Prostate Cancer

The prostate is a walnut-shaped gland located below the bladder.

• The prostate is a walnut-shaped gland that is a part of the male reproductive system that wraps around the male urethra at its exit from the bladder.
• Common problems are benign (noncancerous) enlargement of the prostate called BPH (benign prostatic hyperplasia), acute and chronic infections of the prostate (acute and chronic bacterial prostatitis), and chronic inflammation of the prostate that is not related to bacteria (chronic prostatitis [non-bacterial]).
• Prostate cancer is common in men over 50 years of age, with the risk of developing prostate cancer increasing with aging. Certain populations are at increased risk for developing prostate cancer, particularly African-Americans and men with a first-degree relative, father or brother, diagnosed with prostate cancer at a younger age.
• Symptoms of prostate problems (and prostate cancer) include urinary problems such as
  • decreased force of urine stream;
  • difficulty starting (hesitancy);
  • the need to strain to urinate;
  • stopping/starting of the urine stream (intermittency);
  • frequent urination;
  • dribbling;
  • pain or burning during urination,
  • erectile dysfunction;
  • painful ejaculation;
  • blood in urine or semen and/or deep back, hip, pelvic or abdominal pain;
  • other symptoms may include weight loss, bone pain and lower extremity swelling.
• Prostate cancer screening consists of periodic laboratory testing, usually every 1-2 years, which includes a prostate specific antigen (PSA) test and digital rectal examination. Prostate cancer screening is not for everyone and the pros/cons should be discussed with a primary care provider and/or urologist (specialist who treats problems with the urinary system).
• A concern for prostate cancer is raised when blood testing, PSA, is abnormally increased and/or an abnormal area of the prostate is felt on a rectal examination.
• Prostate cancer is definitively diagnosed by removal of small cores of prostate tissue (prostate biopsies), which are then examined under the microscope by a pathologist.
• Treatments for prostate cancer may include observation, active surveillance, surgery (radical prostatectomy), radiation therapy (external beam or placement of radioactive pellets into the prostate), hormone therapy, chemotherapy, immune/vaccine therapy, and other medical therapies that can affect prostate cancer cell growth.
• Prostate cancer is a leading cause of cancer and cancer death in males; in some men, identifying it early may prevent/delay spread and death from prostate cancer.

Prostate cancer is cancer of prostate gland. The prostate gland is a walnut-sized gland present only in men, found in the pelvis below the bladder. The prostate gland wraps around the urethra (the tube through which urine exits the body) and lies in front of the rectum. The prostate gland secretes part of the liquid portion of the semen, or seminal fluid, which carries sperm made by the testes. The fluid is essential to reproduction.

Prostate cancer is one of the most common types of cancer that develops in men and is the third leading cause of cancer deaths in American men, behind lung cancer and colorectal cancer. In 2017, the American Cancer Society estimated that 161,360 men will be newly diagnosed with prostate cancer and 26,730 men will die from the disease -- though many of them had lived with the disease for years prior to their deaths.

Prostate cancer is comprised nearly always of adenocarcinoma cells -- cells that arise from glandular tissue. Cancer cells are named according to the organ in which they originate no matter where in the body we find such cells. Thus, if prostate cancer cells spread in the body to the bones, it is not then called bone cancer. It is prostate cancer metastatic to the bones. Metastasis is the process of cancer spread through the blood or lymphatic system to other organs/areas throughout the body. Prostate cancer more commonly metastasizes to lymph nodes in the pelvis and to the bones.

The exact causes of prostate cancer are not known. Several risk factors for developing prostate cancer have been identified, but which of these risk factors cause a prostate cell to become cancerous is not fully known. For a cancer to develop, changes must occur in the chemicals that make up the DNA, which makes up the genes in the cell. The genes control how the cell works, for example, how quickly the cell grows, divides into new cells, and dies, as well as correcting any mistakes that occur in the DNA of the cell to keep the cell working normally. Cancer occurs when certain genes that either control the growth or death of the cell are affected, which results in abnormal cell growth and/or death. Genes are inherited (passed on from parents to their children) and thus some changes in the genes (gene mutations) that increase the risk of developing cancer may be inherited. For prostate cancer, approximately 5%-10% of prostate cancers are due to inherited gene changes. Several inherited genes have been identified that increase the risk of prostate cancer, including RNASEL, BRCA 1, and BRCA 2, DNA mismatch genes, HPC1, and HoxB13. Kote-Jarai and colleagues identified that men who carry a hereditary mutation in homeobox 13 (HoxB13) have a higher than average risk of developing prostate cancer. In a systematic review and meta-analysis the investigators noted that in these men with the HoxB13 mutation, the risk of prostate cancer is also affected by a family history of prostate cancer and the year of their birth. Gene changes may also be acquired (develop during the course of your life). These changes are not passed on to children. Such changes may occur when a cell normally undergoes growth and division. It is thought that at times during normal cell growth, risk factors may affect the DNA of the cell.

Certain risk factors may predispose a person to prostate cancer. These include the following:

• Age: Sixty percent of cases of prostate cancer arise in men over 65 years of age. The disease is rare in men under 40.
• Race or ethnicity: African-American men and Jamaican men of African ancestry are diagnosed with prostate cancer more often than are men of other races and ethnicities. Asian and Hispanic men are less likely to develop prostate cancer than are non-Hispanic white males.
• Family history: Prostate cancer can run in families. A man whose father or brother (first-degree relative) has or had prostate cancer is twice as likely to develop the disease. The younger the family member is when he is diagnosed with prostate cancer, the higher the risk is for male relatives to develop prostate cancer. The risk of developing prostate cancer also increases with the number of relatives affected.
• Nationality: Prostate cancer is more common in North America, Europe (especially northwestern countries in Europe), the Caribbean, and Australia. It is less common in Asia, Africa, and South and Central America. Multiple factors, such as diet and lifestyle, may account for this.
• Genetic factors: Mutations in a portion of the DNA called the BRCA2 gene can increase a man's risk of getting prostate cancer, as well as other cancers. This same mutation in female family members may increase their risk of developing breast or ovarian cancer. However, very few cases of prostate cancer can be directly attributed to presently identifiable genetic changes. Other inherited genes associated with an increased risk of prostate cancer include RNASEL, BRCA 1, DNA mismatch genes, HPC1, and HoxB13.
• Other factors: High-fat diets (fatty foods) and diets high in red meats and fatty foods and low in fruits and vegetables appear to be associated with a higher risk of developing prostate cancer. Obesity is also linked to a higher risk of the disease. Increased calcium intake and dairy foods may increase the risk of prostate cancer.

Smoking, a history of sexually transmitted diseases, a history of prostatitis (inflammation of the prostate), and a history of vasectomy have not been proven to play a role in causing prostate cancer. The role of fish oil in risk of prostate cancer remains under investigation.

A patient with early prostate cancer is usually asymptomatic. However, prostate cancer symptoms associated with enlargement of the prostate due to prostate cancer, which may occur with early and late stage/advanced stage disease, include the following:

• Frequent urination, during the day and/or at night
• Difficulty in starting (hesitancy), maintaining, or stopping the urine stream
• A weak or interrupted urine stream
• Straining to urinate
• Inability to urinate (urinary retention)
• Loss of control of urination
• Difficulty urinating when standing, requiring sitting during urination
• Pain with urination or ejaculation
• Blood in the urine or in the semen
• Abnormal rectal examination

Many symptoms of early cancer of the prostate can also be attributed to benign (noncancerous) conditions of the prostate, including benign prostatic hypertrophy (BPH), or infection in the prostate gland or urinary system.

Signs and symptoms of advanced prostate cancer (late stage prostate cancer) that has already spread from the prostate gland to elsewhere in the body (called metastatic prostate cancer) include

• a new dull, then progressively severe, pain in the bones, especially the low back;
• unexplained weight loss;
• fatigue;
• increasing shortness of breath while doing activities previously well tolerated;
• low-impact fracture of bone(s) without a lot of trauma (or broken bone[s] from minor trauma); and
• swelling of the legs related to obstruction of the lymph tissue by prostate cancer.

It is always best to find and diagnose prostate cancer at an early stage and hopefully still confined to its site of origin. At that point, treatments can cure it. When prostate cancer is widespread or metastatic, it can be treated, but it cannot be cured.

There are several different types of specialists involved in the identification and treatment of prostate cancer.

1. The primary provider (PCP) may be the initial medical doctor to discuss prostate cancer screening and/or become concerned about the risk of prostate cancer (because of abnormal rectal examination and/or elevated PSA or family history of prostate cancer [brother or father or multiple family members diagnosed with prostate cancer at < 60 years of age]) during your routine evaluations or due to symptoms and refer you to a urologist for further evaluation.
2. Urologists are the specialists who will initially be involved in the diagnosis of prostate cancer and will perform the prostate biopsy. Depending on the grade and stage of the prostate cancer at the time of the diagnosis, additional specialists may be involved in your care. Urologists perform surgical-based treatments for prostate cancer (radical prostatectomy), minimally invasive treatments (cryotherapy, brachytherapy), and prescribe medications (hormonal therapy).
3. Medical oncologists are medical doctors who specialize in the treatment of cancer. Medical oncologists treat prostate cancer with a variety of medical therapies, including chemotherapy, immune/vaccine, and hormonal therapy.
4. Radiation oncologists are specialists who treat cancer with ionizing radiation. This radiation may be given externally (external beam radiation therapy) or internally through the placement of small radioactive pellets into the prostate (brachytherapy).
5. Often urologists, medical oncologists, and radiation oncologists work together in a multidisciplinary team to review your case and you may meet with one, two, or all of these physicians at some point during your prostate cancer treatment.

The diagnosis of prostate cancer ultimately is based on the pathologist's review of tissue removed at the time of the prostate biopsy. An abnormal PSA and/or abnormal digital rectal examination often are present and are the indications for the prostate biopsy.

Digital rectal examination (DRE): As part of a physical examination, your doctor inserts a gloved and lubricated finger into your rectum and feels toward the front of your body. The prostate gland is a walnut or larger sized gland immediately in front of the rectum, and beneath your bladder. The back portion of prostate gland can be felt in this manner. Findings on this exam are compared to notes about the patient's prior digital rectal examinations.

The exam is usually brief, and most find it uncomfortable due to the pressure used to adequately examine the prostate gland. Findings such as abnormal size, lumps, or nodules (hard areas within the prostate) may indicate prostate cancer.

The national comprehensive cancer network (NCCN) notes that a DRE should not be used as a stand-alone test for detection of prostate cancer but should be performed in men with an elevated PSA. The NCCN also notes that DRE may be considered as a baseline test in all patients, as it may help identify high-grade cancers associated with a normal PSA.

Prostate specific antigen (PSA) blood test: The PSA blood test measures the level of a protein found in the blood that is produced by the prostate gland and helps keep semen in liquid form. The PSA test can indicate an increased likelihood of prostate cancer if the PSA is at an increased or elevated level or has changed significantly over time, but it does not provide a definitive diagnosis. Prostate cancer can be found in patients with a low PSA level, but this occurs less than 20% of the time.

If the PSA level is elevated (levels can depend upon your age, on the size of your prostate gland on examination, certain medications you may be taking, or recent sexual activity) or has increased significantly over time, further testing may be needed to rule out prostate cancer.

PSA measurements are often tracked over time to look for evidence of a change. The amount of time it takes for the PSA level to increase is referred to as PSA velocity. The time it takes for the PSA to double, known as the PSA doubling time, can be also tracked. PSA velocity and PSA doubling time can help your doctor determine whether prostate cancer may be present.

The presence of an abnormal result on digital rectal examination, or a new or progressive abnormality in a PSA test may lead to a referral to a physician who specializes in diseases of the urinary system (a urologist) who may perform further testing, such as a biopsy of the prostate gland.

Prostate biopsy: A biopsy refers to a procedure that involves taking of a sample of tissue from an area in the body. Prostate cancer is only definitively diagnosed by finding cancer cells on a biopsy sample taken from the prostate gland.

The urologist may have you stop medications such as blood thinners (for example, warfarin [Coumadin]), aspirin, ibuprofen [Advil, Motrin], and certain herbal supplements) before the biopsy. An antibiotic is often prescribed to help prevent an infection related to the procedure. Some urologists may actually place a small swab into your rectum a week or so prior to the procedure to determine the best antibiotic to give you (selective target antibiotic prophylaxis). You may be asked to do a cleansing enema at home before the biopsy appointment and will be instructed to take the antibiotic 30 to 60 minutes prior to the biopsy to prevent an infection. On the day of the biopsy, the doctor will apply a local anesthetic by injection or topically as a gel inside the rectum over the area of prostate gland. You will be asked to lie on your side with your knees pulled up to your chest. Sometimes you may be asked to lie on your stomach. An ultrasound probe is then placed in the rectum. This device uses sound waves to take a picture of the prostate gland and helps guide the biopsy device. The device used is a spring-loaded needle that allows the urologist to remove tiny cores of tissue from the prostate gland. Usually, 12 cores are obtained, six from each side. Two cores are taken from the upper, middle, and lower portions of each side of the prostate gland. The cores are examined under the microscope by a pathologist (a doctor who specializes in examining tissues to make a diagnosis). Results may take several days.

If you do not have an anus (due to previous surgery), then transperineal prostate biopsy is performed. During this procedure, which is often performed under sedation, the biopsy needle is inserted through the perineum (area between the scrotum and the anus) into the prostate.

A biopsy procedure is usually uncomplicated, with just some numbness, pain, or tenderness in the area for a short time afterward. Occasionally, a patient has some blood in the urine, stool, or the ejaculate after the procedure. Rarely, the patient may develop an infection after a biopsy procedure (urinary tract infection, prostate infection, testis infection) or be unable to urinate. If one develops a fever after the procedure, has continued blood in the urine or ejaculate, or has troubles urinating, further evaluation by the performing doctor is needed.

The result of the pathologist's analysis of the biopsy cores under the microscope is the only way to diagnose prostate cancer. The prostate biopsy technique samples many areas of the prostate but rarely the biopsy can miss small areas of prostate cancer in the prostate. Thus, if the initial biopsy results are negative but the urologist is still suspicious based on the results of the examination, the ultrasound images seen during the procedure, or the PSA, additional biopsies or tests may be recommended.

The pathologist's report on the biopsy sample showing prostate cancer will contain much detailed information. The size of the biopsy core and the percentage of involvement of each core will be reported. Most importantly the prostate cancer present will be assigned a numerical score, which is usually expressed as a sum of two numbers (for example, 3 + 4) and is referred to as the Gleason Score. This characterizes the appearance of the cancer cells and helps predict its likely level of aggressiveness in the body. A Gleason score of 6 or less indicates a low grade prostate cancer, whereas scores of 8-10 indicate a high-grade prostate cancer. A new prostate cancer grading system was developed in 2014 to help assess risk and assign a Gleason grade group. This grade group is particularly useful in Gleason score 7, where the predominant cell type could be a 4 or a 3, which may impact prostate cancer risk.

• Gleason grade group 1: Gleason score < 6
• Gleason grade group 2: Gleason score 3+4= 7
• Gleason grade group 3: Gleason score 4+3 = 7
• Gleason grade group 4: Gleason 4+4 =8, 3+5 = 8 and 5+3 = 8
• Gleason grade group 5: Gleason score 9 and 10

The Gleason score and the extent of involvement of the biopsy core expressed as a percentage, as well as the PSA level as well as your general state of health and otherwise estimated life expectancy, all help to allow doctors to make their best recommendations for you regarding how your cancer should be treated.

The PSA test is a tool for use by your doctor, but it is not a perfect way to tell whether or not a patient has prostate cancer because is not sensitive enough to pick up all prostate cancers. It is not specific enough in that it may be elevated in people without prostate cancer, such as those whose prostate glands are infected, inflamed, or enlarged but not cancerous. The PSA level can be affected by medications used to treat benign enlargement of the prostate (BPH), 5 alpha reductase inhibitors (finasteride, dutasteride), which lower the PSA by approximately 50% within 6 months to a year of being on this medication. It is also elevated for several days after a digital rectal exam or after ejaculation. Nevertheless, it accurately measures the amount of PSA in the blood at the time that it is drawn. Once a single PSA test has been obtained, the level of the PSA on follow-up tests is not as important as the rate of change of the PSA (how quickly it is increasing).

The interpretation of the PSA result must be done with care. PSA results must be, for example, interpreted in the context of the patient's age. Younger men (under 70 years of age and definitely under 60 years of age) may have either more aggressive prostate cancers or live long enough to experience the adverse effects of undetected/untreated prostate cancer. Conversely, men over 70 often have more indolent or slow-growing prostate cancers or other medical conditions that may be greater threats to their lives over the next 10 years than may prostate cancer, and thus less aggressive evaluation and treatment may be warranted.

Prostate cancer risk increases as men age. It is estimated 16% of men will be diagnosed with prostate cancer in their lifetime, and yet only 3% will die of it. Many men likely have small prostate cancers present by the time they are over 60 years of age, with estimates ranging from 30%-40% having prostate cancer cells in their prostates. The risk of developing these small cancers also likely further increases with age. Most of these cancers are not life threatening. They are very slow-growing and not aggressive in their tendency to spread as they are never discovered or symptomatic during the men's lives. Diagnosing these prostate cancers may only increase the cost and result in treatment-related complications in these men.

Talk to your doctor about the risks and benefits of prostate cancer screening and having PSA testing if you are 40 years of age with a family history of prostate cancer (or age 50 if you do not have a family history), or are of African-American ancestry. The test results should be considered in the context of the prostate size, family history of prostate cancer, race and ethnicity, and rectal examination findings. Further there should be attention given to the pattern of change in his serial PSA measurements.

Numerous different ways to refine the use of PSA testing have been attempted. Some of these include evaluations of the

• PSA doubling time, which refers to how long it has taken for the PSA to double;
• PSA velocity, which looks at how rapidly the PSA values have changed over time;
• PSA density, which looks at the PSA result and considers the prostate gland volume as determined on ultrasound evaluation; and
• PSA fractionation, which is another test that measures the amount of free PSA versus protein-bound PSA in the bloodstream. The lower the percentage of free PSA, the higher the risk of cancer.

In prostate cancer patients whose PSA was initially elevated, the PSA is an excellent tool to assist in decisions about care and in follow-up both during and after treatment.

Other tests that may help evaluate risk for prostate cancer and need for biopsy are used to decide treatment.

Several prostate cancer risk calculators have been developed to help determine the risk of having prostate cancer using multiple factors. Some of these risk calculators include Sunnybrook-, ERSPC-, and PCPT-based risk calculators. The calculators determine the risk of having prostate cancer on biopsy by combining several factors including age, family history of prostate cancer, race, DRE, and PSA. These calculators may help determine the need for biopsy but should be used in conjunction with your doctor's clinical judgment and patient preferences.

The use of MRI (magnetic resonance imaging), multiparametric MRI, to select individuals who need a prostate biopsy or to guide needle placement during the biopsy, is controversial. Currently, the NCCN does not recommend that MRI alone should be used to decide whether a biopsy should be performed and notes that a negative MRI does not indicate that a biopsy should be deferred in a man with indications for a first-time biopsy. The NCCN also doesn't uniformly support the use of this study to direct prostate biopsy needle placement at this time.

Biomarkers have been developed to help define the probability of prostate cancer prior to proceeding to biopsy. The goals of the biomarker tests are to decrease the risk of unnecessary biopsies and increase the likelihood of cancer detection without missing a significant number of prostate cancers. The biomarker tests may be most useful in men with PSA levels between 3 and 10 ng/mL. Currently, the NCCN recommends consideration of percent free PSA (%fPSA), Prostate Health Index (PHI), and 4Kscore in patients with PSA levels > 3 ng/mL who have not had an initial prostate biopsy. For individuals who have had at least one negative prostate biopsy but who are thought to be at higher risk for prostate cancer (increasing PSA), the NCCN recommends %fPSA, PHI, 4Kscore, PCA3, and ConfirmMDx. Select MDx is a biomarker that can be obtained prior to initial biopsy and after negative biopsy. At present, no test has been established to be superior to another. Prior to having such studies done, it is advisable to ensure that your insurance company covers these tests.

The term to stage a cancer means to describe the evident extent of the cancer in the body at the time that the cancer is first diagnosed. Clinical staging of prostate cancer is based on the pathology results, physical examination, PSA, and if appropriate, radiologic studies. The stage of a cancer helps doctors understand the extent of the cancer and plan cancer treatment. Results of the treatment of similar Gleason score prostate cancer found at the same or similar stage can help the doctor and patient to make important decisions about choices of treatment to recommend or to accept.

Cancer staging is first described using what is called a TNM system. The "T" refers to a description of the size or extent of the primary, or original, tumor. "N" describes the presence or absence of, and extent of spread of the cancer to lymph nodes that may be nearby or further from the original tumor. "M" describes the presence or absence of metastases -- usually distant areas elsewhere in the body other than regional (nearby) lymph nodes to which the cancer has spread. Cancers with specific TNM characteristics are then grouped into stages, and the stages are then assigned Roman numerals with the numerals used in increasing order as the extent of the cancer being staged increases or the cancer prognosis worsens. Prognosis is finally reflected by considering the patient's PSA score at presentation as well as their Gleason score in assigning a final stage designation.

The American Joint Commission on Cancer (AJCC) system for prostate cancer staging is as follows:

T designations refer to the characteristics of the prostate cancer primary tumor.

T1 prostate cancers cannot be seen on imaging tests or felt on examination. They may be found incidentally when surgery is done on the prostate for a problem presumed to be benign, or on needle biopsy for an elevated PSA.

• T1a means that the cancer cells comprise less than 5% of the tissue removed.
• T1b means that cancer cells comprise more than 5% of the tissue removed.
• T1c means that the tissue containing cancer was obtained by needle biopsy for an elevated PSA.

T2 prostate cancers are those that can felt (palpated) on physical examination of the prostate gland (on digital rectal exam) or that can be visualized with imaging studies such as ultrasound, X-ray, or related studies. The prostate gland is comprised of two halves or lobes. The extent of involvement of those lobes is described here.

• T2a means the cancer involves one half of one lobe of the prostate or less.
• T2b means the cancer involves more than half of one lobe but does not involve the other lobe of the prostate.
• T2c means that the cancer has grown into or involves both lobes of the prostate.

T3 prostate cancers have grown to the extent that the tumor extends outside of the prostate gland. Adjacent tissues, including the capsule around the prostate gland, the seminal vesicles, as well as the bladder neck, may be involved in T3 tumors.

• T3a means that the cancer has extended beyond the capsule (the outer edge) of the prostate gland but not into the seminal vesicles.
• T3b means that the cancer has invaded into the seminal vesicles.

T4 prostate cancers have spread outside of the prostate gland and have invaded adjacent tissues or organs. This may be determined by examination, biopsy, or imaging studies. T4 prostate cancer may involve the pelvic floor muscles, the urethral sphincter, the bladder itself, the rectum, or the levator muscles or the pelvic wall. T4 tumors have become fixed to or invaded adjacent structures other than the seminal vesicles.

Traditionally, advanced prostate cancer was defined as disease that had widely metastasized beyond the prostate, the surrounding tissue, and the pelvic lymph nodes and was incurable. However, a more contemporary definition includes patients with lower grade disease with an increased risk of progression and/or death from prostate cancer in addition to those with widely metastatic disease.

The NCCN guidelines prostate cancer version 2.2017 indicate the following:

CT scan is used for the initial staging in select patients including

• T3 or T4 disease, and
• T1 or T2 disease and nomogram probability of lymph node involvement > 10% may be candidates for pelvic CT. A nomogram is a predictive tool that takes a set of information (data) and makes a prediction about outcomes.

Standard MRI techniques can be considered for the initial evaluation of high-risk patients including

• T3 or T4 disease, and
• T1 or T2 disease and nomogram indicating probability of lymph node involvement > 10% may be candidates for pelvic MRI.

Bone scan is recommended in the initial evaluation of patients at high risk for skeletal metastases including

• T1 disease with PSA > 20, T2 disease and PSA > 10, Gleason score > 8 or T3/T4 disease; and
• any stage disease with symptoms of bone metastases (for example, bone pain).

N designations refer to the presence or absence of prostate cancer in nearby lymph nodes, including what are referred to as the hypogastric, obturator, internal and external iliac, and sacral nodes.

• N0 means that there is no prostate cancer evident in the nearby nodes.
• N1 means that there is evidence of prostate cancer in the nearby nodes.
• NX means that the lymph nodes cannot or have not been assessed.

M refers to the presence or absence of prostate cancer cells in distant lymph nodes or other organs. Prostate cancer that has spread through the bloodstream most often first spreads into the bones, then into the lungs and liver.

• M0 means that there is no evidence of spread of prostate cancer into distant tissues or organs.
• M1a means that there is spread of prostate cancer into distant lymph nodes.
• M1b means that there is evidence that prostate cancer has spread into bones.
• M1c means that prostate cancer has spread into other distant organs in addition to or instead of into the bones.

Stratifying prostate cancer by risk

The NCCN guidelines stratify prostate cancer by risk. The risk groups are based on the staging of the prostate cancer, the Gleason score, PSA, and number and extent of biopsy cores positive for cancer. The risk stratification may help decide what treatment option is best for each individual.

Very low risk: stage T1c, Gleason score ≤ 6, Gleason grade group 1, PSA < 10 ng/mL, < 3 prostate biopsy cores positive for cancer, < 50% cancer in any core, PSA density < 0.15 ng/mL/g

Low risk: stage T1-T2a, Gleason score ≤ 6, Gleason grade group 1, PSA < 10 ng/mL

Intermediate risk: stage T2b-T2c, Gleason score 3+4 = 7, Gleason grade group 2 or Gleason score 4+3=7, Gleason grade group 3, or PSA 10-20 ng/mL

High risk: stage T3a or Gleason score 8, Gleason grade group 4, or Gleason 9-10, Gleason grade group 5, PSA > 20 ng/mL

Very high risk: stage T3b-T4, primary Gleason pattern 5, Gleason grade group 5 or > 4 cores with Gleason 8-10, Gleason grade group 4-5

Treatment options for prostate cancer are many, and while this is an advantage in that prostate cancer is such a common disease in men, it can also be a cause of great confusion. The following overview presents some information about these options, but it is not a complete explanation of any of these. You can find more information on treatment options in the NCCN Clinical Practice Guideline for Patients on Prostate Cancer for 2017 and the Physician Data Query (PDQ) web site of the National Cancer Institute, as well as information from the American Urological Association, and the American Cancer Society.

Several new biomarkers have been developed in an effort to improve decision making in men considering active surveillance and in treated men considering adjuvant therapy or treatment of recurrence. These include Oncotype DX, Prolaris, and ELAVL1.

The NCCN treatment recommendations based on risk stratification are as follows:

Very low risk

• Life expectancy < 10 years -- observation
• Life expectancy 10-20 years -- active surveillance
• Life expectancy > 20 years -- active surveillance, EBRT, brachytherapy, or RRPX

Low risk

• Life expectancy < 10 years -- observation
• Life expectancy > 10 years -- active surveillance, EBRT, brachytherapy, or RRPX

Intermediate risk

• Life expectancy < 10 years -- observation; EBRT +/- ADT (4-6 months), +/- brachytherapy; brachytherapy
• Life expectancy > 10 years -- RRPX +/- lymph node dissection EBRT +/- ADT (4-6 months) +/- brachytherapy; brachytherapy

High risk

• EBRT + ADT (2-3 years); EBRT + brachytherapy +/- ADT; RRPX in select individuals

Very high risk

• EBRT + long-term ADT; EBRT + brachytherapy +/- long-term ADT; RRPX + lymph node dissection ADT or observation in select patients

Conventional medical treatment options for prostate cancer include the following:

• Observation
• Active surveillance
• Surgery (radical prostatectomy: open, laparoscopic, robotic, perineal)
• Radiation therapy (external beam therapy and brachytherapy)
• Focal therapy, including cryotherapy
• Hormonal therapy
• Chemotherapy
• Immunotherapy/vaccine and other targeted therapies
• Bone-directed therapy (bisphosphonates and denosumab)
• Radiopharmaceuticals (radioactive substances used as drugs)
• Research techniques including high-intensity focused ultrasound (HIFU) and others

These two options are not the same. Both observation and active surveillance therapies share in common the decision up front to hold on treatment of the cancer and to follow the cancer periodically to determine if there is progression. Observation involves monitoring the course of the prostate cancer with the goal of treating the cancer with palliative care for the development of symptoms or changes in physical examination or PSA that suggest that symptoms will develop soon. Observation treatment is not trying to cure the cancer, rather to treat symptoms of cancer progression. Thus, observation treatment is preferred for men with low-risk prostate cancer and with a life expectancy of less than 10 years.

Active surveillance involves actively monitoring the course of the prostate cancer with the intent to intervene, with the intention to cure if the cancer appears to be progressing. Active surveillance is preferred for men with very low risk prostate cancer and a life expectancy of < 20 years. Cancer progression may have occurred if a repeat biopsy shows a high Gleason score (Gleason 4 or 5) or if cancer is found in a greater number of the biopsies or a greater extent of the core compared to prior biopsy.

The NCCN guidelines for prostate cancer (version 2.2017) note the following for active surveillance for prostate cancer:

1. The PSA test should be obtained no more than every 6 months unless clinical changes support more frequent testing.
2. A DRE should be performed no more than every 12 months unless clinical changes support more frequent examination.
3. A repeat prostate biopsy should be done within 6 months if the initial biopsy removed less than 10 cores or the examination findings were not consistent with the biopsy results.
4. A repeat biopsy should be considered as frequently as every year to assess for progression of the cancer.
5. If one's life expectancy is less than 10 years, then repeat biopsy is not needed.
6. If the PSA is rising and biopsy is negative, consider multiparametric MRI.

Active surveillance has advantages and disadvantages: From an advantage standpoint, it avoids unnecessary treatment and possible side effects of such treatments. Disadvantages of active surveillance include the risk of missed opportunity for cure, although the risk of this is very low if you are followed regularly, and the need for periodic prostate biopsies and the side effects of prostate biopsy.

Observation has advantages and disadvantages. From an advantage standpoint, observation avoids/delays the possible side effects of treatment. There is, however, the risk of troubles urinating (urinary retention) or bone fractures occurring before treatment is started.

As reported in the journal European Urology, Dr. Lu-Yao and colleagues performed a population-based cohort study that included 31,137 Medicare patients 65 years of age and older diagnosed with localized prostate cancer in 1992-2009 who initially received conservative management (no surgery, radiotherapy, cryotherapy, or androgen-deprivation therapy) who were followed until death or Dec. 31, 2009 (for prostate cancer specific mortality), and Dec. 31, 2011, for overall mortality and found that the 15-year outcomes with conservative management of newly diagnosed T1c Gleason 5-7 prostate cancer for men 65 years of age and older were excellent (15-year risk of prostate cancer specific mortality of 5.7%), whereas in men with T1c Gleason 8-10 prostate cancer there was a significant risk of prostatic cancer risk mortality (22%).

The removal of the entire prostate gland and the urethra that runs through the prostate and the attached seminal vesicles is referred to as a radical prostatectomy. A variety of approaches are available for performing this procedure. The type of approach may vary with your surgeon's preference, your physique, and medical conditions. Traditionally, radical prostatectomy was performed through an incision that extended from below the belly button (umbilicus) down to the pubic bone or through an incision underneath the scrotum (perineal approach). In an effort to decrease the morbidity of the procedure, laparoscopic approaches to performing a radical prostatectomy were developed. The use of the robot to perform the laparoscopic radical prostatectomy, robotic-assisted radical prostatectomy, is currently the most common method to perform a radical prostatectomy. Compared to open radical prostatectomy, robot assisted laparoscopic radical prostatectomy is associated with less postoperative discomfort and sooner return to full activity, as well as less intraoperative blood loss with comparable outcomes regarding urinary continence, erectile function. Radical prostatectomy is an appropriate treatment option for those individuals with clinically localized prostate cancer that can be removed completely surgically and who have a life expectancy of 10 or more years and have no medical contraindications to surgery.

In some men, a pelvic lymph node dissection may be recommended depending on the Gleason score, PSA, and radiologic findings. This involves removing lymph nodes in the pelvis that are common sites for prostate cancer to spread. This may be performed at the time of the radical prostatectomy or rarely as a separate procedure prior to definitive therapy.

Side effects of radical prostatectomy may have a significant impact on quality of life. Thus, it is essential that you discuss with your surgeon prior to the surgery the risk of such side effects occurring, as well as treatments that can occur after surgery to treat such sides effects.

Erectile dysfunction is a side effect of radical prostatectomy. The risk of developing erectile dysfunction varies with your age, erectile function status prior to surgery, and the need to remove one, both, or neither of the pelvic nerve bundles during the radical prostatectomy. The pelvic nerve bundles lie on either side of the prostate, just outside the capsule or outer edge of the prostate. The pelvic nerve bundles are involved in the erectile process, the ability to have an erection. Impotence -- or the inability to have and sustain an erection of a quality sufficient for successful intercourse -- can occur after radical prostatectomy due to trauma, damage, or removal of the pelvic nerve bundles. Nerve-sparing radical prostatectomy can be performed in select individuals with lower risk prostate cancer. Even after nerve-sparing radical prostatectomy, one may experience transient erectile troubles related to reversible trauma to the nerves during surgery. Specialists treating erectile dysfunction may recommend penile rehabilitation therapy in hopes of helping the nerves recover their function better and faster after radical prostatectomy.

Urinary incontinence is another risk after radical prostatectomy. The radical prostatectomy involves the removal of a portion of the urethra, which passes through the prostate gland. During the procedure, the urethra is sewn back to the bladder. When the prostate gland is removed, there may be some trauma to the sphincter around the urethra, which helps prevent leakage of urine. As with the risk of erectile troubles, the risk of incontinence may vary with your continence status prior to surgery, whether or not you have had prior surgery on the prostate (transurethral prostatectomy [TURP]) and the function of your sphincter muscle prior to surgery.

Both erectile dysfunction and urinary incontinence are treatable conditions. The treatment for either may involve medical and/or surgical therapies. You should discuss such risks and the treatment of these with your surgeon prior to surgery.

Other risks of radical prostatectomy include infection, bleeding, discomfort, and blood clots (deep venous thrombosis [DVT]) and rarely death. To help prevent a DVT, you may be asked to wear special compression devices on your legs or be administered a blood thinner.

Radical prostatectomy is rarely performed as a salvage procedure after other primary therapy, such as radiation therapy, has failed. The risk of complications, such as, erectile dysfunction, incontinence, bleeding, and stricture, are greater with salvage therapy.

Radiation therapy as with surgical therapy is a potentially curative treatment that uses radiation to kill cancer cells. Radiation therapy can be performed via external beam therapy (EBRT) or the placement of radioactive seeds into the prostate (prostate brachytherapy).

EBRT

An X-ray machine uses a low energy radiation beam to take a picture of a portion of the body. Radiation therapy machines put out high energy beams that can be focused very precisely to deliver treatment to a site. The radiation does not "burn out" the cancer, but damages the cells' DNA, which causes the cancer cells to die. This process can take some time to occur after the radiation treatments have been given.

The radiation passes directly through the tissues in EBRT. Radiation treatment used today delivers very little energy to normal tissues. It just passes through. Most of the energy is able to be focused and delivered directly to the area of the prostate gland containing cancer. This process minimizes damage to healthy tissue.

EBRT can be administered in a variety of different ways including 3-D CRT, IMRT, and others. EBRT is classically administered in brief daily treatments, 5 days a week over several weeks. While the radiation does not remain in the body with this approach, the effect of the daily fractions is cumulative. Newer forms of EBRT using machines called CyberKnife allow the treatment to be completed in shorter periods of time.

A recently popular technique of EBRT is called proton beam radiation, which can theoretically more closely focus on the area being treated. Proton beam radiation therapy is more expensive. Its side effects presently appear similar to those discussed for standard radiation therapy, except for an increased incidence of gastrointestinal side effects with Proton beam radiation. Studies comparing the effectiveness and overall results of conventional radiation therapy versus proton beam therapy have not been completed yet.

Radiation therapy to the prostate gland by external beam technique may cause fatigue and bladder and/or rectal irritation. One may experience frequency of urination or stools and blood in the urine or stools. These effects are usually temporary but may recur or persist long after treatments are finished. Radiation damage to adjacent tissues can cause skin irritation and local hair loss. Delayed onset of impotence can occur after radiation therapy due to its effect on normal tissues, including nerves adjacent to the prostate. Radiation therapy may be given alone or in combination with hormonal therapy, which can also shrink up the prostate gland, thereby reducing the size of the radiation area or field that needs to be treated. The NCCN guidelines recommend that patients with high-risk and very-high-risk prostate cancer receive neoadjuvant/concomitant/adjuvant hormone therapy (androgen deprivation therapy [ADT]) for a total of 2-3 years if the overall health of the patient permits and that patients with intermediate-risk prostate cancer be considered for 4-6 months of neoadjuvant/concomitant/adjuvant hormone therapy (ADT). Pelvic lymph node radiation may be considered for high-risk and very high-risk prostate cancer patients. Patients with low-risk prostate cancers should not receive ADT or lymph node radiation.

EBRT is appropriate for men who are candidates for radical prostatectomy but do not wish to undergo the surgery or who are not ideal surgical candidates.

EBRT may also be used to treat recurrent prostate cancer localized to the prostate bed (where the prostate was before it was removed surgically). It is also used to treat bone metastases (spread of the prostate cancer to the bone) to reduce pain or if the cancer is pressing on important structures, including the spinal cord.

Brachytherapy refers to the use of radiation sources -- sometimes referred to as seeds -- placed into the prostate gland. Brachytherapy may be done with what is called low-dose rate (LDR) or high-dose rated (HDR) technique. In LDR brachytherapy, types of radioactive seeds, which only briefly put out a form of radiation that does not travel very far through tissues, are permanently implanted in the prostate gland. High-dose rate (HDR) brachytherapy involves the temporary placement of different types of seeds or sources that give off higher amounts of more penetrating radiation. These seeds administer higher doses of radiation for longer periods of time and cannot be left in the body. Such sources are placed in the prostate gland through surgically implanted tubes. These HDR sources are removed along with the tubes in a couple of days. In LDR brachytherapy, the seeds are placed in the operating room using image guidance to ensure the seeds go into the right places -- 40-100 seeds may be placed. With LDR, you can go home shortly after you wake up after the procedure. In HDR, you must stay at the hospital for a few days. If the prostate gland is large, hormonal treatment (ADT) may be used to shrink the gland before the brachytherapy is done. Brachytherapy may also be combined with external beam radiation therapy to further increase the dose of radiation therapy given to the prostate gland.

Brachytherapy can cause some blood in the urine or semen. It can cause a feeling similar to constipation due to the swelling of the prostate gland. One can also experience transient troubles urinating, called urinary retention, related to swelling of the prostate gland, that may require short-term catheter placement. It can also make you feel that you want to move your bowels more often. There may be some long-term problems with irritation of the rectum, difficulty urinating due to scar tissue formation, and even delayed-onset impotence.

The NCCN guidelines version 2.2017 indicate that brachytherapy can be used as a single therapy (monotherapy) in patients with low-risk cancers and select individuals with low-volume intermediate risk cancers. Intermediate-risk prostate cancers can be treated by a combination of brachytherapy and EBRT +/- 4-6 months of neoadjuvant, concomitant/adjuvant ADT.

High-risk patients can be treated with a combination of EBRT and brachytherapy +/- 2-3 years of neoadjuvant/concomitant/adjuvant ADT.

Patients with a very large prostate or very small prostate, those with symptoms of bladder outlet obstruction, or who have had a previous transurethral resection of the prostate (TURP) are more difficult to treat and have a greater risk of side effects.

Brachytherapy can be used as a salvage therapy for recurrent/persistent prostate cancer after external beam radiation therapy (EBRT). The risk of side effects is increased when used as a salvage therapy.

Focal therapy involves ablation of the prostate cancer within the prostate with preservation of the surrounding healthy tissue. A number of focal therapies are being investigated, and a comparison of the efficacy of each of these therapies cannot be made given the limited data on many of these therapies. Focal therapies being investigated include cryotherapy, high-intensity focused ultrasound, laser ablation, photodynamic therapy, irreversible electroporation, radiofrequency ablation, and focal brachytherapy. As many of these are considered experimental, only cryotherapy will be briefly reviewed.

Cryotherapy is a minimally invasive therapy that damages tissue by local freezing.

Cryotherapy is most frequently used as a salvage treatment after failure of radiation therapy. As an outpatient, hollow needles are placed into the prostate through the perineum (the space between the scrotal sac and the anus) under image guidance. A gas is passed through the needles to freeze the prostate. Warm liquid is passed through the urethra at the same time to protect it. The needles are removed after the procedure. While potentially effective for local control of cancer in the prostate gland, the side effects can be significant and include pain and the inability to urinate. Potential long-term effects include tissue damage in needle-insertion areas, impotence, and incontinence. Cryotherapy is not currently recommend as a primary treatment for management of prostate cancer.

Prostate cancer is highly sensitive to and dependent on the level of the male hormone testosterone, which drives the growth of prostate cancer cells in all but the very high-grade or poorly-differentiated forms of prostate cancer. Testosterone belongs to a family of hormones called androgens, and today front-line hormonal therapy for advanced and metastatic prostate cancer is called androgen deprivation therapy (ADT).

In the past, this was accomplished by surgical castration called bilateral orchiectomy. In that procedure, the testes were both removed. Today, doctors can block the function of the testes in a controllable and most often reversible fashion with drugs that prevent the production of testosterone (medical castration). These agents can result in shrinkage of the prostate gland, can stop prostate cancer cells from growing for up to several years, and can relieve pain caused by prostate cancer that has spread or metastasized into the bones by shrinking the cancer. The use of ADT does not produce a cure. Over time, the prostate cancer cells will develop an ability to grow despite the lack of hormones (castrate resistance). Another form of hormonal therapy is the use of androgen receptor blockers; these medications prevent testosterone from attaching (binding) to the prostate cancer cell and being absorbed into the cell where it can help the cell survive and grow.

Hormonal treatment today is primarily used in the treatment of locally advanced and metastatic prostate cancer. It may be used in conjunction with primary curative therapies (surgical and radiation based) to shrink the cancer/prostate to increase the likelihood of cure of the treatment, neoadjuvant therapy, and with radiation therapy for several years after treatment (adjuvant therapy). However, the primary role of ADT is in the treatment of widespread or metastatic prostate cancer. While it is not a curative treatment in that setting, it can both reduce symptoms and slow down the growth of the prostate cancer to prolong life.

Today medicines used to block testosterone production by the testes include:

• LH-RH agonists: Leuprolide (Lupron), goserelin (Zoladex), histrelin (Supprelin LA), and triptorelin (Trelstar) are examples of these mediations. These are either given by injection into the muscle or under the skin at varying intervals of at least 1 month or longer.
• LH-RH antagonists: Degarelix (Firmagon) is a monthly injection that is given under the skin.

Medications that block the action of testosterone include the androgen receptor blockers

• Flutamide (Eulexin), bicalutamide (Casodex), nilutamide (Nilandron), and an even more effective form called enzalutamide (Xtandi): Xtandi is recommended for use only in individuals with castrate-resistant prostate cancer (prostate cancer that is refractory to traditional ADT), including those with and without metastases. Xtandi is different than the other androgen receptor blockers in that it has three mechanisms of action: (1) It prevents androgens (testosterone) from binding to the androgen receptor, (2) it prevents the androgen receptor from moving into the central area (nucleus) of the cell, and (3) it prevents binding of the androgen receptor to DNA and stimulating growth. The most common side effects of Xtandi include fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, swelling of the legs, shortness of breath with exertion, headache, hypertension, dizziness, and weight loss. Less commonly, seizures and posterior reversible encephalopathy syndrome characterized by seizure, headache, lethargy, confusion, and blindness may occur. A newer androgen receptor blocker with a similar mechanism of action as Xtandi, apalutamide (Erleada), is indicated for use in men with nonmetastatic castrate resistant prostate cancer.

Both surgical and medical castration result in impotence. They also can cause hot flashes, fatigue, anemia, and thinning of the bones (osteoporosis) over time. These drugs may be given individually or combined with an androgen receptor blocker in what is called a combined androgen blockade.

Other hormonal treatment options include:

• Estrogen: This female hormone has been utilized in the treatment of prostate cancer as it also results in medical castration. Its mechanism of action remains under study, and its association with a high risk of heart attack and blood clots when used in high doses has diminished the frequency of its use, particularly in front-line therapy. Other side effects include breast enlargement/pain (gynecomastia). Estrogen and related drugs may still have a role in the treatment of metastatic prostate cancer in select individuals.
• Adrenal androgen synthesis inhibitors: The adrenal glands, a pair of small glands that are located above the kidneys, also produce a small amount of testosterone. Individuals on traditional ADT have testicular production of testosterone suppressed but still may have testosterone production from the adrenal glands. In individuals on ADT who have continued growth of the prostate cancer (rising PSA), the use of adrenal androgen synthesis inhibitors may be useful. This group includes a drug called ketoconazole, which was primarily developed to treat fungal infections, but has shown to be effective in the treatment of prostate cancer. More recently, an agent called abiraterone acetate (Zytiga) has been developed. It has a similar effect on androgen synthesis, but it is more powerful than an older agent called ketoconazole (Nizoral) and has fewer side effects. The use of Zytiga in combination with prednisone is considered in individuals failing traditional ADT and individuals who have castrate-resistant prostate cancer (failed first-line ADT). More common side effects of Zytiga include fatigue, back or joint discomfort, peripheral edema, diarrhea, nausea, constipation, and low potassium levels. Blood pressure, liver tests, potassium, and phosphate levels should be monitored regularly when initially using Zytiga.
• Steroids: These agents including prednisone may have beneficial hormonal effects in prostate cancer, including slowing the production of androgen by the adrenal glands. They often make the patient feel better, but have many side effects including inducing or worsening diabetes, fluid retention, cataract formation, weight gain, and osteoporosis.
• Agents that block the conversion of testosterone to its active metabolite: Finasteride (Proscar) and dutasteride (Avodart) are not approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer, however, they have been used (off-label) in treating prostate cancer by preventing the conversion of testosterone to its active metabolite called DHT (dihydrotestosterone). These drugs are frequently utilized for the symptoms of prostate enlargement in men without prostate cancer and appear to reduce the risk of development of prostate cancer. Their side effects are limited. They are used in combination with other agents to optimize androgen blockade. As these medications are not currently approved for use in men with prostate cancer, consult with your physician and insurance provider to ensure that their use is medically appropriate and will be covered.

Chemotherapy or "chemo" for prostate cancer involves the use of medications either in pill form or by injection into the veins, which can kill or at least slow the growth of metastatic prostate cancer cells. It does not presently have a role in the treatment of early stage prostate cancer except as part of clinical trials/research studies. The use of chemotherapy in metastatic prostate cancer is presently not a potentially curative treatment, but it can relieve symptoms of prostate cancer, and can prolong life. It is usually used in the setting of CRPC, castration- (medical or surgical) resistant prostate cancer.

Chemotherapy drugs work in many different ways. These drugs may damage the DNA of the cancer cells or disrupt the cells ability to divide (mitosis). These effects can cause cells to die. Not all prostate cancer cells may be sensitive to these drugs, but some may be. A tumor (a mass of cancer cells) will shrink if more cells are killed and removed than continue to grow and divide. As many normal tissues in the body also undergo the same patterns of growth and mitosis, these drugs have numerous side effects due to their effects on normal tissues.

Active chemotherapy drugs for the treatment of prostate cancer today include:

• Taxotere (Docetaxel) -- first-line chemotherapy option
• Carbazitaxel (Jevtana) -- option in individuals who have failed docetaxel
• Mitoxantrone (Novantrone)

Although traditionally recommended for men with castrate-resistant prostate cancer, the NCCN recommended the use of docetaxel in combination with ADT and EBRT in men with high- and very-high-risk localized prostate cancer.

When these types of drugs are given to patients with prostate cancer they can help reduce pain and shrink tumors. Patients who respond to these drugs often live longer than those who do not respond.

The immune system works by trying to very specifically target infections or to attack and kill cells which are either cancerous or are not our own. The immune system attempts to eliminate these invading problems using antibodies and cells called T-lymphocytes; in cases of cancer the immune system still struggles to control the problem for many reasons. The cancer seems often to either depress or overwhelm the immune system. Immune therapies (immunotherapy) attempt to boost the capability of our immune system.

Provenge (Sipuleucel-T) is a form of immunotherapy, a vaccine therapy, used to treat prostate cancer that has metastasized. It is appropriate in patients whose cancer is no longer responding to hormonal therapy but who are asymptomatic or minimally symptomatic. These patients may be showing a rise in PSA level after previous hormonal treatment has kept the PSA down for a long time.

Provenge therapy involves taking some of your own blood cells and growing them outside the body in the presence of a substance that is specific for prostate cancer. The cells are then given back to you by infusing them into the bloodstream. These cells can attack prostate cancer cells, and can help program other blood cells to do the same. Such treatment causes few side effects, including mild to moderate chills, fever, and headache, and can prolong survival by several months.

Bone health is an essential component of prostate cancer treatment. Both the disease itself, as well as the treatment of the disease with androgen deprivation therapy, can have a significant impact on bone health. Several bone-targeted therapies have been approved.

The bisphosphonates are a group of drugs used to treat several conditions people can get including osteopenia and osteoporosis. They also can lower elevated blood levels of calcium in people with cancer. They work by affecting cells in the bones called osteoclasts, which work to remove bone. These drugs encourage the death of the osteoclasts. In prostate cancer they impact the course of skeletal-related events including reducing pain in the bones, and delaying the progression of bone metastases associated problems including the appearance of fractures (breaks in bones). While the bisphosphonates can affect the growth of prostate cells in the laboratory, they are presently not considered a targeted or direct-acting drug like a chemotherapy or hormonal treatment. They have also not been shown to prevent the appearance of bone metastases in prostate cancer patients. Nonetheless, they are an important part of the treatment of prostate cancer patients with bone metastases.

The most potent of the bisphosphonates is called zoledronic acid (Zometa). It is given intravenously. Its side effects are primarily reactions to the drug infusion. The dose of Zometa may need to be adjusted if the patient's blood tests show signs of deterioration in the function of the patient's kidneys. In addition, its use can predispose patients to serious dental conditions including what is called osteonecrosis of the jaw, which can result in breakdown of the bone of the jaw after dental extractions. It is advised that you see your dentist and have needed dental procedures performed prior to the start of a bisphosphonate.

Denosumab (Xgeva) is a monoclonal antibody agent that inhibits the work of osteoclasts in a manner different from bisphosphonates. The medication inhibits a protein that tells the osteoclasts to remove bone. This drug is useful as a treatment for all of the conditions for which bisphosphonates are used. Given as an injection under the skin at intervals, it has a better side effect profile than the bisphosphonates. It does not require dose adjustments if kidney function deteriorates. It can still cause osteonecrosis of the jaw to occur. It is considered an important new drug in the treatment of bone metastases in prostate cancer patients. In some studies it appears to be more effective than Zometa in delaying the initial onset of skeletal-related events in patients with bone metastases.

The use of substances that are radioactive as a treatment for bone metastases has been tried for years. Strontium-89 and samarium-153 have been used in the past. They decrease pain in patients with prostate cancer with bone metastases but they do not prolong life; these medications lower levels of healthy blood cells in patients who receive them.

Recently a form of radium called Ra-223 (Xofigo) has been approved for use in prostate cancer patients with metastases to bone but not to other internal organs. Radium is like calcium and it migrates to bone where it acts locally. As an alpha emitter, radiation from radium does not travel far enough in the body to damage other healthy tissues. Unlike the bisphosphonates, the use of this agent reduces pain and can prolong survival. It is administered by an injection into a vein. It can cause nausea, diarrhea, and low blood counts.

A patient is noted to have metastatic castrate resistant prostate cancer if the individual has progressive prostate cancer with metastases while on ADT. The individual should have a serum testosterone level obtained to make sure that it is at castrate level (< 50 ng/dL while on ADT). If the testosterone level is > 50 ng/dL, this would indicate that the source of the progression is inadequate androgen deprivation and alternative ADT should be considered. If the individual is determined to have a castrate level of testosterone on ADT with progression of disease (rising PSA) on ADT, the individual is considered to have metastatic castrate-resistant prostate cancer. If metastases are identified, then the individual has metastatic castration-resistant prostate cancer. Over the past several years, a number of therapies have been approved for the treatment of metastatic castrate-resistant prostate cancer, including a new androgen receptor blocker, chemotherapy, immunotherapy/vaccine therapy, as well as bone-directed therapies. Though each of these therapies have unique ways in which they work and different side effects, all have been demonstrated to prolong survival by approximately 3-4 months each. The sequencing of the various treatments (which should be used first) is not well defined at present. Sipuleucel-T, a vaccine immunotherapy, is the only agent that is specifically approved for use early on in the time frame before one has significant symptoms (asymptomatic or minimally symptomatic). Studies are ongoing to evaluate the best sequence of treatments.

High-intensity focused ultrasound (HIFU) is an approach to therapy that is presently approved for use in Europe, and is under study in the U.S. It uses high intensity sound waves focused on the prostate gland to heat and thereby kill cancer cells. It should only be used as part of a research study (a clinical trial). The safety, side effects, and comparative effectiveness to surgery and radiation therapy must be established.

Clinical trials are research studies being conducted to evaluate new treatments for prostate cancer. These include approaches such as HIFU, as well as modifications of surgical and radiation techniques, and new drugs and immune therapy approaches. The National Comprehensive Cancer Network, a group assembled from the major comprehensive cancer centers of the U.S., considers that the best care of a cancer patient is afforded by their participation in a clinical trial. Patients with prostate cancer should always ask if there is a clinical trial option for them at any point in their therapy. Clinical trial participation assures you that your treatment has been considered by numerous cancer experts and is at least as good as a standard treatment that you may receive off of a clinical trial. In addition, the results of your treatment will be carefully analyzed in anonymous fashion, and results can be used to help others.

In addition to standard types of prostate cancer treatments, there are other approaches that patients may choose during their treatment for their disease.

Some of these treatments are called complementary treatments and may help with control of symptoms or problems the patient may be experiencing. Examples of these include acupuncture for pain control, yoga and meditation for relaxation, as well as guided imagery, aromatherapy, and other techniques. Tell your doctors about all treatment approaches you are engaged in. These approaches usually will be of no harm to you, and may be very beneficial. Knowing what you are doing may help your doctor to better understand and coordinate your treatments and medications. Herbal therapies have been demonstrated in the lab to affect prostate cancer cells, but in many cases, have not been proven to be clinically effective. PC-SPES is an herbal therapy that has been used in the past for prostate cancer. It was associated with an increased risk of blood clots. Thus, prior to taking this or other herbal therapies, discuss these therapies with your doctor.

Be very careful about alternative treatments. The vast majority of medical professionals keep up-to-date on the latest advances, or are willing to research them for patients when asked. No truly effective treatments are being withheld from patients, though alternative care providers often say they are in an attempt to sell patients on their types of treatment. Such alternative therapies can do harm to patients, and can interfere with conventional treatment. Alternative care providers can be reasonably said to be preying on the desperation of cancer patients.

If nutritional supplements are suggested in addition to conventional therapy by an alternative care professional, tell all your doctors what you are taking. Some nutritional substances can interfere with the effectiveness of some conventional cancer treatments. Some "natural" substances can be toxic and can result in side effects or problems your regular doctor may not recognize unless they know what you are taking.

Prostate cancer patients, like all cancer patients, are frightened. Discuss your anxiety and concerns with your primary care doctor, urologist, and radiation and medical oncologists. They have many ways to help.

Staging evaluation is essential for the planning of treatment for prostate cancer. A basic staging evaluation includes the patient examination, blood tests, and the prostate biopsy including ultrasound images of the prostate. Further testing and calculations may be performed to best estimate a patient's prognosis and help the doctor and patient decide upon treatment options. Prognosis refers to the likelihood that the cancer can be cured by treatment, and what the patient's life expectancy is likely to be as a consequence of having had a prostate cancer diagnosis.

If a cancer is cured, your life expectancy is what it would have been had you never been diagnosed with prostate cancer. If the cancer cannot be cured due to it recurring in distant locations as metastases, or recurs either locally (where it started) or in an area no longer able to be treated in a curative manner, then estimates can be made of what is likely to be your survival based again on group statistics for people who have been in the same situation.

Nomograms are charts or computer-based tools that use complex math from analysis of many patients' treatment results. They help to estimate the likelihood of a patient surviving free of recurrence after a treatment. They also can determine the likelihood of a cancer being found confined to the prostate, or spread beyond the prostate, or into the nearby lymph glands. Your doctor will likely input the data from your staging evaluation into a nomogram in order to best counsel you regarding your treatment options.

The prognosis for prostate cancer varies widely, and depends on many factors, including the age and health of the patient, the stage of the tumor when it was diagnosed, the aggressiveness of the tumor, and the cancer's responsiveness to treatment, among other factors. The 5-year survival rate for most men with local or regional prostate cancer is 100%. Ninety-eight percent are alive at 10 years. For men diagnosed with prostate cancer that has spread to other parts of the body, the 5-year survival rate is 30%.

For a disease as common as prostate cancer, a condition which one man in six will be diagnosed with in their lifetime, the ideal approach is to prevent men from getting prostate cancer.

Two clinical trials referred to as the Prostate Cancer Prevention Trial (PCPT) and the subsequent Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial were conducted over the past two decades. These studies demonstrated that both finasteride and dutasteride (Propecia and Avodart), when used in men between 50 and 75 years of age, reduced the incidence of prostate cancer by 28% and 23% respectively as compared to similar men taking a placebo.

The reduction in the overall incidence of prostate cancer was significant. The use of these drugs and their FDA-approval for prevention has been slow to come in part because of the lingering concern over the high-grade prostate cancer risk. Men in these trials got less prostate cancer if treated with these drugs, but the prostate cancers that they did get were more often high-grade (had higher Gleason scores) and thus appeared to be at risk for behaving more aggressively. Men with a family history of prostate cancer or other high risk factors, and in fact any man, should discuss the use of these drugs for this purpose.

Trials have been conducted on several vitamins and nutritional supplements and naturally-occurring compounds in an attempt to prevent prostate cancer.

• Vitamin E and selenium were not effective in the prevention of prostate cancer in the SELECT trial. Vitamin E supplementation may have increased the incidence of prostate cancer.
• Lycopene was also ineffective as a preventive agent.
• Pomegranate juice had no meaningful impact on prostate cancer prevention.
• Green tea had some early results suggestive of a possible protective effect, and a larger trial is under way.
• Vitamin D and its derivatives have been studied in prostate cancer. There is no evidence that vitamin D protects against prostate cancer. The vitamin D derivative, calcitriol, has some therapeutic utility against this disease, and is still under study.

Prostate cancer is the most common cancer in men (after skin cancer), and the second leading cause of death from cancer in men. The biology of prostate cancer is better understood today than it was in the past. The natural history of the disease and its staging have been well defined. There are numerous potentially curative approaches to prostate cancer treatment when the disease is localized. Treatment options also exist for prostate cancer that has spread. Ongoing research continues to search for treatments for metastatic prostate cancer.

Coping with prostate cancer

The diagnosis of cancer can cause great anxiety to the individual and his family and friends. At times, one may have troubles coping with the diagnosis, the disease, and its treatment. Searching online for information may prove overwhelming also and may not be the best resource. Ask your physician or local hospital about local resources. Often, there are local prostate cancer support groups which may help you cope with your feelings and provide local resources for more knowledge. You may consider contacting one or more of the following organizations: US Prostate Cancer Foundation, American Urological Association Foundation, Centers for Disease Control and Prevention, American Cancer Society, and Patient Advocates for Advanced (Prostate) Cancer Treatment. The Internet has provided access to a number of sites focusing on prostate cancer treatment and outcomes. The National Cancer Institute and the National Comprehensive Cancer Network (NCCN) have patient information as well as the American Urological Association.