Europe, Canada, and parts of Central and South America.

Contraindications to HIFU for prostate cancer include a prostate volume larger than 40 grams, which can prevent targeted HIFU waves from reaching the anterior and anterobasal regions of the prostate, anatomic or pathologic conditions that may interfere with the introduction or displacement of the HIFU probe into the rectum, and high-volume calcification within the prostate, which can lead to HIFU scattering and transmission impairment.^[116]

HIFU is currently not approved for medical use in the United States. Current NCCN guidelines for the treatment of prostate cancer do not include HIFU as part of standard of care, though many promising clinical trials exist. Many patients have received the HIFU procedure at facilities in Canada, and Central, and South America.

Palliative care

Palliative care for advanced stage prostate cancer focuses on extending life and relieving the symptoms of metastatic disease. As noted above, Abiraterone Acetate is showing some promise in treating advance-stage prostate cancer. It causes a dramatic reduction in PSA levels and Tumor sizes in aggressive advanced-stage prostate cancer for 70% of patients. Chemotherapy may be offered to slow disease progression and postpone symptoms. The most commonly-used regimen combines the chemotherapeutic drug docetaxel with a corticosteroid such as prednisone.^[117] Bisphosphonates such as zoledronic acid have been shown to delay skeletal complications such as fractures or the need for radiation therapy in patients with hormone-refractory metastatic prostate cancer.^[118]. Alpharadin is a new alpha emitting pharmaceutical targeting bone metastasis. The phase II testing shows prolonged patient survival times, reduced pain, and improved quality of life.

Bone pain due to metastatic disease is treated with opioid pain relievers such as morphine and oxycodone. External beam radiation therapy directed at bone metastases may provide pain relief. Injections of certain radioisotopes, such as strontium-89, phosphorus-32, or samarium-153, also target bone metastases and may help relieve pain.

Alternative therapies

As an alternative to active surveillance or definitive treatments, other therapies are also under investigation for the management of prostate cancer. PSA has been shown to be lowered in men with apparent localized prostate cancer using a vegan diet (fish allowed), regular exercise, and stress reduction.^[119] These results have so far proven durable after two-years' treatment. However, this study did not compare the vegan diet to either active surveillance or definitive treatment, and thus cannot comment on the comparative efficacy of the vegan diet in treating prostate cancer.^[120]

Many other single agents have been shown to reduce PSA, slow PSA doubling times, or have similar effects on secondary markers in men with localized cancer in short term trials, such as pomegranate juice or genistein, an isoflavone found in various legumes.^[121][122]

The potential of using multiple such agents in concert, let alone combining them with lifestyle changes, has not yet been studied. A more thorough review of natural approaches to prostate cancer has been published.^[123]

Neutrons have been shown to be superior to X-rays in a the treatment of prostatic cancer. The rationale is that tumours containing hypoxic cells (cells with enough oxygen concentration to be viable, yet not enough to be X-ray-radiosensitive) and cells deficient in oxygen are resistant to killing by X-rays. Thus, the lower oxygen enhancement ratio (OER) of neutrons confers an advantage. Also, neutrons have a higher relative biological effectiveness (RBE) for slow-growing tumours than X-rays, allowing for an advantage in tumour cell killing. ^[124]

Prognosis

Prostate 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 and reduced-fat dairy products to which vitamin A palmitate has been added^[125] (although it must be noted, that people that 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).^[126] 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 United States men. Prostate cancer affected eighteen percent of American men and caused death in three percent in 2005.^[127] In Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and Europe in the 1990s.^[128] In India in the 1990s, half of the people with prostate cancer confined to the prostate died within ten years.^[129] African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in Shanghai, China.^[130] In Nigeria, two percent of men develop prostate cancer and 64% of them are dead after two years.^[131]

In patients that 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.^[132]

In 1941, Charles Huggins reported that androgen ablation therapy causes regression of primary and metastatic androgen-dependent prostate cancer.^[133] 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.^[134] 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.^[135] Androgen at a concentration of 10-fold higher than the physiological concentration has also been shown to cause growth suppression and reversion of androgen-independent prostate cancer xenografts or androgen-independent prostate tumors derived in vivo model to an androgen-stimulated phenotype in athymic mice.^[136][137] These observation suggest the possibility to use androgen to treat the development of relapsed androgen-independent prostate tumors in patients. Oral infusion of green tea polyphenols, a potential alternative therapy for prostate cancer by natural compounds, has been shown to inhibit the development, progression, and metastasis as well in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops prostate cancer.^[138]

Many 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 to 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 3 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 using 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^[139]; the SEARCH registry, representing data from several Veterans Administration and active military medical centers^[140]; a multi-institutional cohort in Germany^[141]; and the prostatectomy cohort at Johns Hopkins University.^[142]

Epidemiology

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.^[1] 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.^[143][144] However, these high rates may be affected by increasing rates of detection.^[145]

Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is the most common type of cancer in men in the United States, where it is responsible for more male deaths than any other cancer, except 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. However, many men that develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. That is because malignant neoplasms of the prostate are, in most cases, slow-growing, and because most of those affected are over 60. Hence they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers, or old age. 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 rate by 30%. There had been a controversy about this also increasing the risk of more aggressive cancers, but more recent research showed this was not the case.^[38][146]

Potential mechanisms of disease progression

The insulin-like growth factor signaling axis is thought to play a key role in the progression of prostate carcinoma. It consists of two ligands (IGF-1 and IGF-2), two receptors (IGF-IR and IGF-IIR) and six related high-affinity IGF-binding proteins (IGFBP 1-6).^[147] Altered expression of IGF axis members has been implicated in the development of many different types of cancers, including prostate.^[148][149]

History

Although the prostate was first described by Venetian anatomist Niccolò Massa in 1536, and illustrated by Flemish anatomist Andreas Vesalius in 1538, prostate cancer was not identified until 1853.^[150] Prostate cancer was initially considered a rare disease, probably because of shorter life expectancies and poorer detection methods in the 19th century. The first treatments of prostate cancer were surgeries to relieve urinary obstruction.^[151] Removal of the entire gland (radical perineal prostatectomy) was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.^[152] Surgical removal of the testes (orchiectomy) to treat prostate cancer was first performed in the 1890s, but with limited success. Transurethral resection of the prostate (TURP) replaced radical prostatectomy for symptomatic relief of obstruction in the middle of the 20th century because it could better preserve penile erectile function. Radical retropubic prostatectomy was developed in 1983 by Patrick Walsh.^[153] This surgical approach allowed for removal of the prostate and lymph nodes with maintenance of penile function.

In 1941, Charles B. Huggins published studies in which he used estrogen to oppose testosterone production in men with metastatic prostate cancer. This discovery of "chemical castration" won Huggins the 1966 Nobel Prize in Physiology or Medicine.^[154] The role of the hormone GnRH in reproduction was determined by Andrzej W. Schally and Roger Guillemin, who both won the 1977 Nobel Prize in Physiology or Medicine for this work. Receptor agonists, such as leuprolide and goserelin, were subsequently developed and used to treat prostate cancer.^[155][156]

Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiation became more popular as stronger radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds was first described in 1983.^[157] Systemic chemotherapy for prostate cancer was first studied in the 1970s. The initial regimen of cyclophosphamide and 5-fluorouracil was quickly joined by multiple regimens using a host of other systemic chemotherapy drugs.^[158]

Jonathan Simons and his laboratories at Johns Hopkins and Emory made original contributions in the molecular biology of cytokines in human prostate cancer metastasis, and in the molecular pharmacology and genetic therapy of metastatic prostate cancer.

Prostate cancer models

Scientists have established a few prostate cancer cell lines to investigate the mechanism involved in the progression of prostate cancer. LNCaP, PC-3 (PC3), and DU-145 (DU145) are commonly used prostate cancer cell lines. The LNCaP cancer cell line was established from a human lymph node metastatic lesion of prostatic adenocarcinoma. PC-3 and DU-145 cells were established from human prostatic adenocarcinoma metastatic to bone and to brain, respectively. LNCaP cells express androgen receptor (AR); however, PC-3 and DU-145 cells express very little or no AR. AR, an androgen-activated transcription factor, belongs to the steroid nuclear receptor family. Development of the prostate is dependent on androgen signaling mediated through AR, and AR is also important during the development of prostate cancer. The proliferation of LNCaP cells is androgen-dependent but the proliferation of PC-3 and DU-145 cells is androgen-insensitive. Elevation of AR expression is often observed in advanced prostate tumors in patients.^[159][160] Some androgen-independent LNCaP sublines have been developed from the ATCC androgen-dependent LNCaP cells after androgen deprivation for study of prostate cancer progression. These androgen-independent LNCaP cells have elevated AR expression and express prostate specific antigen upon androgen treatment. The paradox is that androgens inhibit the proliferation of these androgen-independent prostate cancer cells.^{[161][162][163]}

References