prostate cancer

Prostate Cancer
Classification and external resources
Micrograph of prostate adenocarcinoma, acinar type, the most common type of prostate cancer. Gleason pattern 4. Needle biopsy. H&E stain.
ICD-10	C61
ICD-9	185
OMIM	176807
DiseasesDB	10780
MedlinePlus	000380
eMedicine	radio/574
MeSH	D011471

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. On the other hand, the more aggressive prostate cancers account for more cancer-related mortality than any other cancer except lung cancer.^[3] About two-thirds of cases are slow growing, the other third more aggressive and fast developing.^[4]

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.^[5] Moreover, prostate test screening is controversial at the moment and may lead to unnecessary, even harmful, consequences in some patients.^[6] Nonetheless, 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.

Management strategies for prostate cancer should be guided the severity of the disease. Many low-risk tumors can be safely followed with active surveillance. Curative treatment generally involves surgery, various forms of radiation therapy, or, less commonly, cryosurgery; hormonal therapy and chemotherapy are generally reserved for cases of advanced disease (although hormonal therapy may be given with radiation in some cases).

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.

Signs and symptoms

Early prostate cancer usually causes no symptoms. 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.^[7]

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.^[8]

Causes

The specific causes of prostate cancer remain unknown.^[9] 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.^[10] 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.^[11] 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.^[12] 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.^[13] Men with high blood pressure are more likely to develop prostate cancer.^[14] There is a small increased risk of prostate cancer associated with lack of exercise.^[15] A 2010 study found that prostate basal cells were the most common site of origin for prostate cancers.^[16]

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.^[17] In the United States, prostate cancer more commonly affects black men than white or Hispanic men, and is also more deadly in black men.^{[18] [19]} 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.^[20]

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.^[21] Other linked genes include the Hereditary Prostate cancer gene 1 (HPC1), the androgen receptor, and the vitamin D receptor.^[18] TMPRSS2-ETS gene family fusion, specifically TMPRSS2-ERG or TMPRSS2-ETV1/4 promotes cancer cell growth.^[22]

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"^[23] Relative frequency of loss of E-cadherin and CD44 has also been observed.

Dietary

While a number of dietary factors have been linked to prostate cancer the evidence is still tentative.^[24] Evidence supports little role for dietary fruits and vegetables in prostate cancer occurrence.^[25] Red meat and processed meat also appear to have little effect.^[26] Lower blood levels of vitamin D may increase the risk of developing prostate cancer.^[27] This may be linked to lower exposure to ultraviolet (UV) light, since UV light exposure can increase vitamin D in the body.^[28]

Green tea may be protective (due to its catechins content),^[29] although the most comprehensive clinical study indicates that it has no protective effect.^[30] Other holistic methods are also studied.^[31]

Taking multivitamins more than seven times a week may increase the risks of contracting the disease.^[32][33] 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.^[34] 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.^[34]

High alcohol intake may increase the risk of prostate cancer and interfere with folate metabolism.^[35] 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.^[35] 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.^[35] Folate's effect however was only significant when coupled with low alcohol intake.^[35] 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.^[35] There was no association found in this study between folic acid supplements and risk of prostate cancer.^[35]

Medication exposure

There are also some links between prostate cancer and medications, medical procedures, and medical conditions.^[36] Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk.^[37]

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.^[38] Finally, obesity^[39] and elevated blood levels of testosterone^[40] 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.^[41]

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.^[42]

Viral

In 2006, researchers associated a previously unknown retrovirus, Xenotropic MuLV-related virus or XMRV, with human prostate tumors.^[43] Subsequent reports on the virus have been contradictory. A group of US researchers found XMRV protein expression in human prostate tumors,^[44] while German scientists failed to find XMRV-specific antibodies or XMRV-specific nucleic acid sequences in prostate cancer samples.^[45]

Pathophysiology

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.^[46] 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.^[47] 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.^[48] 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.

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.^[49]

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.^[50]

RUNX2 is a transcription factor that prevents cancer cells from undergoing apoptosis thereby contributing to the development of prostate cancer.^[51]

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.^[52] 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.^[53] Macrophage inhibitory cytokine-1 (MIC-1) stimulates the focal adhesion kinase (FAK) signaling pathway which leads to prostate cancer cell growth and survival.^[54]

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.^[55] 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.^[56]

Diagnosis

The American Cancer Society's position regarding early detection is "Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. The American Cancer Society believes that men should not be tested without learning about what we know and don’t know about the risks and possible benefits of testing and treatment. Starting at age 50, (45 if African American or brother or father suffered from condition before age 65) talk to your doctor about the pros and cons of testing so you can decide if testing is the right choice for you."^[57]

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, less invasive testing can be conducted.

According to Professor Hardev Pandha, The Prostate Project Chair of Urological Oncology at the University of Surrey's Postgraduate Medical School, a non-invasive test looking for the presence of the protein Engrailed-2 (EN2) in the urine to be more reliable and accurate than existing tests.

"In this study, we showed that the new test was twice as good at finding prostate cancer as the standard PSA test. Only rarely did we find EN2 in the urine of men who were cancer free, so if we find EN2 we can be reasonably sure that a man has prostate cancer. EN2 was not detected in men with non-cancer disorders of the prostate such as prostatitis or benign enlargement. These conditions often cause a high PSA result, causing considerable stress for the patient and sometimes also unnecessary further tests such as prostate biopsies." ^[58]

There are also several other tests that can 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.

Prostate imaging

Ultrasound (US) and Magnetic Resonance Imaging (MRI)are the two main imaging methods used for prostate cancer detection. Urologists use transrectal ultrasound during prostate biopsy and can sometimes see a hypoechoic area. But US has poor tissue resolution and thus, is generally not clinically used. In contrast, prostate MRI has superior soft tissue resolution. MRI is a type of imaging that uses magnetic fields to locate and characterize prostate cancer. Multi-parametric prostate MRI consists of four types of MRI sequences called T2 weighted imaging, T1 weighted imaging, Diffusion Weighted Imaging, MR Spectrocopic Imaging and Dynamic-Contrast Enhanced Imaging.^[59] Genitourinary radiologists use multi-parametric MRI to locate and identify prostate cancer. Currently, MRI is used to identify targets for prostate biopsy using fusion MRI with ultrasound (US) or MRI-guidance alone. In men who are candidates for active surveillance, fusion MR/US guided prostate biopsy detected 33% of cancers compared to 7% with standard ultrasound guided biopsy. ^[60] Prostate MRI is also used for surgical planning for men undergoing robotic prostatectomy. It has also shown to help surgeons decide whether to resect or spare the neurovascular bundle, determine return to urinary continence and help assess surgical difficulty. ^[61]. Some prostate advocacy groups believe prostate MRI should be used to screen for prostate cancer--"manogram"-- like mammogram is for breast cancer. NIH-funded clinical trials are underway to delineate the value of MRI for some of these applications.^[62]

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.^[63]

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. Prostate specific membrane antigen is a transmembrane carboxypeptidase and exhibits folate hydrolase activity.^[34] This protein is overexpressed in prostate cancer tissues and is associated with a higher Gleason score.^[34]

Tumor markers

Tissue 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.^[64]

Small cell carcinoma is a very rare (1%^[65]) type of prostate cancer that cannot be diagnosed using the PSA.^[65][66] As of 2009^[update] 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.^[66] 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%.^[67]

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.^[68]

The expression of Ki-67 by immunohistochemistry may be a significant predictor of patient outcome for men with prostate cancer.^[69]

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.^[70]

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.^[71]

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.

Screening

Prostate 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. Such screening is controversial and, in some patients, may lead to unnecessary, even harmful, consequences.^[6] 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.^[5] More recently, the United States Preventive Services Task Force (USPSTF) recommended against the PSA test for prostate cancer screening in healthy men.^[72] This USPSTF recommendation, released in October 2011, is based on "review of evidence" studies concluding that "Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary."^[73]

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.^[74][75]

Prevention

There is a significant relation between lifestyle (including food consumption) and cancer prevention.^[76]

Medications

Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride^[77] and dutasteride,^[78] 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.^[79] 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.^[79]

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.^[80]

Ejaculation frequency

More 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.^[81][82] The results contradict those of previous studies, that suggested that having 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.^[83] 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."^[84]

Diet

Consuming fish appears to lower prostate cancer deaths but not the occurrence of prostate cancer.^[85] Omega-3 fatty acids are unlikely to prevent prostate cancer.^[86] There is no evidence that vitamin supplements affect risk.^[87] Trans fats may be associated with an increased risk of cancer but the evidence is still limited.^[88] The American Dietetic Association and Dieticians of Canada report a decreased incidence of prostate cancer for those following a vegetarian diet.^[89]

Management

Making decisions

The first decision to be made in managing prostate cancer is whether any treatment at all is needed. Prostate cancer, especially the most common, low-grade forms found in the typical elderly patient, often grows so slowly that no treatment is required at all. Donald Gleason, the inventor of the Gleason score, advocated for renaming the very common 3+3 prostate "cancer" to prostate adenosis, because he believed it so unlikely to harm the patient.^[90] Treatment may also be inappropriate or impossible if the patient has other serious health problems or is not expected to live long enough for symptoms to appear.

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. A combination of the treatment options is often recommended for managing prostate cancer.^[91][92][93]

The National Comprehensive Cancer Network (NCCN) offers evidence-based guidelines for prostate cancer that can guide treatment choices for specific clinical situations. This requires a good estimation of the patient's long-term health-adjusted life expectancy, because this factor is the most important determinant of survival in newly diagnosed patients. A simplified approach shows how to estimate health-adjusted life expectancy and apply the NCCN guidelines so that patients can have a roadmap to reach the decision recommended for their clinical situation, which they can alter according to their personal values, including fear of cancer and fear of side effects.^[94]

Patients can also use a newly developed 18-item questionnaire to learn whether they have good knowledge and understanding about their treatment options before they choose an option. Most newly diagnosed patients who have already made a treatment choice can not correctly answer over half of the questions.^[94]

The selection of treatment options involves many factors. For example, if radiation therapy is done first, and fails, then radical prostatectomy is a very technically challenging surgery and may not be feasible. On the other hand, radiation therapy done after surgical failure may have many complications.^[95] The desire to maximize subsequent options in case of failure may affect the treatment decision.

Active surveillance

Many men diagnosed with low-risk prostate cancer are eligible for active surveillance. This term implies careful observation of the tumor over time, with the intention of treatment for cure if there are signs of cancer progression. Active surveillance is not synonymous with watchful waiting, an older term which implies no treatment or specific program of monitoring, with the assumption that palliative, not curative, treatment would be used if advanced, symptomatic disease develops.

Active surveillance involves monitoring the tumor for signs of growth or the appearance of symptoms. The monitoring process may involve serial PSA, physical examination of the prostate, and/or repeated biopsies. The goal of surveillance is to avoid overtreatment and the sometimes serious, permanent side effects of treatment for a slow-growing or self-limited tumor that would never cause any problems for the patient. This approach is not used for aggressive cancers, but it may cause anxiety for patients who wrongly believe that all cancer is deadly or themselves to have a life-threatening cancer.

For the 50% to 75% of patients with prostate cancer that will cause no harm before the man dies of something unrelated, active surveillance may be the best choice.^[96]

Aggressive treatment

Treatment for aggressive prostate cancers involves 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.^[97][98][99]

Because of PSA screening, almost 90% of patients are diagnosed when the cancer is localized to the prostate gland and its removal by surgery or radiotherapy will in most cases lead to a cure. Because of this almost 94% of U.S. patients choose treatment. However, in 50% to 75% of these patients the cancer would not have affected their survival even without treatment, and by accepting treatment they have a high chance of sexual, urinary, and bowel side effects. For instance, two-thirds of treated patients cannot get sufficient erections for intercourse, and almost a third have urinary leakage. However, some cancers will grow faster and prostate cancer is the second most common reason of cancer death in U.S. men, after lung cancer.

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.^[100] Though US National Comprehensive Cancer Network guidelines^[101] 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 ^[102] 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.

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.^[103]

Castration-resistant prostate cancer

Most 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.^[104] 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.^[105][106] 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.^[107]

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, thalidomide and prednisone appears effective in the treatment of CRPC.^[108]

The immunotherapy treatment with sipuleucel-T is also effective in the treatment of CRPC with a median survival benefit of 4.1 months.^[109]

The second line hormonal therapy abiraterone (Zytiga) completed a phase 3 trial for CRPC patients who have failed chemotherapy in 2010. Results were positive with 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).^[110]

Experimental

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.^[111]

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, the clusterin protein inhibitor OGX-011, and the bone metastasis-targeting cabozantinib (XL-184). Tasquinimod had good results in a phase II trial.

Prognosis

Prostate cancer rates are higher and prognoses are 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.^[112]) 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.^[113] In Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and Europe in the 1990s.^[114] In India in the 1990s, half of the people with prostate cancer confined to the prostate died within ten years.^[115] African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in Shanghai, China.^[116] In Nigeria, two percent of men develop prostate cancer, and 64% of them are dead after two years.^[117]

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.^[118]

In 1941, Charles Huggins reported that androgen ablation therapy causes regression of primary and metastatic androgen-dependent prostate cancer.^[119] 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.^[120] 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.^[121]

Classification systems

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 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;^[122] the SEARCH registry, representing data from several Veterans Administration and active military medical centers;^[123] a multi-institutional cohort in Germany;^[124] and the prostatectomy cohort at Johns Hopkins University.^[125] More recently, it has been shown to predict metastasis and mortality following prostatectomy, radiation therapy, watchful waiting, or androgen deprivation therapy.^[126]

Epidemiology

Age-standardized death from prostate cancer per 100,000 inhabitants in 2004.^[127]

  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.^[128][129] 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.^{[128][129][130]} However, these high rates may be affected by increasing rates of detection.^[131] Many suggest that prostate cancer may be under reported, yet BPH incidence in China and Japan is similar to rates in Western countries.,^[132][133]

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.^[134] 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.^[79][135]

More than 80% of men will develop prostate cancer by the age of 80.^[136] 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.^[137]

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.^[138] 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.^[139] Removal of the entire gland (radical perineal prostatectomy) was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.^[140] 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.^[141] 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.^[142] 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.

GnRH receptor agonists, such as leuprolide and goserelin, were subsequently developed and used to treat prostate cancer.^[143][144]

Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiotherapy became more popular as stronger [X-ray] radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds (for prostate cancer) was first described in 1983.^[145]

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.^[146]

Cell-of-origin

On 30 July 2010 Owen Witte M.D. et al. of UCLA published a series of studies in Science during which they had introduced viruses known to cause cancerous mutation in prostate cells: AKT, ERG, and AR into isolated samples of basal and luminal cells and grafted the treated tissue into mice. After 16 weeks, none of the luminal samples had undergone malignant mutation, while the basal samples had mutated into prostate-like tubules which had then developed malignancy and formed cancerous tumors, which appeared identical to human samples under magnification. This led to the conclusion that the prostate basal cell may be the most likely "site of origin" of prostate cancer.^[147]

Society and culture

Discrimination

People with prostate cancer generally encounter significant disparities in awareness, funding, media coverage, and research—and therefore, inferior treatment and poorer outcomes—compared to other cancers of equal prevalence.^[148] In 2001 The Guardian noted that Britain had 3,000 nurses specializing in breast cancer, compared to only one for prostate cancer. It also discovered that the waiting time between referral and diagnosis was two weeks for breast cancer but three months for prostate cancer.^[149] A 2007 report by The National Prostate Cancer Coalition stated that for every prostate cancer drug on the market, there were seven used to treat breast cancer. The Times also noted an "anti-male bias in cancer funding" with a four to one discrepancy in the United Kingdom by both the government and by cancer charities such as Cancer Research UK.^[148][150] Equality campaigners such as author Warren Farrell cite such stark spending inequalities as a clear example of governments unfairly favouring women's health over men's health.^[151]

Disparities also extend into areas such as detection, with governments failing to fund or mandate prostate cancer screening while fully supporting breast cancer programs. For example, a 2007 report found 49 U.S. states mandate insurance coverage for routine breast cancer screening, compared to 28 for prostate cancer.^[148][152] Prostate cancer also experiences significantly less media coverage than other, equally prevalent cancers, with a study by Prostate Coalition showing 2.6 breast cancer stories for each one covering cancer of the prostate.^[148]

Prostate Cancer Awareness Month

Prostate Cancer Awareness Month takes place in September in a number of countries. A light blue ribbon is used to promote the cause.^[153][154]

Research

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.^[155][156] 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 catechins, 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.^[157]

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).^[158] Altered expression of IGF axis members has been implicated in the development of many different types of cancers, including prostate.^[159][160]

A genistein derivative KBU2046 is under investigation for prostate cancer.^[161] MDV3100 is in phase III trials for HRPC (chemo-naive and post-chemo patient populations).^[162]

The approach of hypofractionation in the treatment of prostate cancer has come full circle, with a resurgence of interested in the last 10 years. Hypofractionation is a treatment regimen during which higher doses of radiaiton are given in fewer visits. Meta analysis of trials show that if the α/β ratio of the cancer cells is lower than the surround normal tissues', hypofractionation provides a therapeutic advantage in terms of greater sensitivity of of the cancer cells as compared to the surroudning normal tissues. Even when the α/β ratio is not that low, the use of hypofractionation is proving to be a viable option for shortnening overall treatment time without compromisng efficacy. Future studies dealing with hypofractionation should will focus on optimal doses as well as minimizing side-effects.^[163]

Because the rectum is very sensitive to radiation and is located just under the prostate, it is known as the "dose limiting structure", limiting the dose delivered to the prostate. To reduce the potential for rectal irradiation and its resulting toxicity, absorbable spacers are under development to physically separate the prostate from the rectum. If successful, such spacers should enable dose escalation and hypofractionation.^[164].

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.^[165][166] 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.^{[167][168][169]}

Diagnosis

At present, an active area of research and non-clinically applied investigations involve 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 cell models.^[170]

EN2

Presence of the EN2 (gene) in urine has been correlated to a high probability of prostate cancer.^[171] Co-researchers Hardev Pandha, and Richard Morgan published their findings in the 1 March 2011 issue of the journal Clinical Cancer Research.^[172] A laboratory test currently identifies EN2 in urine, and a home test kit is envisioned similar to a home pregnancy test strip. According to Morgan, "We are preparing several large studies in the UK and in the US and although the EN2 test is not yet available, several companies have expressed interest in taking it forward." ^[58]

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 fluid massaged from the prostate by the doctor and first-void urinated out within a limited amount of urine into the specimen container. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. The test result is currently reported as a specimen ratio of PCA3 mRNA to PSA mRNA. Although not a replacement for serum PSA level, the PCA3 test is an additional tool to help decide whether, in men suspected of having prostate cancer (especially if an initial biopsy fails to explain the elevated serum PSA), a biopsy/rebiopsy is really needed. The higher the expression of PCA3 in the sample, the greater the likelihood of a positive biopsy; i.e., the presence of cancer cells in the prostate.

Early prostate cancer antigen-2

It was reported in April 2007 that research is being conducted on 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.^[173][174]

Thrombophlebitis is associated with an increased risk of prostate cancer and may be a good way for physicians to remind themselves to screen patients with thrombophlebitis for prostate cancer as well since these two are closely linked.^[175]

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.^[176]

References

External links

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