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Prevention and Treatment of Prostate Cancer

What is the prostate gland?

The prostate gland is an organ that is located at the base or outlet (neck) of the urinary bladder. (See the diagram that follows.) The gland surrounds the first part of the urethra. The urethra is the passage through which urine drains from the bladder to exit from the penis. One function of the prostate gland is to help control urination by pressing directly against the part of the urethra that it surrounds. The main function of the prostate gland is to produce some of the substances that are found in normal semen, such as minerals and sugar. Semen is the fluid that transports the sperm to assist with reproduction. A man can manage quite well, however, without his prostate gland.

In a young man, the normal prostate gland is the size of a walnut (<30g). During normal aging, however, the gland usually grows larger. This hormone-related enlargement with aging is called benign prostatic hyperplasia (BPH), but this condition is not associated with prostate cancer. Both BPH and prostate cancer, however, can cause similar problems in older men. For example, an enlarged prostate gland can squeeze or impinge on the outlet of the bladder or the urethra, leading to difficulty with urination. The resulting symptoms commonly include slowing of the urinary stream and urinating more frequently, particularly at night. Patients should seek medical advice from their urologist or primary-care physician if these symptoms are present.

What is prostate cancer?

Prostate cancer is a malignant (cancerous) tumor (growth) that consists of cells from the prostate gland. Generally, the tumor usually grows slowly and remains confined to the gland for many years. During this time, the tumor produces little or no symptoms or outward signs (abnormalities on physical examination). However, all prostate cancers do not behave similarly. Some aggressive types of prostate cancer grow and spread more rapidly than others and can cause a significant shortening of life expectancy in men affected by them. A measure of prostate cancer aggressiveness is the Gleason score (discussed in more detail later in this article), which is calculated by a trained pathologist observing prostate biopsy specimens under the microscope.

As the cancer advances, however, it can spread beyond the prostate into the surrounding tissues (local spread). Moreover, the cancer also can metastasize (spread even farther) throughout other areas of the body, such as the bones, lungs, and liver. Symptoms and signs, therefore, are more often associated with advanced prostate cancer.

Why is prostate cancer important?

Prostate cancer is the most common malignancy in American men and the second leading cause of deaths from cancer, after lung cancer. According to the American Cancer Society's most recent estimates, 192,280 new cases of prostate cancer would be diagnosed in 2009 and 27,360 would die from the disease.

The estimated lifetime risk of being diagnosed with the disease is 17.6% for Caucasians and 20.6% for African Americans. The lifetime risk of death from prostate cancer similarly is 2.8% and 4.7% respectively. As reflected in these numbers, prostate cancer is likely to impact the lives of a significant proportion of men that are alive today.

Over the years, however, the death rate from this disease has shown a steady decline, and currently, more than 2 million men in the U.S. are still alive after being diagnosed with prostate cancer at some point in their lives.

Although it is subject to some controversy, many experts in this field, therefore, recommend that beginning at age 40, all men should undergo screening for prostate cancer.

What are prostate cancer causes?

The cause of prostate cancer is unknown, but the cancer is not thought to be related to benign prostatic hyperplasia (BPH). The risk (predisposing) factors for prostate cancer include advancing age, genetics (heredity), hormonal influences, and such environmental factors as toxins, chemicals, and industrial products. The chances of developing prostate cancer increase with age. Thus, prostate cancer under age 40 is extremely rare, while it is common in men older than 80 years of age. As a matter of fact, some studies have suggested that among men over 80 years of age, 50%-80% of them may have prostate cancer! More than 80% of prostate cancers are diagnosed in men older than 65 years of age.

As mentioned previously, African-American men are 1.6 times more likely than white men to develop prostate cancer. They are also 2.4 times more likely to die from their disease as compared to white men of a similar age. These differences in diagnosis and death rates are, however, more likely to reflect a difference in factors such as environmental exposure, diet, lifestyle, and health-seeking behavior rather than any racial susceptibility to prostate cancer. Recent studies indicate that this disparity is progressively decreasing with chances of complete cure in men undergoing treatment for organ-confined prostate cancer (cancer that is limited to within the prostate without spread outside the confines of the prostate gland), irrespective of race.

Genetics (heredity), as just mentioned, plays a role in the risk of developing a prostate cancer. Prostate cancer is more common among family members of individuals with prostate cancer. This risk may be two to three times greater than the risk for men without a family history of the disease. Earlier age at diagnosis (<60 years) in a first-degree relative (father or brother) and disease affecting more than one relative also increases the risk for developing prostate cancer.

Testosterone, the male hormone produced by the testicles, directly stimulates the growth of both normal prostate tissue and prostate cancer cells. Not surprisingly, therefore, this hormone is thought to be involved in the development and growth of prostate cancer. The important implication of the role of this hormone is that decreasing the level of testosterone should be (and usually is) effective in inhibiting the growth of prostate cancer.

Recent evidence has suggested that sexually transmitted infections are risk factors for developing prostate cancer. Men with a history of sexually transmitted infections have a 1.4 times greater chance of developing prostate cancer as compared men without this history.
Although still unproven, environmental factors, such as cigarette smoking and diets that are high in saturated fat, seem to increase the risk of prostate cancer. There is also a suggestion that obesity leads to an increased risk of having more aggressive, larger prostate cancer, which results in a poorer outcome after treatment. Additional substances or toxins in the environment or from industrial sources might also promote the development of prostate cancer, but these have not yet been clearly identified. Geographical influences also seem to play a role in the development of prostate cancer with men living in the Scandinavian and North American countries being at a higher risk for the disease as compared to those residing in Asian countries.

Of note, there is no proven relationship between the frequency of sexual activity and the chances of developing prostate cancer.

What are prostate cancer symptoms and signs?

In the early stages, prostate cancer often causes no symptoms for many years. As a matter of fact, these cancers frequently are first detected by an abnormality on a blood test (the PSA, discussed below) or as a hard nodule (lump) in the prostate gland. Occasionally, the doctor may first feel a hard nodule during a routine digital (done with the finger) rectal examination. The prostate gland is located immediately in front of the rectum.

Rarely, in more advanced cases, the cancer may enlarge and press on the urethra. As a result, the flow of urine diminishes and urination becomes more difficult. Patients may also experience burning with urination or blood in the urine. As the tumor continues to grow, it can completely block the flow of urine, resulting in a painfully obstructed and enlarged urinary bladder. These symptoms by themselves, however, do not confirm the presence of prostate cancer. Most of these symptoms can occur in men with non-cancerous (benign) enlargement of the prostate (the most common form of prostate enlargement). However, the occurrence of these symptoms should prompt an evaluation by the doctor to rule out cancer and provide appropriate treatment.

Furthermore, in the later stages, prostate cancer can spread locally into the surrounding tissue or the nearby lymph nodes, called the pelvic nodes. The cancer then can spread even farther (metastasize) to other areas of the body. Symptoms of metastatic disease include fatigue, malaise, and weight loss. The doctor during a rectal examination can sometimes detect local spread into the surrounding tissues. That is, the physician can feel a hard, fixed (not moveable) tumor extending from and beyond the gland. Prostate cancer usually metastasizes first to the lower spine or the pelvic bones (the bones connecting the lower spine to the hips), thereby causing back or pelvic pain. The cancer can then spread to the liver and lungs. Metastases (areas to which the cancer has spread) to the liver can cause pain in the abdomen and jaundice (yellow color of the skin) in rare instances. Metastases to the lungs can cause chest pain and coughing.

What are the screening tests for prostate cancer?

Screening tests are those that are done at regular intervals to detect a disease such as prostate cancer at an early stage. If the result of a screening test is normal, the disease is presumed not to be present. If a screening test is abnormal, the disease is then suspected to be present, and further tests usually are needed to confirm the suspicion (that is, to make the diagnosis definitively). Prostate cancer usually is suspected initially because of an abnormality of one or both of the two screening tests that are used to detect prostate cancer. These screening tests are a digital rectal examination and a blood test called the prostate specific antigen (PSA).

In the digital rectal examination, the doctor feels (palpates) the prostate gland with his gloved index finger in the rectum to detect abnormalities of the gland. Thus, a lump, irregularity, or hardness felt on the surface of the gland is a finding that is suspicious for prostate cancer. Accordingly, doctors usually recommend doing a digital rectal examination in men age 40 and over.

The PSA test is a simple, reproducible, and relatively accurate blood test. It is used to detect a protein (the prostate specific antigen) that is released from the prostate gland into the blood. The PSA level is usually higher than 4ng/mL in people with prostate cancer than in people without the cancer. Situations of large prostate size, infection and inflammation are other reasons why the PSA may be elevated. The PSA, therefore, is valuable as a screening test for prostate cancer. Accordingly, doctors usually recommend doing a PSA in men age 40 and over. Subsequent screening is recommended based on individual preference and assessment of risk for developing prostate cancer. For example, patients with a high risk of developing prostate cancer due to a family history or a high initial

PSA should have more frequent evaluation (usually annually).
Although, still considered controversial, most urologists recommend regular screening for prostate cancer in men who are likely to live for more than 10 years (for example, life expectancy > 10 years). The American Urological Association (AUA) issued their latest guidelines for prostate cancer in 2009. According to these, men at the age of 40 should be offered a baseline PSA test and a prostate exam (digital rectal exam or DRE) to ascertain the risk of prostate cancer. Subsequent screening and tests may be performed according to the findings on this initial evaluation and an individual's risk of getting the disease on the basis of other factors such as race, ethnicity, and family history of prostate cancer. As mentioned, most urologists currently would advise some form of screening in men with a life expectancy greater than 10 years. Most frequently, it would be performed on an annual basis. Although, there is no definite cutoff age to stop prostate cancer screening, most physicians would rarely screen men more than 75 years of age for this disease.
Results of the PSA test under 4 nanograms per milliliter of blood are generally considered normal. (See the next two sections on false-positive elevations of the PSA and on refinements in the PSA test.) There is a recent trend, however, to perform prostate biopsy in all patients with a PSA more than 2.5 ng/ml in order to detect prostate cancer at an earlier (and hopefully, completely curable) stage. The American Urological Association guidelines (2009) do not define a definite cutoff point but advise that all the other risk factors for prostate cancer should be taken into account while making a decision on whether to proceed for a biopsy. One of the important factors that need to be considered is the rate at which the PSA value has increased over time on repeated measurements (PSA velocity). Results between 4 and 10 are considered borderline. These borderline values are interpreted in the context of the patient's age, symptoms, signs, family history, and changes in the PSA levels over time. Results higher than 10 are considered abnormal, suggesting the possibility of prostate cancer. It has been shown that the higher the PSA value, the more likely the diagnosis of prostate cancer. Moreover, the level of PSA tends to increase when the cancer has progressed from organ-confined prostate cancer to local spread to distant (metastatic) spread. Very high values, such as 30 or 40 and over, are usually caused by prostate cancer.

What are false-positive elevations in the PSA test?

False-positive elevations in the PSA are increases in the PSA that are caused by conditions other than prostate cancer. For example, benign prostatic hyperplasia (BPH) and infection or inflammation of the prostate (prostatitis) from whatever cause can elevate the PSA. Note also that even a rectal examination or an ejaculation within the prior 48 hours can sometimes elevate the PSA. False-positive elevations are usually in the 4 to10 range, but they can go as high as 25 or 30. At these higher levels, however, caution in the interpretation of the test is warranted because a prostate cancer may well be present. Non-prostatic diseases or infections, medications, foods, smoking, and alcohol do not cause false-positive elevations of the PSA.

The ability of the PSA test to detect prostate cancer (called the sensitivity of the test) is high. The reason for this is that most patients, although not all, with prostate cancer have a borderline or an abnormally elevated PSA. The ability of the test to exclude other diagnoses (called the specificity of the test), however, is lower because of the other conditions that can cause false-positive elevations of the PSA.

What refinements have been made in the PSA test?

Recently, several refinements have been made in the PSA blood test. The purpose of these refinements is to help doctors to better assess a borderline or an elevated PSA. The goal is to determine more accurately who has prostate cancer and who has a false-positive elevation of the PSA from another condition. In other words, the purpose of the improvements is to improve the sensitivity and the specificity of the test.

One refinement is called the PSA ratio. This ratio is determined by dividing the amount of PSA that circulates freely in the bloodstream by the amount of PSA that is bound to proteins in the bloodstream. Research has shown the PSA that circulates freely in the blood tends to be associated with benign prostatic hyperplasia (BPH) whereas the PSA that is bound to protein tends to be linked with prostate cancer. Thus, a high PSA ratio suggests a false-positive elevation of the PSA and weighs against the diagnosis of prostate cancer. In contrast, a high PSA with a low PSA ratio favors the diagnosis of prostate cancer.
Another recent modification of the PSA test is based on the observation that as men age the amount of PSA in the blood can normally rise without the presence of a prostate cancer. Thus, doctors can use what is referred to as an age-specific PSA, especially to evaluate borderline values. In the age-specific PSA, the normal values are adjusted for the age of the patient. Accordingly, the age-specific normal ranges are 0 to 2.5 for men in their 40s, 0 to 3.5 in their 50s, 0 to 4.5 in their 60s, and 0 to 6.5 for men 70 years of age and over. Therefore, as an example, a PSA of 4 would be considered borderline for men in their 30s and 40s but could be normal for men in their 50s, 60s, and 70s.

Furthermore, another improvement of the PSA test is called the PSA velocity or slope. The velocity is calculated as the rate at which the PSA changes with repeated testing over time. The more rapid the rise in the PSA, the more likely is the presence of a prostate cancer. The less rapid the rise in the PSA, the less likelihood there is that a prostate cancer is present.

Prostate cancer gene 3 (PCA3) is a new gene-based test carried out on a urine sample. PCA3 is highly specific for the diagnosis of prostate cancer. Therefore, in contrast to PSA, the PCA3 is not increased by conditions such as benign enlargement or inflammation of the prostate. The PCA3 urine test can provide additional information over a PSA test that may help in deciding whether a prostate biopsy is really needed.

How is prostate cancer diagnosed and graded?

Prostate cancer is diagnosed from the results of a biopsy of the prostate gland. If the digital rectal exam of the prostate or the PSA blood test is abnormal, a prostate cancer is suspected. A biopsy of the prostate is usually then recommended. The biopsy is done from the rectum (trans-rectally) and is guided by ultrasound images of the area. A small piece of prostate tissue is withdrawn through a cutting needle. The TRUS-guided Tru-Cut biopsy is currently the standard method to diagnose prostate cancer. Although initially a 6-core set was the standard, currently most experts advocate sampling a minimum of 10-12 pieces of the prostate to improve the chances of detection of the cancer and also to provide a better idea regarding the extent and areas of involvement within the prostate. Multiple pieces are taken by sampling the base, apex, and mid gland on each side of the gland. More cores may be sampled to increase the yield, especially in larger glands.

A pathologist, a specialist physician who analyzes tissue samples under a microscope, then examines the pieces under the microscope to assess the type of cancer present in the prostate and the extent of involvement of the prostate with the tumor. One also can get an idea about the areas of the prostate that are involved by the tumor by assessing which of the pieces contain the cancer and which of them do not. Another very important assessment that the pathologist makes form the specimen is the grade (Gleason's score) of the tumor. This indicates how different the cancer cells are from normal prostate tissue. Grade gives an indication of how fast a cancer is likely to grow and has very important implications on the treatment plan and the chances of cure after treatment. A Gleason score of 6 is supposed to indicate low-grade (less aggressive) disease while that of 8-10 demonstrates high grade (more aggressive) cancer; 7 is regarded as somewhere in between these two.

How is the staging of prostate cancer done?

The staging of a cancer refers to determining the extent of the disease (where in the body have the prostate cancer cells spread). Once a prostate cancer is diagnosed on a biopsy, additional tests are done to assess whether the cancer has spread beyond the gland.
Radionuclide bone scans can determine if there is a spread of the tumor to the bones. The radioactive substance highlights areas where the cancer has affected the bones. This test is usually reserved for men with prostate cancer who have deep bone pain or a fracture or who have biopsy findings and high PSA values (>10-20 ng/ml) suggestive of advanced or aggressive disease.

Chest X-ray can be used to detect whether or not cancer has spread to the lungs. Ultrasound tests can be used to look for the effects of a urinary blockage on the kidneys. This study can also be used to assess the bladder for any sign of urinary obstruction due to prostate enlargement by looking at the thickness of the bladder wall as well as the amount of urine remaining within the bladder after an attempt at passing urine.

Additionally, CT scans (coaxial tomography) and MRIs (magnetic resonance imaging) can determine if the cancer has spread to adjacent tissues or organs such as the bladder or rectum or to other parts of the body such as the liver or lungs. Newer scanning using a method called PET scan can sometimes help to detect hidden locations of cancer that has spread to various areas of the body.
Cystoscopy is usually performed in selected situations. A thin, flexible, lighted tube with a tiny camera on the end is inserted through the urethra to the bladder. The camera transmits images to a video monitor. This may show whether the cancer has spread to the urethra or bladder and may be utilized to take a biopsy from these organs.

To summarize, doctors do the staging of prostate cancer based primarily on the results of the prostate biopsy, possibly other biopsies, and imaging tests. In staging a cancer, doctors assign various letters and numbers to the cancer, depending on which of the classifications for staging they use. The numbers and letters in the different classifications define the volume or amount of the tumor and the spread of the cancer. The stage of the prostate cancer, therefore, helps to predict the expected course of the disease and determine the choice of treatment.

The stages of prostate cancer are categorized as follows:

• Stage I (or A): The cancer cannot be felt on a digital rectal exam, and there is no evidence that it has spread outside the prostate. These are often found incidentally after surgery for an enlarged prostate.
• Stage II (or B): The tumor is larger than a stage I and can be felt on a digital rectal exam. There is no evidence that the cancer has spread outside the prostate. These are usually found on a biopsy when a man has an elevated PSA level.
• Stage III (or C): The cancer has invaded other tissues neighboring the prostate.
• Stage IV (or D): The cancer has spread to lymph nodes or to other organs.

Most doctors currently use the 2002 TNM (Tumor, Node, Metastases) staging system for prostate cancer. This is based on a combination of three criteria: extent of the primary tumor (T stage), involvement of lymph nodes by the cancer (N stage), and the presence or absence of spread to distant areas of the body in the form of metastasis (M stage). The TNM 2002 staging system is as follows:

Evaluation of the (primary) tumor ("T")

• TX: The primary tumor cannot be evaluated.
• T0: There is no evidence of tumor.
• T1: Tumor is present but not detectable clinically or with imaging.
• T1a: Tumor was incidentally found in less than 5% of prostate tissue resected (for other reasons).
• T1b: Tumor was incidentally found in greater than 5% of prostate tissue resected.
• T1c: Tumor was found in a needle biopsy performed due to an elevated serum PSA.
• T2: The tumor can be felt (palpated) on examination but has not spread outside the prostate.
• T2a: The tumor is in half or less than half of one of the prostate gland's two lobes.
• T2b: The tumor is in more than half of one lobe, but not both.
• T2c: The tumor is in both lobes.
• T3: The tumor has spread through the prostatic capsule (if it is only partway through, it is still T2).
• T3a: The tumor has spread through the capsule on one or both sides.
• T3b: The tumor has invaded one or both seminal vesicles.
• T4: The tumor has invaded other nearby structures.

It should be stressed that the designation "T2c" implies a tumor which is palpable in both lobes of the prostate. Tumors which are found to be bilateral on biopsy only but which are not palpable bilaterally should not be staged as T2c.

Evaluation of the regional lymph nodes ("N")

• NX: The regional lymph nodes cannot be evaluated.
• N0: There has been no spread to the regional lymph nodes.
• N1: There has been spread to the regional lymph nodes.

Evaluation of distant metastasis ("M")

• MX: Distant metastasis cannot be evaluated.
• M0: There is no distant metastasis.
• M1: There is distant metastasis.
• M1a: The cancer has spread to lymph nodes beyond the regional ones.
• M1b: The cancer has spread to bone.
• M1c: The cancer has spread to other sites (regardless of bone involvement).

What are the treatment options for prostate cancer?

Deciding on treatment can be difficult, partly because the options for treatment today are far better than they were 10 years ago but also because not enough reliable data are available on which to base the decisions. Accordingly, scientifically controlled, long-term studies are still needed to compare the benefits and risks of the various treatments.

To decide on treatment for an individual patient, doctors categorize prostate cancers as organ-confined (localized to the gland), locally advanced (a large prostate tumor or one that has spread only locally), or metastatic (spread distantly or widely). The treatment options for organ-confined prostate cancer or locally advanced prostate cancer usually include surgery, radiation therapy, hormonal therapy, cryotherapy, combinations of some of these treatments, and watchful waiting. A cure for metastatic prostate cancer is, unfortunately, unattainable at the present time. The treatments for metastatic prostate cancer, which include hormonal therapy and chemotherapy, therefore, are considered palliative. By definition, the aims of palliative treatments are, at best, to slow the growth of the tumor and relieve the symptoms of the patient.

What about prostate cancer surgery?

The surgical treatment for prostate cancer is commonly referred to as a radical prostatectomy, which is the removal of the entire prostate gland. The entire prostate, seminal vesicles, and ampulla of the vas deferens are removed, and the bladder is connected to the membranous urethra to allow free urination.

The radical prostatectomy is the most common treatment for organ confined or localized prostate cancer in the United States. This operation is currently performed in about 36% of patients with organ-confined (localized) prostate cancer. The American Cancer Society estimates a 90% cure rate nationwide when the disease is confined to the prostate and the entire gland is removed. The potential complications of a radical prostatectomy include the risks of anesthesia, local bleeding, impotence (loss of sexual function) in 30%-70% of patients, and incontinence (loss of control of urination) in 3%-10% of patients.

Great strides have been made in lowering the frequency of the complications of radical prostatectomy. These advances have been accomplished largely through improved anesthesia and surgical techniques. The improved surgical techniques, in turn, stem from a better understanding of the key anatomy and physiology of sexual potency and urinary continence. Specifically, the recent introduction of nerve-sparing techniques for the prostatectomy has helped to reduce the frequency of impotence and incontinence. Of men who undergo these newer techniques, 98% are continent, and 60% are able to have an erection.

Radical prostatectomy can be performed by open surgery, laparoscopic surgery, or by robotic surgery (robotic assisted radical prostatectomy). Currently, almost 70% of radical prostatectomy surgeries in the U.S. are performed using the of the Da Vinci robotic system. For robot-assisted surgery, five small incisions are made in the abdomen through which the surgeon inserts tube-like instruments, including a small camera. This creates a magnified three-dimensional view of the surgical area. The instruments are attached to a mechanical device, and the surgeon sits at a console and guides the instruments through a viewing device to perform the surgery. The instrument tips can be moved in a variety of ways under the control of the surgeon to achieve greater precision in surgery. So far, studies show that traditional open prostatectomy and robotic prostatectomy have had similar outcomes related to cancer-free survival rates, urinary continence, and sexual function. However, in terms of blood loss during surgery and pain and recovery after the procedure, robotic surgery has been shown to have a significant advantage.

If post-treatment impotence does occur, it can be treated by sildenafil (Viagra) tablets, injections of such medications as alprostadil (Caverject) into the penis, various devices to pump up or stiffen the penis, or a penile prosthesis (an artificial penis). Incontinence after treatment often improves with time, special exercises, and medications to improve the control of urination. Occasionally, however, incontinence requires implanting an artificial sphincter around the urethra. The artificial sphincter is made up of muscle or other material and is designed to control the flow of urine through the urethra.

Transurethral resection of the prostate (TURP) involves the removal of a part of the prostate by an instrument inserted through the urethra. It is used as an alternative to prostatectomy in patients with extensive disease or those who are not fit enough to undergo radical prostatectomy to remove tissue that is blocking urine flow. This is often referred to as a channel TURP.

What about radiation therapy for prostate cancer?

The goal of radiotherapy is to damage the cancer cells and stop their growth or kill them. This works because the rapidly dividing (reproducing) cancer cells are more vulnerable to destruction by the radiation than are the neighboring normal cells. Clinical trials have been conducted using radiation therapy for patients with organ-confined (localized) prostate cancer. These trials have shown that radiation therapy resulted in a rate of survival (being alive) at 10 years after treatment that is comparable to that for radical prostatectomy. Incontinence and impotence can occur as complications of radiation therapy, as with surgery, although perhaps less often than with surgery. More data are needed, however, on the risks and benefits of radiation therapy beyond 10 years, especially because late recurrences (reappearances) of the cancer can sometimes occur after radiation.

Choosing between radiation and surgery to treat organ-confined prostate cancer involves considerations of the patient's preference, age, and coexisting medical conditions (fitness for surgery), as well as of the extent of the cancer. Approximately 30% of patients with organ-confined prostate cancer are treated with radiation. Sometimes, oncologists combine radiation therapy with surgery or hormonal therapy in an effort to improve the long-term results of treatment in the early or later stages of prostate cancer.

Radiation therapy can be given either as external beam radiation over perhaps six or seven weeks or as an implant of radioactive seeds (brachytherapy) directly into the prostate. In external beam radiation, high energy X-rays are aimed at the tumor and the area immediately surrounding it. In brachytherapy, radioactive seeds are inserted through needles into the prostate gland under the guidance of transrectally taken ultrasound pictures. Brachy, from the Greek language, means short. The term brachytherapy thus refers to placing the treatment (radiation therapy) directly into or a short distance away from the cancerous target tissue. The theoretical advantage of brachytherapy over external beam radiation is that delivering the radiation energy directly into the prostate tissue should minimize damage to the surrounding tissues and organs.

Potential disadvantages of radiation therapy include a transient swelling of the prostate that may cause obstruction to the flow of urine and increase symptoms that may already be present because of an enlarged prostate. Side effects of external beam radiation include skin burning or irritation and hair loss at the area where the radiation beam goes through the skin. Both can cause severe fatigue, diarrhea, and discomfort on urination. These effects are almost always temporary. However, there are concerns about the long-term effects of radiation, and although still not proven, some studies have reported a higher chance of developing bladder or rectal cancer many years after undergoing radiation for prostate cancer. Although surgery can be done in case radiation therapy fails to cure prostate cancer (salvage radical prostatectomy), it is fraught with greater surgical difficulty and involves a significantly higher chances of complications like impotence and urinary incontinence.

What about hormonal treatment for prostate cancer?

The male (androgenic) hormone is called testosterone. It stimulates the growth of cancerous prostatic cells and, therefore, is the primary fuel for the growth of prostate cancer. The idea of all of the hormonal treatments (medical and surgical), in short, is to decrease the stimulation by testosterone of the cancerous prostatic cells. Testosterone normally is produced by the testes in response to stimulation from a hormonal signal called LH-RH. The LH-RH stands for luteinizing hormone-releasing hormone and is also called gonadotropin-releasing hormone. This hormone comes from a control station in the brain and travels in the bloodstream to the testes. Once there, the LH-RH stimulates the testes to produce and release testosterone.

Hormonal treatment, also referred to as androgen deprivation (depriving the prostate of testosterone), can be accomplished surgically or medically. The surgical hormonal treatment is removal of the testes in an operation called an orchiectomy or a castration. This surgery thus removes the body's source of testosterone. The medical hormonal treatment involves taking one or two types of medication. One type is referred to as the LH-RH agonists. They work by competing with the body's own LH-RH. These drugs thereby inhibit (block) the release of LH-RH from the brain. The other type of drug is referred to as anti-androgenic, meaning that these drugs work against the male hormone. That is, they work by blocking the effect of testosterone itself on the prostate.

Today, most men electing hormonal treatment choose medication over surgery, probably because they view surgical castration as more devastating cosmetically or psychologically. Actually, however, the effectiveness and side effects of medical hormonal treatment as compared to surgical hormonal treatment are very much the same. Both types of hormonal treatment usually effectively eliminate stimulation of the cancer cells by testosterone. Some tumors of the prostate, however, do not respond to this form of treatment. They are referred to as androgen-independent prostate cancers. The principal side effects of all of these hormonal treatments (that is, the side effects of androgenic deprivation) are enlarged breasts (gynecomastia) that often are tender, flushing (like hot flashes), and impotence.
The LH-RH agonists, leuprolide (Lupron) or goserelin (Zoladex), are given as monthly injections in the doctor's office. The anti-androgenic drugs, flutamide (Eulexin) or bicalutamide (Casodex), are oral capsules that are used usually in combination with the LH-RH agonists. The LH-RH agonists are often effective alone. The anti-androgenic drugs are added, however, if the cancer progresses despite the use of the LH-RH agonists. The hormonal treatments may have value, as well, when combined with radiation therapy. Current evidence suggests that hormonal therapy enhances the therapeutic effect of radiation.

Generally, hormonal treatment is reserved for individuals who have advanced prostate cancer with local spread or metastases. Occasionally, an individual with organ-confined (localized) prostate cancer will receive hormonal treatment because he has severe associated medical problems or simply because he refuses to undergo surgery or radiation. Hormonal treatment is used in less than 10% of men with organ-confined (localized) prostate cancer. Remember that the intent of hormonal therapy usually is palliative. This means that the goal is to control the cancer rather than cure it because a cure is not possible.

What is cryotherapy for prostate cancer?

Cryotherapy is one of the newer treatments that is being evaluated for use in the early stage of prostate cancer. This treatment kills the cancer cells by freezing them. The freezing is accomplished by inserting a freezing liquid (for example, liquid nitrogen or argon) through needles directly into the prostate gland. The procedure is accomplished under the guidance of ultrasound images. Actually, cryotherapy is not a new technique. Rather, it is a modification of a procedure that was tried previously but had an unacceptably high rate of complications. Thus, cryotherapy was used in the 1960s to freeze the lining of the stomach to treat ulcers but was discontinued because it also severely damaged the lining of the stomach.

At present, cryotherapy is recommended for patients with locally advanced prostate cancer who, for whatever reason, are not candidates for the more established treatments. Cryotherapy is further being studied to determine which other patients might benefit from this treatment. For example, studies are under way to establish whether cryotherapy is beneficial as an initial treatment for organ-confined (localized) prostate cancer. The effectiveness of cryotherapy in eliminating prostate cancer, however, has not yet been proven. We do know that sometimes the freezing liquid fails to kill all of the cancer cells. Moreover, the potential side effects of this treatment include damage to the urethra and bladder. This damage can cause obstruction (blockage) of the urethra, fistulas (abnormal tunnels) that leak urine, or serious infections.

What is HIFU for prostate cancer?

HIFU, which stands for high intensity focused ultrasound, was first developed as a treatment of benign prostatic hyperplasia (BPH) and now is also being used as a procedure for the killing of prostate cancer cells. This procedure utilizes transrectal (across the rectum) ultrasound that is highly focused into a small area, creating intense heat of 80-100 C, which is lethal to prostate cancer tissue. However, the published clinical experience with HIFU for this application is limited and the procedure is not yet approved by the FDA for use in the United States.

What is chemotherapy for prostate cancer?

Chemotherapeutic agents, or chemotherapy, are anticancer drugs. They are used (for hormone resistant prostate cancer) as a palliative treatment (palliation to relieve symptoms) in patients with advanced cancer for whom a cure is unattainable. Recall that the goal of palliation is simply to slow the tumor's growth and relieve the patient's symptoms. Chemotherapy is not ordinarily used for organ-confined or locally advanced prostate cancers because a cure in these cases is possible with other treatments. Currently, chemotherapy is used only for advanced metastatic prostate cancers that have failed to respond to other treatments.

Several chemotherapeutic agents have been used effectively to palliate metastatic prostate cancer. One such agent is estramustine (Emcyt). Another agent called mitoxantrone (Novantrone) has been shown to be effective in combination with prednisone for palliating androgen-independent prostate cancer. As mentioned previously, metastatic tumors that have not responded specifically to hormonal therapy are referred to as castrate-resistant prostate cancers. Newer chemotherapy medicines like docetaxel (Taxotere) have shown some promise in prolonging the survival of some patients with extensive prostate cancer. They may also decrease the pain related to widespread cancer. However, this comes at the cost of significant side effects that may impact quality of life.

The more common side effects of chemotherapy include weakness, nausea, hair loss, and suppression of the bone marrow. The suppression of marrow, in turn, can decrease the red blood cells (causing anemia), the white blood cells (leading to infections), and the platelets (resulting in bleeding).

What are the differences between hormonal treatment and chemotherapy?

Hormonal therapy is the mainstay of treatment for symptomatic, advanced-staged prostate cancer. A vast majority of prostate cancers, particularly initially, are dependent on testosterone (the male hormone produced by the testes) for their growth and spread. The objective of hormonal treatment is to withdraw this source of sustenance for prostate cancer cells in an attempt to slow down or control this disease. The following are treatments available for hormonal therapy:

Orchiectomy is the surgical removal of the testicles. Luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide (Lupron, Viadur, Eligard), goserelin (Zoladex), or buserelin (Suprefact), stop the production of testosterone from the testes and induce a state of "medical castration" (castration without surgery). Many men prefer this over surgical castration.

Antiandrogens, such as flutamide (Eulexin) or bicalutamide (Casodex), block the action of testosterone on the prostate cancer cells and other parts of the body. Each of the above two classes of medicines produce symptomatic relief in about 80% of patients. Improvement is often dramatic.

Side effects of these medications vary. Orchiectomy and LHRH agonists may cause impotence, hot flashes, and loss of sexual desire. Antiandrogens may cause nausea, vomiting, diarrhea, and breast enlargement or tenderness. Any of these therapies can weaken bones and lead to osteoporosis and bone fracture.

Other agents that are helpful include the following: progestins such as megestrol acetate given daily orally and other drugs that inhibit androgen production such as aminoglutethimide (Cytadren) or ketoconazole (Nizoral, Extina, Xolegel, Kuric). These agents are effective but are sometimes difficult to tolerate. Corticosteroids are often given simultaneously.

As opposed to hormonal therapy, chemotherapy provides relief in only 20%-25% of symptomatic patients with prostate cancer. Various regimens are being used. Estramustine, cisplatin, 5-FU, vinorelbine, and mitoxantrone are the most popular agents. However, recently docetaxel (Taxotere) has become the drug of choice used by oncologists in treating castrate-resistant prostate cancer (prostate cancer which has become unresponsive to hormonal therapy).

When to use hormonal therapy and chemotherapy depends on the nature of the prostate cancer itself. If the prostate cancer is hormone-sensitive, then hormonal therapy is the therapy of choice. When the cancer becomes hormone-resistant (for example, manipulation of the hormone levels has no effect on the prostate cancer), then the only potential therapy available to the patient is chemotherapy. Chemotherapy, then, is used generally when advanced prostate cancer is hormone-resistant. Unfortunately, chemotherapy after hormone therapy is nowhere near as effective as hormonal therapy because the cancer itself has often evolved to become more aggressive so that the prognosis is significantly worse. When prostate cancer transforms from being hormone-sensitive to hormone-resistant, the prognosis has taken a significant turn for the worse and the chemotherapy option at that particular time is usually the only treatment option available.

Other factors considered in choosing treatment include the age, general health, and preference of the individual and the Gleason score and stage of the cancer. The results of the PSA test sometimes also can help to decide on the treatment. For example, a borderline elevation of the PSA (4-10), if shown to be due to a prostate cancer, suggests that the cancer is confined to the gland. If other tests also point to an organ-confined tumor, surgery or possibly radiation can be considered to attempt a cure. In contrast, a very high PSA (for example, over 30 or 40) raises the possibility of metastases. If the metastases are then confirmed by other tests, the treatment options would be limited to hormonal therapy or chemotherapy.

PSA tests also should be done periodically after treatment to help assess the results of treatment. For example, an increasing PSA suggests growth or spread of the cancer, despite the treatment. In contrast, a decreasing PSA indicates improvement. As a matter of fact, a post-treatment undetectable PSA (PSA less than 0.05 or 0.1 ng/ml) may indicate complete control or cure of the cancer.

What about herbal or other alternative medicine treatments for prostate cancer?

Alternative medicine, also called integrative or complementary medicine, includes such non-traditional treatments as herbs, dietary supplements, and acupuncture. A major problem with most herbal treatments is that their composition is not standardized. Moreover, the way herbal treatments work and their long-term side effects usually are not known. Currently, there is no evidence to prove that these medications have any therapeutic benefit in prostate cancers that have become resistant to conventional treatments.

What is active surveillance for prostate cancer?

Active surveillance is observing a patient while no immediate treatment is given. Such a patient usually has a less aggressive, small-sized, organ-confined tumor and no symptoms. This management strategy is based on the premise that most early prostate cancers are slow-growing tumors and will remain confined to the prostate gland for a significant length of time. This implies that in selected patients it may be possible to defer definitive treatment for many years or avoid it altogether thereby preventing the side effects associated with treatments like surgery or radiation. Understand, however, that although active surveillance involves no actual treatment, the patient still needs close follow-up and monitoring. The follow-up involves frequent visits to the doctor, perhaps every three to six months. The visits include questions about new or worsening symptoms and digital rectal examinations for any change in the prostate gland. In addition, blood tests are done to watch for a rising PSA, and imaging studies can be conducted to detect the spread of the cancer. Most experts also recommend performing a confirmatory set of prostate biopsies to ensure that there is low-volume disease. Additional prostate biopsy is required every year to detect any increase in the volume and Gleason grade of the cancer. As mentioned before, Gleason grade is a measure of aggressiveness of the tumor and increase in this value may point toward a need to treat the cancer with other means. If the history, examinations, or any of the tests signal the possibility of an advancing cancer, the active surveillance usually is discontinued and active treatment is recommended, often with radiotherapy or surgery.

Active surveillance is different from watchful waiting. Watchful waiting means following up patients without any tests or biopsies and treating them only when symptoms arise. This is reserved for men who have a life expectancy of less than 10 years. Therefore, watchful waiting seems to make sense for organ-confined (localized) prostate cancers in men who are elderly. Additionally, watchful waiting often is the most appropriate choice in men who are ill with other serious medical diseases, such as heart or lung disease, poorly controlled high blood pressure, diabetes, AIDS, or other cancers.

Active surveillance and watchful waiting in prostate cancer, however, remains controversial. Some medical authors have stated outright that it is not a good choice. They point out that few doctors would just watch other cancers to see whether they would spread without treatment. Furthermore, the treatment for an individual could become less effective in the future if and when the cancer does progress. Moreover, there is no standardized protocol for selecting appropriate patients for active surveillance with different institutions having their own different guidelines. Studies are under way to compare these protocols with more established methods of treatment, and more information is likely to emerge in the future.

Can prostate cancer be prevented?

No specific measures are known to prevent the development of prostate cancer. At present, therefore, we can hope only to prevent progression of the cancer by making early diagnoses and then attempting to cure the disease. Early diagnoses can be made by screening men for prostate cancer with PSA and digital rectal examination The purpose of the screening is to detect early, tiny, or even microscopic cancers that are confined to the prostate gland. Early treatment of these malignancies (cancers) can stop the growth, prevent the spread, and possibly cure the cancer.

Based on some research in animals and people, certain dietary measures have been suggested to prevent the progression of prostate cancer. For example, low-fat diets, particularly avoiding red meats, have been suggested because they are thought to slow down the growth of prostate tumors in a manner not yet known. Soybean products, which work by decreasing the amount of testosterone circulating in the blood, also reportedly can inhibit the growth of prostate tumors. Finally, other studies show that tomato products (lycopenes), the mineral selenium, and vitamin E might slow the growth of prostate tumors in ways that are not yet understood.
Recently, studies have shown that certain medications (finasteride [Propecia] and dutasteride [Avodart]) decrease the chances of getting prostate cancer when taken over the long term. These medications are currently used for shrinking the size of the prostate and relieving symptoms associated with benign (non-cancerous) enlargement of the prostate. However, they may have a future role for decreasing the chances of development of prostate cancer in men who are at high risk for the disease.

What will be the future treatments for prostate cancer?

The treatment of organ-confined prostate cancer to date has involved cutting out, radiating, or freezing the gland in trying to cure the disease. In more advanced cases, the goal has been to control the cancer for at least some time by using hormonal treatment or chemotherapy. Earlier diagnosis and improved treatment techniques in recent years have certainly led to better results.
The key to curing prostate cancer, however, ultimately will come from an understanding of the genetic basis of this disease. Genes, which are chemical compounds located on the chromosomes, determine the characteristics of individuals. Accordingly, investigators at research centers have focused on identifying and isolating the gene or genes responsible for prostate cancer. For example, studies are being conducted in men who have a family history of prostate cancer to try to uncover the genetic links of the disease. The investigators ultimately will try to block or modify the offending genes so as to prevent or alter the disease.

Recently, the FDA approved a prostate cancer vaccine called sipuleucel-T (Provenge) that has been made for people who are at an advanced stage of prostate cancer. Although clinical experience with this vaccine is limited, it has been shown to improve survival in patients whose cancer has become resistant to hormones. This treatment involves taking a patient's own white blood cells and using a drug that trains them to more actively attack cancer cells. Once these cells are removed from the patient, they are treated with the drug and placed back into the patient. After the treatment of these cells, it kills cancer cells while leaving normal cells unharmed.
Another area of research is focal therapy for prostate cancer that attempts to mirror the evolution of breast cancer treatment, which often involves "lumpectomy" as part of the initial management of the disease. It involves treatment of only that part of the prostate that is affected by cancer and uses methods like cryotherapy (freezing), HIFU (heating), and brachytherapy (seed implantation) to treat the cancer. Focal therapy is still at its infancy and its role is unclear because of unresolved problems related to lack of a proper method for complete evaluation of cancer location within the prostate and the potential coexistence of many different cancerous areas within the same prostate.

There is also a great interest in inventing better methods to image prostate cancer to detect its location and spread in the body. Newer techniques like MRS (magnetic resonance spectroscopy), PET (positron emission tomography) and certain molecular imaging techniques hold promise in this regard.

Prostate Cancer At A Glance

• Prostate cancer is the second leading cause of deaths from cancer among U.S. men.
• While the causes of prostate cancer are still unknown, some risk factors for the disease, such as advancing age and a family history of prostate cancer, have been identified.
• Prostate cancer is often initially suspected because of an abnormal PSA blood test or a hard nodule (lump) felt on the prostate gland during a routine digital (done with a finger) rectal examination.
• Refinements in the PSA test, including the PSA ratio, age-specific PSA, and PSA velocity or slope have improved the accuracy of the test.
• If one of the screening tests is abnormal, the diagnosis of prostate cancer should be suspected and a biopsy of the prostate gland is usually done.
• The diagnosis of prostate cancer is made when cancerous prostatic cells are identified in the biopsy tissue under a microscope.
• In some men, prostate cancer is life threatening, while in many others, it can exist for many years without causing health problems.
• The choice of treatment for prostate cancer depends on the size, aggressiveness, and extent or spread of the tumor, as well as on the age, general health, and preference of the patient.
• The many options for treating prostate cancer include surgery, radiation therapy, hormonal treatment, cryotherapy, chemotherapy, combinations of some of these treatments, and watchful waiting/active surveillance.
• Research is under way to identify the genes that cause prostate cancer.

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