Is It Low Risk?

Prostate cancer develops in the prostate, a gland positioned just below the bladder in men. In older men, the cancer usually is localized (confined to the prostate gland) and considered low risk. “Low-risk prostate cancer means that based on the patient’s clinical characteristics, there is a low chance of progression,” says Ash K. Tewari, MD, System Chair of Urology at Mount Sinai. “However, in some cases, a low-risk cancer may advance, which means it has spread beyond the capsule of the prostate into neighboring structures, or metastasize, which means it has spread to distant organs.” Dr. Tewari adds that risk stratification is used to help predict which localized prostate cancers may or may not progress to advanced or metastatic disease. “Patient characteristics used to stratify risk include blood tests to check a person’s prostate-specific antigen, or PSA, level, clinical stage, the Gleason score, and the percentage of biopsy specimens that were positive for cancer,” he says.

• PSA is a protein produced by the prostate gland. High and/or increasing PSA levels can signal prostate cancer and cancer progression. However, elevated PSA does not always indicate cancer— for example, PSA levels may be high in men with benign prostatic hyperplasia (an enlarged prostate, which is common in older men).

• A prostate biopsy involves using a needle to remove small samples of the prostate that can be examined under a microscope for the presence of cancer cells.

• The Gleason score uses samples from a prostate biopsy and assigns a score of 1 through 5 based on how similar the cancer appears to normal prostate tissue. Scores are assigned to the two most prevalent types of cancer cell and then added together for a final score of between 2 and 10.

• Clinical stage is used to determine whether a cancer has spread and if so, how far. The most widely used staging system is the TNM system, in which T is the extent of the primary tumor, N denotes whether the cancer has spread to nearby lymph nodes, and M indicates metastasis.

Managing Low-Risk Disease

Dr. Tewari says that men are not sent home without follow-up after a diagnosis of low-risk cancer. “Instead, clinicians recommend active surveillance, so that the cancer can be monitored and treated accordingly if it evolves into intermediate or high-risk disease,” he explains. “Active surveillance programs can be tailored to the individual patient based on their clinical characteristics as well as their life expectancy. Aspects of active surveillance typically involve a PSA blood test every six months along with biopsies every one to three years, and annual digital rectal exams and magnetic resonance imaging scans.”

Active surveillance comes with fewer potential complications than more radical treatment strategies (see Radical Treatments May Cause Long-Term Complications), but it is not entirely risk-free. For example, transrectal biopsies involve sampling the prostate gland using a needle inserted into the gland via the rectum. Rarely, the needle may be contaminated by bacteria in the rectum. If the bacteria are then introduced into the bloodstream or prostate, this can result in an infection, although such infections are rare. The other type of biopsy—transperineal— involves the biopsy needle being inserted through the skin of the perineum (the area between the anus and scrotum). “Compared with transrectal biopsy, the transperineal approach is less likely to cause an infection,” Dr, Tewari says. “However, there is a low risk of bleeding and difficulty passing urine afterward.”

More Men Choosing Active Surveillance

The number of Americans with prostate cancer who choose active surveillance over radiotherapy or surgery to remove the prostate gland rapidly increased between 2010 and 2018, according to a study published in JAMA Internal Medicine, April 3. The numbers rose from 16 to 60 percent for men with low-risk cancer and from 8 percent to 22 percent for men with intermediate-risk cancers that were not thought likely to spread further. The data are encouraging, but there is still some room for improvement. Active surveillance still is more likely to be utilized in Europe than the United States, and the study also suggests that Hispanic Americans and people living in rural areas are less likely to be offered, or to choose, this option.

Another recent study (JAMA Network Open, March 2), including 20,000 men treated at nearly 350 urology practices across the United States, also pointed to an increase in the use of active surveillance, from about 27 percent in 2014 to about 60 percent in 2021. However, the researchers noted that compared with white men, Black men were less likely to be offered active surveillance. Dr. Tewari says this likely is because Black men are more likely to develop prostate cancer that spreads. “The reasons for this are not completely clear,” he says. “The disparity is an active area of research into possible genetic and environmental explanations.”

Unsure What to Choose?

Previous studies suggest that about 50 percent of men discontinue active surveillance within five years of being diagnosed with prostate cancer, usually because the cancer has progressed. However, research indicates that some men opt for more radical treatment out of a desire to “do something,” or because they are afraid their cancer will progress. Typically, these are younger men. “An older man who has trouble getting around the house, has had a heart attack, and smokes may warrant a different decision from someone who runs five miles a day and takes no medications,” Dr. Tewari confirms. However, he adds that a patient’s own wishes and perspectives are crucial ingredients to making the right decision—and if you are in your late 60s, in good health, and have a long life expectancy, you may feel that active surveillance isn’t the right option for you. If you feel this way, it’s important to keep in mind that active surveillance doesn’t equate to doing nothing to manage your cancer—it is a proven approach that helps preserve your quality of life while providing the option to intervene if necessary. This was underlined by a recent study that is the first to fully evaluate the three major treatment options for low-risk prostate cancer.

The study (New England Journal of Medicine, April 27) included 1,643 men, ages 50 to 69 years, who were diagnosed with localized prostate cancer after a PSA blood test. They were randomized to active surveillance, radical prostatectomy, or radiotherapy and followed over an average of 15 years. About 97 percent of the participants survived 15 years after diagnosis, irrespective of which treatment they received. Around one-quarter of the men undergoing active surveillance had still not needed any invasive treatment for their cancer after 15 years. Participants in all three groups reported similar overall quality of life in terms of their general mental and physical health. But the negative effects of surgery or radiotherapy on urinary, bowel, and sexual function were found to persist much longer than previously thought: up to 12 years for some of the participants.

Cancer Progression

Dr. Tewari says that identifying which men with prostate cancer will progress from the low-risk category is an active area of research. “Advances are being made in imaging, genomics, and molecular biology,” he notes. “In the future, artificial intelligence may serve as another avenue to analyze large data sets of patients and identify novel biomarkers that may help predict progression.”

If your cancer progresses, or you would initially prefer a more definitive treatment approach than active surveillance, it is vital that you discuss not just the effectiveness of the different options with your doctor, but also the possible side effects and how you might manage these if they occur. Above all, remember that prostate cancer is not a death sentence—the fiveyear survival rate is 99 percent, and the American Cancer Society estimates that there are more than 3 million prostate cancer survivors in the United States.

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Robotic prostatectomy is used to treat prostate cancer. A man’s prostate gland is about the size of a walnut and it sits underneath the bladder. The main function of the prostate is to make ejaculation fluid. Prostate cancer is the most common cancer in men, but not all men need a prostatectomy.

Who Needs a Prostatectomy?

Prostate cancer is usually a slow growing cancer. If you have this type of prostate cancer, you and your doctor may decide to watch the cancer by doing blood tests, prostate exams, and prostate biopsy. In many cases, surgery is never needed.

Some prostate cancers grow quickly. These cancers can cause death if not treated. In fact, prostate cancer is the second leading cause of cancer deaths in men. Cancers that grow quickly are called aggressive. When you have a biopsy to diagnose prostate cancer, the cells will be examined and given a score for aggressiveness. This is called a Gleason score. A Gleason score less than 6 is a slow growing cancer. A score of seven is in the middle, and a score of 8 to 10 is aggressive. Prostatectomy may be the best treatment for an aggressive cancer.

What Happens During a Robotic Prostatectomy?

During a robotic prostatectomy, the surgeon will control robotic arms from computer controls.

You will be asleep under general anesthesia. Your surgeon will make 5 keyhole incisions in your lower belly. A robotic camera will be placed through one incision, and thin surgical arms will be placed through the others. Your surgeon will sit at the control console and maneuver the camera and robotic arms.

During the procedure, the camera will give your surgeon a clear view that can be magnified up to 15 times what would be seen without magnification. Using the surgical arms, tiny blood vessels and nerves can be avoided and spared. After freeing the prostate from the surrounding tissue, it is pulled out through one of the key holes.

Benefits of Robotic Surgery Over Open Surgery

Robotic arms are steadier than any human hand. The “wrists” of a robotic arm can move in all directions and angles. These advantages along with the magnified view result in these advantages compared to traditional open prostatectomy:

• Less bleeding
• Less pain after surgery
• Time spent in hospital is as short as one or two days
• Faster recovery at home and 90% of patients return to regular activities in only two to three weeks
• Less need for narcotic pain medication

What Are the Risks of Robotic Prostatectomy?

The risks of robotic prostatectomy are about the same as with an open prostatectomy. The two biggest risks are leaking of urine and erectile dysfunction (ED). Leaking of urine – called urinary incontinence – usually occurs in the days after surgery but gradually improves. Over 95 percent of men will regain good bladder control. ED is not being able to get or keep an erection. The likelihood of ED after surgery depends on a man’s age and how sexually active he was before surgery. Most men experience only temporary ED.

What Are the Warning Signs of Prostate Cancer?

Risk factors for prostate cancer include age, family history, race, and obesity. You may be at higher risk for prostate cancer if you are over age 50, have a family history of prostate cancer, are overweight, or if you are a Black man. See your doctor if you have any of these symptoms:

• Trouble passing urine
• A weak flow of urine
• Blood in your urine or semen
• Pain in your bones
• Unintentional weight loss

To learn more about prostate health and the latest breakthroughs and procedures, see our latest report Prostate Health written by the editors at Men’s Health Advisor in cooperation with Cleveland Clinic.

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Your doctor may elect to biopsy your prostate based on whether or not you have possible symptoms of prostate cancer, on your PSA levels, and/or on your digital rectal exam (DRE) findings.

There are differing opinions among professional medical organizations about whether performing a biopsy based on abnormal PSA results alone is appropriate. A number of other tests (e.g., PCA3 and PSA velocity) have been developed as screening tools in an effort to either avoid unnecessary biopsy or improve prostate gland cancer detection. Most experts agree, however, that there isn’t enough evidence yet to make them part of a routine screening process. You and your healthcare provider should discuss these options prior to a biopsy.

If prostate cancer is suspected, your doctor will perform a biopsy guided by transrectal ultrasound. A small ultrasound probe is inserted into the rectum to guide the biopsy needle to the biopsy locations. The needle is inserted through the wall of the rectum into the prostate gland to retrieve small pieces of tissue. Typically, at least 12 samples of tissue are taken from different areas of the prostate. This can be done on an outpatient basis and is usually a brief procedure.

The tissue samples are sent to a pathology lab for examination. If cancer cells are evident, they typically are graded using a system called the Gleason score, an indicator of how likely the cancer is to spread. Tissue from two different parts of the prostate gland are examined and given a score from 1 to 5; the numbers from each part are then added together to create the Gleason score. A lower score suggests a lower likelihood of spreading, while a higher score suggests a greater chance.

Once a diagnosis of prostate cancer has been made, additional tests will be performed to determine whether or not the cancer has spread beyond the prostate. These test results, along with the Gleason score, will be used to assign the disease a prostate cancer stage. The system most often used is the American Joint Committee on Cancer “TNM” system, which provides a Roman numeral staging score from I-IV based on the size of the primary Tumor, whether or not there is lymph Node involvement, whether the tumor has Metastasized, the PSA level at diagnosis, and the Gleason score.

First line of defense in detecting prostate cancer is the digital rectal exam (DRE), plus a measurement for prostate specific antigen (PSA) in the blood. These steps are controversial, however, because some contend PSA has led to over-diagnosis and debilitating over treatment for cancers that aren’t lethal.

The more advanced the cancer, the higher the TNM stage number. For example, in stage I prostate cancer, the cancer has not spread beyond the prostate itself while in stage IV prostate cancer, the cancer has spread beyond the prostate, either to nearby organs and/or lymph nodes or to more distant sites in the body.

Tests performed to help stage the cancer may include:

• Computed Tomography (CT): CT scans are used to look for evidence of metastasis, particularly to lymph nodes.
• Magnetic Resonance Imaging (MRI): MRI is also used to look for evidence of metastasis.
• Bone Scan: Since bone is one of the most common places for prostate cancer to metastasize, bone scans are often used to look for disease spread.
• Positron Emission Tomography (PET): PET scans can also be used to look for evidence of metastasis. They are particularly helpful in looking for evidence of disease recurrence in men who have been previously treated for prostate cancer.
• Lymph Node Biopsy: Knowing whether or not your prostate cancer has spread to lymph nodes is an important part of determining what treatment regimen you should receive. Imaging tests such as CT scans can help provide information as to whether or not the lymph nodes are involved, but biopsying lymph nodes is the only way to definitively make this determination. If your doctor doesn’t anticipate surgery as a part of the treatment regimen, he may opt to biopsy your lymph nodes laparoscopically. In other situations, your surgeon may biopsy your lymph nodes during an operation to remove your prostate gland.

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active surveillance: Close observation of prostate cancer with periodic testing and initiation of curative therapy if testing suggests cancer progression, offered to patients with low-risk (and some with intermediate-risk) prostate cancer.

adjuvant: An additional treatment used to increase the effectiveness of the primary therapy; radiation therapy and hormonal therapy are often used as adjuvant treatments following a radical prostatectomy.

androgen: A type of hormone that promotes the development and maintenance of male sex characteristics.

androgen-deprivation therapy (ADT): Treatment that halts production of male hormones that fuel prostate cancer.

benign: Not cancerous.

benign prostatic hyperplasia (BPH): Non-cancerous condition in which an overgrowth of prostate tissue pushes against the urethra and the bladder and restricts or blocks the flow of urine.

biopsy: The removal of cells or tissues for examination under a microscope.

brachytherapy: A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor.

cryotherapy: A procedure in which extremely cold temperatures are used to destroy cancer cells in the prostate.

digital rectal examination (DRE): An examination in which a doctor inserts a lubricated, gloved finger into the rectum to feel for abnormalities.

dysplasia: Cells that look abnormal under a microscope but are not cancer.

endorectal: Through the rectum; there are endorectal MRIs as well as ultrasound to visualize a specific area.

epithelium: A thin layer of tissue that covers organs, glands, and other structures within the body.

erectile dysfunction (ED): An inability to have an erection of the penis adequate for sexual intercourse.

external-beam radiation: A form of radiation therapy in which the radiation is delivered by a machine pointed at the area to be radiated.

fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope; also called needle biopsy.

free-PSA (fPSA): One of two forms of prostate-specific antigen (PSA) in the blood, which is not bound to a protein (thus “free”).

Gleason score/Gleason grade: A system of grading the aggressiveness of prostate cancer cells based on their appearance under a microscope.

gonadotropin-releasing hormone (GnRH): A hormone made by the hypothalamus; GnRH causes the pituitary gland to make luteinizing hormone (LH) and follicle stimulating hormone (FSH).

grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread.

high-intensity focused ultrasound (HIFU): A procedure in which high-energy sound waves are aimed at cancerous areas in the prostate.

hormone-refractory prostate cancer: Prostate cancer that resists androgen-deprivation therapy (ADT); also, and more appropriately, known as castration-resistant prostate cancer.

hyperplasia: An abnormal increase in the number of cells in an organ or tissue.

hypertrophy: The enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells.

immunoassay: A test that uses the binding of antibodies to antigens to identify and measure certain substances.

immunotherapy: A type of treatment that boosts or restores the immune system to fight cancer, infections, and other diseases.

impotence: The inability to have an erection of the penis adequate for sexual intercourse.

incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence).

intensity-modulated radiation therapy (IMRT): A type of three-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor.

interstitial radiation therapy (IRT): A procedure in which radioactive material sealed in needles, seeds, wires, or catheters is placed directly into or near a tumor; also known as brachytherapy.

intraepithelial: Within the layer of cells that form the surface or lining of an organ.

laparoscopy: The insertion of a thin, lighted tube through the abdominal wall to inspect the inside of the abdomen and remove tissue samples.

luteinizing hormone (LH): The pituitary hormone that causes the testicles in men and ovaries in women to manufacture hormones; also called a luteinizing hormone-releasing hormone, or LHRH.

lymph nodes: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue.

lymphocyte: A type of white blood cell.

marker: A diagnostic indication that disease may develop.

metastasis: The spread of cancer from one part of the body to another.

morbidity: A disease or the incidence of disease within a population.

neoadjuvant therapy: Treatment given before the primary treatment.

neoplasia: Abnormal and uncontrolled cell growth.

nerve sparing: A surgical technique during a prostatectomy in which one or both of the neurovascular bundles controlling erections are spared.

orchiectomy: Surgery to remove one or both testicles.

palliative: Designed to produce relief from symptoms without curing.

prostate gland: A gland in the male reproductive system just below the bladder.

prostatectomy: An operation to remove part or all of the prostate.

prostate-specific antigen (PSA): A substance produced by the prostate that may be found in an increased amount in the blood of men who have prostate cancer, benign prostatic hyperplasia, or infection or inflammation of the prostate.

prostatic: Of or pertaining to the prostate gland.

proton therapy: A type of radiation therapy that delivers a beam of protons to irradiate tumors.

radical prostatectomy: Surgery to remove the entire prostate.

refractory: A term used to describe a disease or condition that does not respond to treatment.

resection: Surgical removal of part or all of an organ.

seminal vesicle: A gland that helps produce semen.

TNM staging system: A system for describing the extent of cancer in a patient’s body.

tomography: A series of detailed pictures of areas inside the body; the pictures are created by a computer linked to an x-ray machine.

transrectal ultrasound (TRUS): A procedure in which a probe that sends out high-energy sound waves is inserted into the rectum.

transurethral resection of the prostate (TURP): Surgical procedure to remove tissue from the prostate using an instrument inserted through the urethra.

tumor: A mass of excess tissue that results from abnormal cell division.

ureter: A tube that carries urine from the kidney to the bladder.

watchful waiting: Close observation of prostate cancer and deferring treatment until symptoms appear or change.

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Still, prostate cancer was responsible for an estimated 31,620 deaths in 2019, according to the American Cancer Society. The risk of prostate cancer increases dramatically with age. Six out of 10 cases are in men over 65, and the average age at diagnosis is 66. Prostate cancer is rare in younger men, but when it does occur, it tends to be more aggressive.

Screening for prostate cancer is controversial. In most men diagnosed with prostate cancer, the disease is slow growing and not life threatening. For these men, diagnosis may lead to unnecessary tests and treatments, not to mention the stress of living under the shadow of a cancer diagnosis. It’s like going for a walk in the woods: Even if there are hundreds of snakes and spiders lurking near the path, the chances are that they will leave you alone. But once someone tells you there are hundreds of snakes and spiders lurking by the path, you begin to get anxious and panicky. The risk is the same, but now you know about it!

Pathology

The prostate is particularly susceptible to gene mutations. Some 95 percent of prostate cancers begin in the semen-­producing glandular cells and are classed as adenocarcinomas. Four percent arise in the prostatic urethra’s transitional cells—the lining of the urethra as it passes through the prostate. In fact, changes begin there with cellular gene mutations years before cancer is detected.

Over time, fast-growing mutations may develop, forming clusters of abnormal cells, tumors, and eventually cancer. Less than 1 percent are squamous cell carcinomas (normally seen on skin), most often occurring after radiation or hormone treatment. Seventy percent arise in the peripheral zone, 15 to 20 percent in the central zone, and 10 to 15 percent in the transitional zone. At biopsy, the majority of cancers are found to be affecting multiple areas of the prostate.

Local Spread

As clusters of cancer cells enlarge, they begin to invade adjacent areas. Tumors arising in the transitional zone spread to the nearby bladder neck. Those arising in the peripheral zone creep into the ejaculatory ducts and seminal vesicles. Later in the process, they may reach, and breach, the sheath of connective tissue around the gland, called the prostatic capsule.

Distant Spread (Metastasis)

Sometimes prostatic cancers spread far beyond the prostate, forming distant cancers or metastases (plural of metastasis). The most common sites for prostatic metastases are in the bones, lungs, liver, and adrenal glands.

Measuring Severity

The severity of prostate cancer is measured using two metrics:

• Grading. The Gleason score defines types of cells, and the level of abnormality (histology).
• Staging. The Tumor-Node-Metastasis (TNM) classification describes how widespread the cancer is.

At diagnosis, most prostate cancers have low levels of abnormal cell changes and remain confined to the prostate. These cancers tend to be slow growing and have good outcomes. The cancers with the worst outcomes tend to have significant cell abnormalities and have spread beyond the capsule of the prostate.

Prostate Cancer Symptoms

Clinical presentation data provide a picture of prostate cancer symptoms:

• 47 percent present with no symptoms; cancer is detected during screening.
• 38 percent present with increased urinary frequency, especially at night.
• 23 percent present with a decreased urine stream.
• 10 percent present with urinary urgency.
• 1 percent present with blood in urine (hematuria) or semen.

Prostate cancer that has spread may present with:

• Reduced appetite and unexplained weight loss
• Bone pain, with or without pathologic fracture
• Feet or ankle pain and swelling
• Kidney failure.

Causes and Risk Factors

The cause of prostate cancer is complex and not fully understood. We do know that the glandular tissue of the prostate is prone to genetic mutations that may be triggered by a variety of factors. In many men, the disease seems to be random, and the cause remains unknown.

The term “risk factors” refers to attributes or exposures in an individual that increase the odds of getting the disease. For prostate cancer, there are many risk factors. Let’s consider the common ones.

Age. The most significant risk factor for developing prostate cancer is one that can’t be helped: aging. Sixty percent of all prostate cancers are diagnosed in men over age 65.

Genetic Factors. Genetics are at play in the 5 to 10 percent of prostate cancer patients who have a strong family history. A man with a first-degree relative (brother or father) with prostate cancer has double the risk of developing the disease and presents six to seven years earlier than other men.

The National Cancer Institute explains that the following factors are suggestive of genetic risk:

• Multiple first-degree relatives with prostate cancer, including three successive generations with prostate cancer on the mother’s or father’s side.
• A relative with early-onset prostate cancer (age ≤55 years).
• Family history of prostate cancer and other cancers (e.g., pancreatic, breast).

Researchers have so far discovered more than 100 gene variations or mutations associated with prostate cancer. Certain clusters of gene variations are helpful for predicting risk and outcome, and some mutations are linked to more aggressive cancers.

Notable culprits are the BRCA1 and BRCA2 mutations, also linked to breast cancer risk in women. Normally, these genes produce proteins that help to suppress cancer. Research suggests that men with BRCA2 mutations who develop prostate cancer are more likely to develop aggressive disease, with advanced staging at diagnosis, higher rates of metastasis, and poorer survival rates. A recent study found that African-­American men with prostate cancer are more likely to have the BRCA1 and BRCA2 genes, a possible explanation for why this group has poorer outcomes.

Herein lies a common dilemma in medicine: What do we do when someone is identified with a genetic risk? There is a danger that this knowledge may cause unnecessary panic and needless tests and treatments. While prostate cancer is very common, most patients do not die from it. But genetic testing—when used prudently—can help identify men with aggressive cancers earlier and potentially save lives. Genetic testing is also increasingly used for targeting treatment.

Epigenetics. Fortunately, men with prostate cancer risk genes are not destined to develop cancer. The field of epigenetics is showing that lifestyle and environmental factors can alter the inheritance and expression of genes. This suggests that improving lifestyles and environment may reduce the risk of prostate cancer, along with the risk of many other chronic illnesses.

Racial Factors. Data from the Centers for Disease Control and Prevention and the National Cancer Institute show that there are racial differences in the incidence of prostate cancer. In one study, African-American men were found to have the highest rates of prostate cancer, followed by white, Hispanic, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander (A/PI) men.

Research suggests that African-American men may be at greater risk, in part, because of genetic factors and hormonal differences. However, diet, income, education, and health-care access may also play a role. African-American men also tend to get prostate cancer earlier and in a more aggressive form than other races, with death rates being significantly higher.

On the plus side, recent research suggests that when African-American men diagnosed with early stage prostate cancer receive equal access to health-care and the most effective treatments, their risk of death is the same as that of Caucasian men.

Lifestyle Factors. One of the likely causes of prostate cancer is inflammation, and there is an established link to lifestyle. The typical Western lifestyle, characterized by sedentary habits and poor diet, is a major cause of inflammation in the body and a significant risk factor for many chronic diseases, including cancer, heart disease, and diabetes.

According to Cancer.org, “Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe, and the lowest rates being in southeastern and south-central Asia and northern Africa.”

The human body is a highly complex, interconnected system. No organ exists in isolation, so what is good for health in general is likely good for the prostate. The body has a remarkable ability to heal itself and maintain a healthy equilibrium, but sometimes our actions push it to the limit, and disease is the result.

There is substantial research linking lifestyle to prostate cancer risk. But due to the complex nature of disease and of lifestyle, it can be difficult to prove that one particular factor causes or prevents a specific disease. For example, men who are obese have an increased risk of prostate cancer, but is this because of the excess body weight itself or because they have a poorer diet and are less likely to exercise? Likewise, men who are strict vegans have a lower risk of prostate cancer, but is this because they eat no animal products or because they are more likely to be non-smokers and lead active lifestyles?

Diet and Nutrition. The links between diet, general health, disease prevention, and longevity are increasingly compelling. Large longitudinal studies—where subjects are followed for years (such as the Framingham Heart Study and the Nurses’ Health Study)—provide strong evidence.

One example of a healthy diet is the Mediterranean diet, which is high in fruits and vegetables, nuts, grains, olive oil, and lean sources of protein and low in factory-produced, processed foods. A comprehensive review of research, published in the journal Nutrients, showed that strict adherence to the Mediterranean diet only slightly lowered the risk of death from prostate cancer, but had a significant effect on the risk of some other cancers (like gastric, liver, pancreatic, and lung cancer).

Diet is also important to health and well being after cancer diagnosis. A study in Cancer Prevention Research compared two basic eating patterns in men who had been diagnosed with non-metastatic prostate cancer. One was a typical Western diet, relatively high in processed and red meats, high-fat dairy, and refined grains. The other was a “prudent” pattern relatively high in fruits, vegetables, fish, legumes, and whole grains. The study found that men with a Western dietary pattern were at greater risk of death from prostate cancer or any cause, compared with those who ate the prudent diet.

Obesity and Metabolic Syndrome. Obesity has been linked to a higher risk of prostate cancer. A recent study in BMC Medicine found that men with a higher body mass index (BMI) and waist circumference (indicators of obesity) had an increased risk of high-risk tumors and were more likely to die of prostate cancer. A possible mechanism for the increased risk of prostate cancer in overweight men is thought to lie with insulin levels. Insulin is a growth factor, so when high, it promotes cell division in abnormal cells.

Metabolic syndrome is a group of risk factors including obesity, high blood pressure, cholesterol abnormalities, high triglycerides, and insulin resistance. It is thought to be a precursor for cardiovascular disease and type 2 diabetes. Research published in 2017 in the International Journal of Cancer suggests that metabolic syndrome is associated with increased risk of fatal prostate cancer.

Other Factors

Also linked to prostate cancer are dietary supplements, heart disease, exercise, and smoking, among other factors.

Dietary Supplements. Many men take dietary supplements to improve health, and assume that supplements cause no harm. But troubling research suggests this is not so. Several studies have linked supplements to increased risk of prostate cancer:

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT) reported that men who took 400 International Units (IU) of vitamin E but no other supplements had a 17 percent higher risk of prostate cancer.
• Zinc: A study from Boston University concluded “long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk of prostate cancer.”
• Folic Acid: University of Southern California researchers found that men who took a 1-milligram daily supplement of folic acid had twice the risk of prostate cancer compared with men who took a placebo.
• Vitamin D: There is conflicting evidence as to whether vitamin D supplements decrease or increase the risk of prostate cancer. However, a 2018 review of 19 studies found that men with higher blood levels of vitamin D also were at greater risk of prostate cancer.

While these studies are not conclusive, they do suggest that if you want to reduce your prostate cancer risk, it may be safer to obtain your nutrients from a healthy diet rather than by taking vitamin supplements.

Heart Disease. Heart disease is the most common cause of death in men. When two diseases are very common, it’s hard to tease out whether one causes the other. Heart disease and prostate cancer share similar risk factors—including poor diet, obesity, smoking, and inactivity—but we cannot say with certainty that heart disease causes prostate cancer (or vice versa).

Smoking. There is no doubt that smoking is bad for health. It increases the risk of major chronic illnesses, like heart disease and lung cancer. At this time, the research that smoking specifically causes prostate cancer is mixed, though preliminary evidence suggests a relationship. A study combining data from 24 studies found that the heaviest smokers had a 24 to 30 percent greater risk of death from prostate cancer, compared with nonsmokers. Another large review, published in 2018, found that men who were smokers at the time of treatment for localized prostate cancer were at greater risk that their cancer would come back and prove fatal.

Alcohol Consumption. Excessive alcohol consumption is bad for you, contributing to heart disease and stroke and other significant health problems. The relationship between drinking and prostate cancer is less clear, although preliminary research suggests a connection. A 2018 study in Cancer Prevention Research found evidence that “heavier alcohol intake earlier in life and higher cumulative lifetime intake were positively associated with high-grade prostate cancer diagnosis, while current intake was unrelated to prostate cancer.” This suggests that alcohol consumption alone may not cause prostate cancer, but if you do develop the disease, the prognosis might be poorer if you are a heavy drinker.

Exercise. While there is solid evidence that regular exercise is good for general health, there is limited evidence of an impact on prostate cancer risk. However, one Harvard study reported that men who engaged in three hours a week of vigorous exercise were 61 percent less likely to die from prostate cancer than men who did less than one hour a week.

Testosterone Levels. In men with prostate cancer, male hormones—testosterone and other androgens—are known to fuel the growth of the cancer. But does testosterone cause prostate cancer? Males castrated before puberty and those with androgen insensitivity syndromes do not develop prostate cancer. Beyond these extreme cases, the relationship between testosterone levels and prostate cancer risk remains unclear.

Some studies have found a possible link between high levels of circulating testosterone and greater risk of prostate cancer, and that lower testosterone is associated with decreased risk. Other studies have not found such connections, and scientists continue to study this important question.

Another related issue is whether testosterone replacement therapy (TRT) poses a cancer risk. TRT is the standard medical treatment for hypogonadism, in which the body doesn’t produce enough testosterone. TRT is also used illegally in bodybuilding and performance enhancement. Medical treatment is not thought to increase the risk of prostate cancer, because it is correcting naturally low testosterone. The jury is out on the risks for men taking testosterone without prescription.

Ejaculation Frequency. Research in the journal European Urology suggests that frequent ejaculation may lower the risk of prostate cancer. The study followed nearly 32,000 men from 1992 to 2010, who periodically filled out health questionnaires. Men who reported 21 or more ejaculations per month were about 20 percent less likely to develop prostate cancer compared to men who reported four to seven monthly ejaculations. It’s unclear why frequent ejaculations would reduce cancer risk. Some speculate that it prevents cancer-causing substances from building up in the prostate.

Vasectomy. Some research found a greater risk of prostate cancer in men who have vasectomies. Half a million American men have a vasectomy each year, so it’s a potentially important risk factor. The American Urological Association reviewed the research on the link and concluded that, based on the results of two meta-analyses, vasectomy is not associated with prostate cancer. A 2017 review in JAMA Internal Medicine confirmed that vasectomy had an insignificant impact on aggressive prostate cancer risk.

Prevention

The development of prostate cancer is complicated, and it is unlikely it can be prevented altogether. However, large observational studies hold out much hope that even though you can’t change your age, your race, or your family history, you still may be able to reduce your overall risk by living a healthy lifestyle. And that also helps prevent heart disease and other important male health problems.

A Closer Look at Lifestyle

If you want to take control of your health and potentially reduce your risk of prostate cancer, here are some strategies that may help.

Improve Your Diet. Eat more fruits and vegetables, eat lean protein, and reduce intake of red meat cooked at high temperatures (processed, grilled, fried, or broiled).

• Eat a wide variety of fruits and vegetables of different colors so you get plenty of micronutrients. Include tomatoes (high in carotenoids) and cruciferous vegetables (such as broccoli and cauliflower).
• Eat antioxidant-rich foods like blueberries, watermelon, and arugula; these may reduce DNA damage.
• Food allergies and insensitivities are increasingly common: Listen to your body and avoid foods that make you feel unwell, even if they are on the “healthy” list.
• Limit full-fat dairy intake.
• Moderate amounts of tea and coffee may be beneficial for prostate health.
• Consider eating more soy, but make sure it’s organic.
• Replace your saturated fat intake with healthier unsaturated fats from sources such as avocados or olives. Eat oily fish like salmon two to three times a week.

Exercise Regularly. This will improve your overall health and may reduce your prostate cancer risk. Research suggests that even if you start exercising in middle or later life, it’s still beneficial for lowering disease risk.

Drugs and Medications. Some research suggests that certain medications may reduce the risk of prostate cancer:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Anaprox).
• Metformin (Glucophage, Glumetza, Fortamet, Riomet), used to treat type 2 diabetes.
• Statins, used to lower bad LDL cholesterol, such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).
• A class of medications called 5-alpha reductase inhibitors—used to help shrink non-cancerous enlarged prostates—can reduce the risk of prostate cancer by about one-fourth. However, they may increase the risk of more aggressive cancers. If you are at high risk, you may wish to discuss the use of these drugs as a preventative measure with your clinician. Commonly prescribed types include dutasteride (Avodart) and finasteride (Proscar).

Diagnosing Prostate Cancer

There are two stages to the diagnostic evaluation for prostate cancer:

• Screening: defined as the testing of individuals with no symptoms in an attempt to catch early disease.
• Investigations: assessments and tests done in individuals with symptoms or where screening has identified a potential problem.

Let’s begin by talking about the PSA test that’s both a screening and diagnostic test.

What Is PSA?

Prostate-specific antigen (PSA) is a blood test commonly used in two scenarios:

• A screening test (men with no symptoms)
• A diagnostic test (men with symptoms)

PSA is a protein made by the prostate to maintain semen’s liquid form, allowing sperm to move freely from the male to the female reproductive system during natural conception. Small quantities of PSA make their way into the bloodstream, allowing for measurement in the PSA blood test. Blood levels of PSA are often elevated in men with prostate cancer, making it a way to pick up cancer early—before clear signs and symptoms become apparent.

Over a billion PSA tests have been done since it was approved by the FDA in 1986 (to monitor treatment response and disease recurrence) and in 1994 (as a screening and diagnostic test).

The PSA test, when used for cancer screening, is controversial because it can lead to unnecessary tests and treatments, but it is also extremely useful as a diagnostic test that has saved millions of lives by picking up aggressive cancers so that men can receive early treatment.

Understanding the PSA Test. The PSA test measures tiny quantities of PSA in the blood. The scale used is nanograms (one-billionth of a gram) per milliliter (one-thousandth of a liter) (ng/ml). A PSA test result under 4 ng/ml traditionally has been considered “normal.” There is, however, a caveat: Some aggressive cancers have a PSA in this range. The Prostate Cancer Prevention Trial (PCPT) warns there is no PSA level at which the prostate cancer risk is zero. For the general male population, a PSA level between 4.1 and 10 carries a 47 percent risk of prostate cancer. PSA over 10 carries a 58 percent risk of prostate cancer, and thereafter the risk is closely correlated to PSA level.

Advanced PSA Measurements. Researchers have not given up on the PSA test as a prostate-cancer screening tool and are continually working to refine and improve it.

Screening

Screening for asymptomatic men (showing no symptoms) for prostate cancer involves the PSA test and sometimes a digital rectal examination (DRE). Routine prostate cancer screening is controversial for two main reasons:

• The risks of screening healthy men may outweigh the potential benefits.
• Prostate cancer is often not life threatening. In fact, in many cases prostate cancers are so slow-growing that they can almost be considered benign.

The goal of prostate cancer screening, therefore, is to detect high-risk tumors while they are treatable and potentially curable.

Digital Rectal Examination (DRE)

This simple test is performed during a physical examination. You lie on your side and the doctor inserts a lubricated, gloved finger (digit) into the rectum. The prostate lies in front of the rectum, so the doctor can feel (palpate) it through the rectal wall. This provides a way to assess the gland’s size and texture, whether it contains lumps, and whether pressing on it causes pain.

While the DRE can be embarrassing and a little uncomfortable, it is a useful screening test and is over in a couple of minutes.

Like the much-maligned PSA test, it is a crude and unreliable test, but doctors believe it is still worth doing in the absence of more definitive screening. It can also detect problems with other organs in the pelvic region, including the bladder and bowel.

To Screen or Not to Screen?

Screening tests are those done on people who feel well, with the aim of detecting serious disease before symptoms arise and before the disease is advanced, thus allowing early treatment and improving outcomes.

All screening tests have their pros and cons. Even a simple test like routine blood pressure monitoring can have a downside: Sometimes blood pressure is elevated due to anxiety about visiting the doctor (white coat syndrome) and testing may cause unwarranted alarm and further unnecessary testing. It’s important to weigh the advantages and disadvantages of any screening test before you make a decision.

Pros and Cons of PSA Screening

As is the case with most cancers, the earlier prostate cancer is detected, the greater the odds of a cure. Proponents argue that screening is the only way to catch prostate cancer at an early stage. They also point to the fact that death rates from prostate cancer have decreased significantly since widespread screening began in the early 1990s.

The great news is that screening has dramatically increased the detection of prostate cancer while it is still localized to the prostate, a significant factor in improved outcomes.

It is now rare for men to be first diagnosed with prostate cancer when it is advanced. Deaths from prostate cancer have significantly declined in the last 20 years, which is great news by any standard.

The Disadvantages of PSA Screening

The extent to which PSA has been responsible for the decline in deaths is controversial. While the drop in deaths from prostate cancer is cause for celebration, opponents of PSA testing suggest that it’s probably because of improved treatments, not PSA screening. They note that the survival rate was already improving in the United States, and survival rates have improved in countries that do not screen.

The case against screening points to these potential problems:

False Negatives. The PSA test misses some cancers. Around 20 percent of men confirmed to have prostate cancer have normal PSA levels (less than 4 ng/ml). False negatives give a false sense of security.

Other Causes of Low PSA. Unfortunately, there are factors that naturally reduce PSA levels, further complicating the interpretation of results. These include:

• Cigarette smoking (past or present).
• Obesity. Greater blood volumes may dilute PSA.

Medications

• BPH treatments. 5-alpha reductase inhibitors like finasteride (Proscar) and dutasteride (Avodart), although they may improve the PSA test’s accuracy.
• Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen (Advil, Motrin).
• Diuretics for high blood pressure. Examples include chlorothiazide (Diuril) and hydrochlorothiazide (Microzide, Dyazide, Maxzide).
• Statins for high cholesterol, such as atorvastatin (Lipitor) and simva­statin (Zocor).

False Positives. Some 70 to 80 percent of men with elevated PSA levels do not have cancer. For these men, a positive test leads to a cascade of testing that often results in the man being told he doesn’t have cancer. That would be fine—if testing caused no harm. However, being told that you have a positive result may cause severe psychological distress for weeks or months.

And when a PSA test result raises suspicions of prostate cancer, the next test is prostate biopsy, which may cause complications such as infection, blood in the semen and/or urine, urinary symptoms, and, possibly, erectile dysfunction. (See page 23 for more about prostate biopsies.)

Other Causes of High PSA. Unfortunately, there are factors that naturally increase PSA levels, further complicating the interpretation of results. These include:

• Prostatitis (non-cancerous inflammation), benign prostatic hypertrophy, and urine infections.
• Tests or surgery on the prostate, including DRE
• Recent ejaculation, especially in older men
• Exercise, most notably bicycle riding (doctors advise not to ride a bicycle for 24 hours before PSA testing)
• Hepatitis
• Bypass surgery

The Unpredictability of Positives. Statistically speaking, a very high PSA level is closely correlated to aggressive prostate cancer. But, when PSA is mildly elevated, the results are less clear-cut. Some men with high PSA turn out to have no cancer or a very slow-growing type, while some men with a low level of PSA turn out to have aggressive cancer.

For example, a study in the New England Journal of Medicine found that 15 percent of men with relatively low PSA levels (less than 4 ng/ml) who had biopsies turned out to have prostate cancer. And 15 percent of those cases were aggressive cancers based on standard tumor staging.

The bottom line is that there appears to be no “safe zone” in PSA testing. A low PSA level indicates potentially lower risk, but doesn’t completely rule out cancer.

Number Needed to Treat. Statistics have measured the number of patients who need to be treated to prevent one extra bad outcome. In 2012, the European Randomized Study of Screening for Prostate Cancer trial showed that “to prevent one prostate cancer death, 935 men would need to be screened and 37 cancers would need to be detected.” Some researchers considered this rate to be unacceptably high.

PSA Screening: The Research

Two major studies have fueled the debates about prostate cancer screening.

PLCO Trial. The National Cancer Institute sponsored the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial in the United States. They followed 77,500 men, all of them between ages 55 and 74, who had no history of prostate, lung, or colorectal cancer. Men were randomized into one of two groups:

• The intervention arm received trial screening, chest x-rays, flexible sigmoidoscopy, PSA blood tests, and digital rectal exams.
• The control arm received standard care.

Enrollment began in 1993, participants were screened through 2006, and data were collected through 2015. Researchers reported that seven to 13 years later, “There was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.”

In other words, the very costly screening program statistically had little effect on outcomes. However, the study has been heavily criticized for several flaws, paramount of which is the fact that 52 percent of the control group was in fact screened at some stage.

European Randomized Study of Screening for Prostate Cancer. The ERSPC, which involved eight European countries, is the largest-ever prostate cancer screening study. A total of 182,000 men (162,000 of them between ages 55 and 69) were randomized into the intervention and control groups. Those in the intervention arm were offered PSA blood tests every two or four years. Those with a PSA level of more than 3.0 ng/ml were offered biopsy. Patient follow-up was extended to 11 years and is ongoing.

In recent analysis, the researchers concluded that “a man who undergoes PSA testing will have his risk of dying from prostate cancer reduced by 29 percent.”

The major downside, as they discovered, was that there were high rates of false positives: 30 percent of those with detected cancers did not have progressive disease. The “number needed to treat” (NNT, or number treated to avoid one death) was 48, which is considered to be high.

Professor Fritz Schroeder, the study coordinator, concluded “screening programs for prostate cancer will not be feasible until the medical communities can confidently balance the risk of reducing death from prostate cancer with these unacceptably high levels of overdiagnosis and overtreatment.”

See screening guidelines on page 21.

Diagnostic Investigations

If you have prostatic symptoms or a high PSA or abnormal DRE results, your doctor will take you through some or all of the following steps.

• Full medical history, including symptoms, surgeries, medications, and family history.
• Full physical examination of all body systems, including a DRE.
• Symptom assessment, such as the AUA Symptom Score.
• Urine test to look for infection, blood, and glucose.
• Blood test for:
  • General health markers (blood count and chemistry).
  • PSA, advanced PSA testing (free PSA, PSA velocity, Prostate Health Index, 4Kscore, or prostate cancer antigen 3.
• Transrectal ultrasound (scans via the rectum, using a probe) to look for abnormalities or lesions.

Transrectal Ultrasound (TRUS) Biopsy. During a TRUS-guided biopsy, an ultrasound probe is inserted into the rectum and a spring-loaded needle takes multiple tiny samples (core needle biopsy). These samples are sent to the laboratory to look for cancerous cells. Performed under local anesthetic in the urologist’s office, the biopsy takes about 15 minutes and is mildly uncomfortable. Sometimes, a biopsy fails to detect cancer when there is a high level of suspicion, so a repeat biopsy may be needed.

Potential complications of a biopsy include bleeding, lower urinary tract symptoms, urinary tract infection, and prostate infection (prostatitis). Some men report worsening of erectile dysfunction. The risk of infection can be reduced by giving prophylactic antibiotics before the biopsy. Men should avoid taking nonsteroidal anti-inflammatory drugs (like aspirin or ibuprofen) and fish oils for three days prior to biopsy, to reduce bleeding risk.

Image-guided targeted fusion biopsy is one of several techniques being used to improve accuracy of biopsy. First the patient undergoes an MRI, during which abnormal areas are flagged. Then an ultrasound-guided biopsy takes samples from these targeted areas.

Post-Diagnosis Investigations

If you have a confirmed diagnosis of prostate cancer, your doctor may want to perform further tests to determine the severity and to check whether it has spread (metastasized). Prostate cancer can be tiny when it first presents, and its spread is unpredictable, so these tests are very useful.

Investigations may include:

• Pelvic ultrasound to look for local spread beyond the prostate.
• Bone scan to look for bone metastases.
• Chest x-ray to look for lung and chest wall metastases.
• Advanced imaging such as CT scans (computed tomography), MRIs (magnetic resonance imaging), and PET scans (positron emission tomography)—which may be used to look for signs of spreading to the lymph nodes, pelvis, or beyond.
• Lymph node biopsy to look for spread to lymph nodes
• Genomic testing to help determine which cancers are benign and low-risk, and which are aggressive and life threatening. Examples include Oncotype DX Genomic Prostate Score (GPS), ProMark, Decipher, and Prolaris.

The results of these tests can be used to guide decisions regarding treatment.

Biopsy Results: Histology

Biopsy samples are evaluated for changes in cells. Changes are seen on the following continuum.

High-Grade Prostatic Intraepithelial Neoplasia (HGPIN or PIN). As with other cancers, prostate cancer starts with precancerous changes that may be discovered via biopsy. PIN is divided into low-grade (mild dysplasia) and high-grade prostatic intraepithelial neoplasia (HGPIN, or severe dysplasia). HGPIN are abnormal cells that have not become invasive and are found in 80 to 100 percent of prostates with carcinoma. This finding suggests that they are a precursor to carcinoma in some men. It should be noted, however, that these cells are detected in up to a quarter of men, most of whom do not go on to develop cancer. In those who do develop carcinoma, PIN predates malignancy by 10 or more years. A small body of evidence suggests that when PIN is found in multiple sites, there is an increased risk of prostate cancer. If PIN is detected, a six-month follow-up biopsy may be recommended.

Atypical Small Acinar Proliferations (Atypia or ASAP). Atypia is a more significant finding than PIN, as approximately 50 percent predate cancer. It is found at biopsy in 2 to 5 percent of men. In atypia, there are abnormal cells; however, they are few in number, and they don’t quite look like cancer cells. Plus other features (such as inflammation) may confuse the picture. Some clinicians describe atypia as “suspicious” or “highly suspicious for cancer” and recommend rebiopsy in six months, with more extensive sampling.

Cancer. If cancer cells are found at biopsy, they will be “graded” to see how abnormal they are. Low-grade cancers most resemble normal tissue and may have only just begun to invade locally. The clinician will also look for evidence of spread beyond the prostate gland.

Measuring Cancer Severity

Clinicians use three main criteria to determine the severity of cancer:

• Blood tests. May include PSA levels, advanced PSA tests, and biomarkers.
• Grading. The Gleason score, which defines types of cells (histology).
• Staging. TNM Classification (tumor node metastasis), which defines where cancer is found.

The Gleason Score. This is the most commonly used grading score for prostate cancer. First developed in 1966, the Gleason score has been refined several times since then. It is based purely on the “architecture” or histology of the cells—that is, how they look in the laboratory. It has been found to be a good indicator of how cancer will progress and, thus, is a useful guide for treatment.

The Gleason score is composed of two scores—one for each of the two most common types of cancer cells found in the biopsy samples. Both types are graded using a scale of 1 to 5. A score of 1 means the cells are very close to normal; a score of 5 means the cells are very abnormal. The scores are added to get a final score between 2 and 10. In practice, prostate cancers are graded as Gleason scores 6 (low risk) through 10 (high risk).

Modified Gleason Score. Some clinicians are shifting over to the new International Society of Urological Pathology (ISUP) score. It ranks cancers from 1 to 5, corresponding to Gleason grade 6 to 10:

• Gleason scores ≤ 6: ISUP grade 1 (low risk, least aggressive)
• Gleason score 3 + 4 = 7: ISUP grade 2 (intermediate risk, favorable)
• Gleason score 4 + 3 = 7: ISUP grade 3 (intermediate risk, unfavorable)
• Gleason score 8: ISUP grade 4 (high risk, most aggressive)
• Gleason score 9 to 10: ISUP grade 5 (high risk, most aggressive)

ISUP’s proponents say that the scale is potentially less confusing to patients because it ranks low-risk cancers as grade 1 instead of grade 6 (as in the conventional Gleason score). Research is ongoing to establish whether using the ISUP grading scheme leads to better overall outcomes, such as fewer cases of over-treating low-risk cancers and being able to identify the most high-risk, potentially aggressive cancers.

Staging Prostate Cancer. TNM Classification was developed by the American Joint Committee on Cancer (AJCC). The tumor node metastasis, or TNM, staging system is used to define prostate cancer progression. It has three components: primary tumor (T), lymph node (N) involvement, and metastasis (M: spread to other organs). See ‘Prostate Cancer Stages’ for a summary of these stages.

Risk Group. Having completed the necessary investigations, your doctor will determine your risk group. This, in turn, will help predict prognosis and guide treatment.

The search for new, more reliable assessments is ongoing.

Enhanced Screening: New Developments

Genetic mutations are occurring all the time in our bodies, but most result in no harm to the individual and the mutation line dies out. When mutations occur in certain genes, disease—including cancer—may follow.

Somatic Mutations. The most common type of mutation involves genes responsible for cell growth, cell repair, and cell division. These so-called somatic mutations can lead to abnormal or uncontrollable cell division, with the result being a tumor.

Somatic mutations are not passed down to future generations. Most prostate cancers are due to these sporadic somatic mutations and are therefore not hereditary or detectable on genetic screening.

Germline Mutations. Less common are “germline mutations” that affect every cell in the body. They are usually triggered by lifestyle and environmental factors and changes in other genes. Germline mutations can be inherited.

Inherited genes implicated in prostate cancer include BRCA1, BRCA2, and HOXB13. BRCA1 and BRCA2 repair damaged DNA and suppress tumors, keeping cell division at a normal level.

Gene Fusion. Gene fusion is a hybrid gene formed from two previously separate genes. The fusion occurs due to DNA damage, when damaged pieces of DNA merge with other fragments of DNA, creating new genes.

Generalized inflammation and environmental factors have been implicated in this process. (The study of gene alteration due to environment, as discussed earlier, is known as epigenetics.)

In as many as 50 percent of men with prostate cancer, there is gene fusion of TMPRSS2 and ERG. TMPRSS2 is a gene that makes an enzyme called transmembrane protease serine 2. ERG is a gene responsible for transcribing DNA for the cancer-causing gene ETS (erythroblast transformation-specific).

Other genetic markers implicated in prostate cancer include: TP53, AR, PTEN, PIK3CA, RB1, APC, CHD1, MYC, and ATM.

The aim of current research is to identify more genes involved in prostate cancer, understand the mode of action, and develop therapies to reduce the burden of disease.

Liquid Biopsies. Liquid biopsies take a urine or blood sample and look for evidence of cancer cells, DNA, or fragments of cancer. They can be used to help detect early cancer, develop a treatment plan, and track progress of treatment. The advantage is that liquid biopsies are far less invasive than repeated prostate biopsies.

For example, the ExoDx Prostate IntelliScore measures exosome (fragments of cells) biomarkers in urine. The Stockholm3 (STHLM3) blood test screens several forms of PSA, other protein biomarkers, and germline genetic markers and clinical variables. One study found that use of the STHLM3 could reduce the number of biopsies by nearly one-third and the number of benign biopsies by 44 percent, according to the researchers.

IsoPSA is another blood test that’s showing promise. A 2017 study reported in European Urology concluded that “IsoPSA demonstrated a 48 percent reduction in false-positive biopsies… [and a] 45 percent reduction in the false-positive rate.”

Still another potential new screening technique is surface-enhanced Raman scattering (SERS). In preliminary research, SERS has shown promise for distinguishing between high- and low-risk prostate cancer based on blood or urine samples.

Prostate Cancer Treatment

It’s normal to feel shocked and overwhelmed by a diagnosis of prostate cancer. But unlike many other cancers, most prostate cancers are slow growing and not life-threatening. The five-year survival rate for local or regional prostate cancer (confined to the prostate and nearby tissues and organs) is virtually 100 percent. But if, at diagnosis, the prostate cancer has spread to more distant parts of the body (i.e., metastatic prostate cancer), the five-year survival rate is around 30 percent.

If you receive a prostate cancer diagnosis, listen carefully to the information your clinical team gives you and take your time to process it. If you’re uncertain about something, ask for clarification either at the time or at a later date. Get as much information as you can in writing, so that you can learn more when the initial shock has died down.

Myriad treatment options exist for prostate cancer. There is no one-size-fits-all approach. Deciding on the best treatment protocol is a complicated process. Prostate cancer treatments involve complex trade-offs, and each treatment has its own risks and benefits.

The big dilemma in prostate cancer is whether to treat it in “low-risk” cases. Some slow-growing cancers pose little immediate risk to health, and there are significant complications to treatment.

The aim of treatment should be to improve longevity and quality of life. A younger man—one who potentially has decades of life ahead of him—may decide that living with cancer and the uncertainty it brings will warrant aggressive treatment with a high chance of a cure. An older man who has other health problems may decide to hold off on treatment until his doctor tells him it’s urgent.

Shared Decision-Making

The American Urological Association (AUA) offers useful guidelines for doctors on how to treat prostate cancer. They recommend beginning with an initial assessment, followed by counseling and then shared discussion regarding treatment options. These options are geared around the following factors:

Risk Category. At diagnosis, cancers are often referred to as low-, intermediate-, or high-risk. Doctors determine the risk according to the characteristics of the tumor, its aggressiveness, and its spread, as assessed via these procedures:

• Blood tests (PSA levels, advanced PSA tests, and biomarkers)
• Grading the types of cancer cells (Gleason score)
• Staging the spread of the cancer (TNM classification)

Life Expectancy. Determined by current age and general health. This may be overwhelming to discuss, but it’s important. As you have learned, many prostate cancers are so slow-growing that they may take decades before they are problematic.

Current Level of Functioning and Lifestyle. It’s important to assess your baseline quality of life, including work, family, love life, leisure time, and so on.

Expected Post-Treatment Function. Consider expectations surrounding your sex life. It’s important to look ahead, too. What would you like your life to look like in five or 10 years?

Your Values and Preferences. Consider the importance of issues like recovery time, side effects, and distance you’re willing to travel for treatment.

Your Clinician’s Preference and Expertise. Many of the treatments discussed later in this chapter are not offered by every doctor. Outcomes are better when the doctor is an expert in a particular technique. As a general rule, look for an experienced surgeon who is completing at least 40 radical prostatectomies each year, as they tend to have better outcomes, with lower complication rates.

Lifestyle. Your clinical team should also talk to you about your modifiable risk factors—smoking, obesity, and diet, for example. Lifestyle changes may have an impact on your risk of cancer progression and also may improve your quality of life, general health, and wellbeing.

Specialists. You may also be referred to a range of specialists (like medical oncologists, radiologists, and surgeons) who can advise you on the various treatment options. You may also be informed of your eligibility to take part in ongoing clinical trials for new therapies.

Research with care. We live in an age when access to medical information is at our fingertips 24/7. It’s great to research and become an expert on your own condition, as then you can make informed decisions and advocate for yourself. There is a down side, however, to personal research. First, you may become frightened or obsessed while reading information that isn’t designed for the public. Plus, there’s a lot of inaccurate information on the internet, and with it comes the potential to make bad decisions. That said, there are some excellent sites that are reliable, among them the National Comprehensive Cancer Network, Cancer.org and Cancer.gov. You may also want to access professionally run community groups and support groups. Also, be extremely wary of getting advice from friends and family: They are biased, don’t understand your clinical picture, and may feed you dubious advice. Your health is too precious to leave to anyone who isn’t a medical professional.

AUA Treatment Guidelines

The American Urological Association (AUA) has published guidelines for treating localized (i.e., nonmetastatic) prostate cancer. Highlights of the recommendations for low-, intermediate-, and high-risk prostate cancer are as follows:

Very-Low/Low-Risk Prostate Cancer

• Active surveillance. Preferred approach for men with very low-risk (localized) prostate cancer and most men with low-risk prostate cancer. Active surveillance refers to deferring treatment until follow-up tests indicate that the cancer is starting to present a greater risk. The intention is still to cure.
• Watchful waiting: May be an option for older men with low-risk cancer whose life expectancy is less than five years. Watchful waiting, or observation, means deferring treatment until symptoms appear or change. It is sometimes confused with active surveillance, in which the intention is to cure, not just relieve symptoms.
• Radical prostatectomy or radiation therapy: For those at higher risk of progression, including younger men with strong family history of prostate cancer and gene markers.
• Hormone therapy (androgen deprivation therapy/ADT): The AUA advises that men with low-risk, localized prostate cancer should not be offered ADT, except to shrink tumors prior to brachytherapy (i.e., “radioactive seed therapy”)
• Cryotherapy and high-intensity-focused ultrasound (HIFU): Both are available, although there’s a lack of strong evidence for their effectiveness in comparison to standard treatment options.

Many men on active surveillance have poor compliance with follow-up, so it’s important to confirm the diagnosis with a repeat biopsy or MRI scan before they enter active surveillance. Up to one in three men, given a low-risk diagnosis, turn out to have cancers that are more advanced, and in rare cases they go on to die of an aggressive cancer. Misdiagnosis is most common in African-­American men.

Intermediate-Risk Cancer

• CT or MRI scan: Doctors should consider CT or MRI, or a bone scan, to accurately determine the stage of unfavorable intermediate-risk cancer.
• Standard treatments: Either a) radical prostatectomy (RP) or b) radiation therapy plus androgen deprivation therapy (ADT).
• Cryosurgery: May be considered in some men who are not good candidates for RP or radiation therapy.
• Active surveillance: May be an option for men with favorable ­intermediate-risk cancer who understand and are willing to accept the higher risk of metastasis.
• Watchful waiting: May be an option for older men whose life expectancy is less than five years.
• High-intensity focused ultrasound (HIFU): Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking.

High-Risk Prostate Cancer

• CT or MRI scan plus bone scan: To accurately determine staging.
• Radical prostatectomy or radiation therapy plus hormone therapy: Standard treatment.
• Active surveillance: Not recommended for men with high-risk localized prostate cancer.
• Watchful waiting: May be considered in men without symptoms and who have a life expectancy of less than five years.
• Cryosurgery, focal therapy, and HIFU treatments: Not recommended for high-risk, localized cancer unless as part of a clinical trial.
• Hormone therapy alone: Not recommended except in men with a life expectancy of less than five years plus local symptoms.
• Genetic counseling: May be considered for the patient and close family, especially if there is a history of other cancers—breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma.

In high-risk prostate cancer, there is more urgency about making treatment decisions. The earlier the treatment is initiated, the better the outcome.

Metastatic Prostate Cancer

• Hormone therapy: Standard treatment.
• Pain relief as needed.
• Palliative care if it becomes necessary.

Radical Prostatectomy

Retropubic radical prostatectomy (RP) is the most common surgery for prostate cancer. It produces excellent outcomes, especially in younger men or healthy older men.

Procedure

Prior to surgery, the bowel is evacuated and cleansed to open up space in the pelvis. The surgery is done under general or spinal anesthetic in the operating room. The surgeon accesses the prostate via an incision in the abdomen or the perineum (the area between the scrotum and anus). The entire prostate gland and seminal vesicles are removed—thus the word “radical.” Local lymph nodes are often removed as a precaution.

Surgery is most effective in men with disease isolated to the prostate (stages T1 and T2), who are healthy, and who are under age 70. A hospital stay of one to three days is usual, but it may take several weeks to feel back to normal. Catheterization for at least a week is recommended, to allow the urethra to heal.

During surgery, the surgeon has to weigh certainty against the risk of complications. Removing more tissue and lymph nodes increases the certainty that all of the cancer has been removed, but increases the risk of damaging the nerves to the penis, leading to impotence, and increases the risk of damaging the urethral sphincter, leading to urinary incontinence.

Techniques

There are several radical prostatectomy techniques, including:

Open. Abdominal incision above the pubic bone or perineum. This gives the surgeon an excellent view of the prostate and surrounding organs in the pelvis and the ability to biopsy local lymph nodes (lymph node dissection). This is the preferred technique for more advanced cancers.

Laparoscopic. A flexible laparoscope is inserted via a small incision in the abdomen, suprapubic area, or perineum, and the prostate is removed. Technically, this is much more difficult, requiring expert training. Lymph nodes cannot be dissected.

Robotic. Robotic procedures now account for 60 percent of RP surgeries in the United States. Three to four incisions are made for robotic arms or laparoscopes. One arm carries a laparoscopic video camera, the other surgical tools. The surgeon sits at a screen and operates the robotic arms with a joystick and pedals. Advantages: Improved accuracy, shorter hospital stay, and less blood loss (and, consequently, a lower transfusion rate). Survival rates are similar to open surgery.

In a recent study in Lancet Oncology, 326 men were assigned at random to undergo either open or robotic radical prostatectomy. After two years of follow-up, the men in both groups had essentially the same outcomes in terms of urinary and sexual function. Both procedures appeared to eliminate cancer equally well.

Nerve-Sparing Radical Prostatectomy. This is a prostatectomy with an added technique that attempts to minimize damage to the neurovascular bundles—the nerves and blood vessels that allow the penis to become erect. These are dissected and spared from removal, with the aim to preserve erectile function and lessen urinary problems. This procedure is delicate and time-consuming. The results cannot be guaranteed, and it takes several months for function to begin to recover.

Perineal Incision Technique. In a ­seldom-used approach, the surgeon makes an incision in the perineum, the area between the scrotum and anus, to gain access to the prostate gland and remove it. The advantage of the perineal incision technique is that it’s easier to perform in overweight men and causes less bleeding and pain. The disadvantage is that lymph nodes cannot be biopsied and nerve damage is more common.

Outcomes. For men with localized cancer, radical prostatectomy has a high cure rate. For those with cancer that has spread beyond the prostate, radiation or hormonal therapy may also be needed.

Open, laparoscopic, and robotic radical prostatectomies have similar outcomes in experienced hands, so the decision as to which technique to use should be determined by the surgeon’s expertise and the patient’s preference.

Potential Complications. Early complications, which usually settle in during the first two weeks after surgery, include bleeding, infection (in scar, urine, or prostate), swelling of the penis and scrotum, abnormal changes in the lymph nodes (lymphadenopathy), and heart problems.

In the 2016 ProtecT Trial of 391 men, there were no deaths after prostatectomy. However, nine men had thromboembolic (blood clot) or cardiovascular events, 14 required substantial blood transfusions, one had a rectal injury, and nine developed anastomoses (abnormal connection between two organs).

Persistent complications include nerve damage and erectile dysfunction (20 to 70 percent) and urinary incontinence (50 percent). Some untreated men also develop these complications during active surveillance, but at a rate half that of surgery.

Urinary control and sexual function can improve, with time, after prostatectomy. One study followed 3,187 men for up to four years after surgery. Among men who had urinary incontinence a year after surgery, 30 percent had good urinary function within two years post-op; 49 percent within three years; and 59 percent within four years. For those with impotence at 12 months post-op, erectile function was restored at two years in 22 percent; at three years in 32 percent; and at four years in 40 percent.

Benefits of Surgery. Surgery removes a lot of uncertainty. Research shows that in men with disease isolated to the prostate, 90 percent are alive and cancer-free 10 years after surgery. A coincidental benefit is that you will never develop benign prostatic hyperplasia, a troublesome condition affecting half of men over the age of 60. Open surgery has the advantage of allowing biopsy of lymph nodes to improve certainty over staging and guide further treatment.

Postsurgical Therapy. Some men will be offered radiation or hormone therapy following surgery. It may be recommended in the following situations:

• Adjuvant therapy. For high-risk patients, where cancer was seen on the outer margin of the removed tissue or where cancer had spread to the seminal vesicles. This is usually performed soon after surgery.
• Salvage therapy. For “biochemical recurrence.” A rise in PSA in the months following surgery is seen in 25 to 30 percent of patients. External-beam radiation is usually offered, but some clinicians prefer hormone therapy.

Pre-RP Lymph Node Biopsy. To be certain of staging, some surgeons perform lymph node biopsy to rule out lymph node involvement and steer treatment.

Radiation

Radiation is a viable alternative to radical prostatectomy, with the potential for cure in localized prostate cancer. It carries with it its own set of risks and benefits. There are two forms of radiation therapy commonly used to treat prostate cancer: external-beam radiation therapy (EBRT) and brachytherapy (implanting tiny radioactive pellets, or “seeds,” into the prostate gland).

External-Beam Radiation Therapy (EBRT)

EBRT can be used as a primary treatment for localized cancers, or following surgery, where biopsy reveals spreading beyond the prostatic capsule, or if PSA rises in the postoperative months.

Procedure. Currently the most widely used radiation therapy, EBRT uses focused high-energy x-rays over multiple sessions to destroy the cancer. It can also be used on diseased lymph nodes. The major disadvantage is that EBRT is time-consuming: The patient receives radiation therapy for about 15 minutes each day, five days a week, for about two months. Straps are used to prevent movement and lead shields protect surrounding organs (testicles and penis).

Good Candidates. EBRT is a good option for older men with other health problems in whom cancer has spread outside of the prostatic capsule (Stage 3) and in men who have already had TURP (transurethral resection of prostate) for benign prostatic hyperplasia. It can also be used in advanced cancers to help reduce the size of the prostate and reduce symptoms.

Advanced EBRT. Technological advances with high-dose EBRT have led to improved precision of this technique:

• 3-dimensional conformal radiation therapy (3D-CRT). The radiation beam is shaped to match the tumor and reduce damage to surrounding healthy tissue. Beams of radiation come from several directions to precisely match the tumor’s height, width, and depth.
• Hypofractionated radiation. This newer technique is gaining popularity. It uses higher doses of radiation over four to five weeks. It has a similar side effect and outcome profile to standard EBRT.
• Intensity-modulated radiation therapy (IMRT). This treatment uses state-of-the-art, targeted, high-dose radiation, minimizing damage and side effects. A 3D map of the tumor is created and high-intensity radiation beams are targeted at the affected areas.
• Proton beam therapy (PBT). This treatment uses protons instead of photons (x-rays). Protons are charged particles that radiate energy. Photon beams are narrow and easier to target, scatter less, and may cause less damage to healthy tissue. Early results are showing similar outcomes to EBRT, but gastrointestinal complications are more common. PBT is not available in all centers, and it may not be covered by insurance, although it may be available as part of a clinical trial.
• Stereotactic body radiation therapy (SBRT). Offered as an alternative to conventional radiation fractionation for low-risk patients, but for intermediate- and high-risk patients it should be offered in a clinical trial setting. These techniques (often referred to by brand names like CyberKnife, Gamma­Knife, or TomoTherapy) speed up the process further, to just five days. They deliver high-dose radiation with pinpoint accuracy. Early results are promising but suggest that side effects may be higher. SBRT may be useful for men whose cancer has spread beyond the capsule or for men who have had a TURP. It is available at only a limited number of centers.

Outcomes. Some evidence suggests that survival rates may be slightly lower in men treated with EBRT rather than radical prostatectomy or brachytherapy.

Potential Complications. EBRT has different complications from surgery. Because the beam cannot discern healthy from cancerous tissue, there’s a chance of healthy tissue being damaged. Common complications include:

• Cystitis (inflammation of bladder), blood in urine, urinary retention, and urinary incontinence.
• Proctitis (inflammation of rectum) and enteritis (inflammation of small intestine), which leads to diarrhea, blood in stool, bloating, rectal leakage, and rectal pain. Bowel symptoms can persist for months.
• Impotence takes time to develop after radiation therapy; five years after treatment it is at a similar level to surgery.
• Fatigue may develop during treatment and last weeks or months after treatment has stopped.
• Lymphedema is the swelling of the legs or genitals. It can occur when the lymph nodes—which normally help drain fluid from an area—are damaged by radiotherapy. It can cause significant discomfort.
• Secondary cancers (bladder, colon, and rectum) are a potential but rare complication.

Complication rates vary between technique and dose used. They also depend on pre-treatment function.

Gastrointestinal (GI) complications are most common with proton-beam therapy, while brachytherapy has the lowest risk of GI problems. In an attempt to reduce GI damage, researchers have developed “tissue spacers” to reduce rectal exposure to radiation. For example, the SpaceOAR (Spacing Organs At Risk) System is an FDA-approved hydrogel that is injected as a liquid, quickly solidifying to create a radiation-absorbing barrier between the prostate and rectum.

Secondary cancers may be slightly higher after EBRT. A study published in The BMJ found that EBRT—but not brachytherapy—potentially increased the risk of bladder and colorectal cancer, although the absolute number of cancers was low. They noted “further studies with longer follow-up are required to confirm these findings.” It would be hard to prove categorically that a secondary cancer was due to radiation, and that the cancer wouldn’t have occurred anyway.

Benefits. Radiation therapy is pain-free, and recovery time is much shorter than with surgery. Plus, there is no anesthesia or surgical wound from which to recover. Compared to surgery, immediate complications are less common.

Brachytherapy (BT) or Seed Therapy

Brachytherapy is also known as internal radiation therapy or interstitial radiation therapy.

Procedure. An outpatient procedure, BT takes about 60 minutes to complete. It requires either general or spinal anesthesia. An ultrasound or MRI-guided needle inserts 50 to 150 “seeds”—pellets the size of a grain of rice—throughout the prostate. It’s like having a mini-x-ray machine embedded into the prostate; it works continuously until it runs out of energy, after about a year.

Good Candidates. For standard brachytherapy, men with low-risk cancer and a small prostate are better candidates. For high-dose brachytherapy, intermediate- and high-risk patients are better candidates.

Outcomes. BT survival rates are similar to surgery. However, quality of life tends to be a little better, as urinary incontinence and sexual problems are less common. Research also suggests that survival rates and quality of life are better after brachytherapy than after EBRT.

Complications. Radiation travels only a few millimeters and thus has little effect on the organs external to the prostate. However, the urethra—which lies in the center of the prostate—may be damaged during radiation, leading to urinary problems in most men. Some men require temporary catheterization during treatment. Physical exercise may reduce urinary symptoms. Rarely, bowel symptoms occur, for a month or so. There is a small radiation risk to people around you, so it is advised that pregnant women and children under 18 should avoid sitting on your lap for extended periods, at least in the first two months. In the first two weeks, the seeds can be ejaculated (in 1 percent of patients), so sex should be avoided; later, a condom should be worn during sex. Urine remains radioactive and toxic for months.

Benefits of brachytherapy. Most men recover quickly from the insertion procedure and are pain-free. There is no abdominal or perineal wound to heal. Compared to EBRT, the time commitment is much lower—one procedure and you’re done.

Which Treatment Is Best?

Studies have compared the outcomes for the main treatment options: radical prostatectomy, EBRT, brachytherapy, and active surveillance. The findings show that each option has its own long-term side-effect profile. Here’s a summary of recent research.

One study reported in Cancer Medicine in 2017 measured quality of life 15 years after prostate cancer treatment, comparing RP, EBRT, and BT. The findings were:

• Impairments in urinary irritation/obstruction. Worse in EBRT or BT.
• Decrease in bowel function. Worse in EBRT. However, newer techniques are improving this.
• Long-term change in urinary incontinence. Worse for patients treated with RP compared to BT.

A study in Radiotherapy Oncology looked at quality of life changes 48 months after treatment in the cases of 907 men. Researchers looked at RP, BT, and IMRT. Findings:

• RP. More urinary incontinence, but less urinary irritation and obstruction than radiotherapy. Very low levels of bowel dysfunction.
• Brachytherapy and IMRT. Better sexual function than in those who had surgery, although all groups had symptoms.

The ProtecT Trial was a large randomized study. Researchers followed patients for 10 years and compared surgery (RP), radiotherapy, and active surveillance. The findings include:

• Prostate cancer–specific mortality. At a similar level in all groups—around 1 percent after 10 years. All-cause mortality was similar in all groups at around 10 percent. Risk of death from cancer was 6.6 percent lower after RP compared to active surveillance at eight years follow-up, and 11 percent lower at 23 years.
• Disease progression and metastasis. RP and radiotherapy progression rates were less than half those of active surveillance.
• Active monitoring. Forty-four percent of the patients who were assigned to active monitoring did not receive radical treatment and avoided side effects. Fifty-six percent went on to need treatment over the 10-year period.
• Number needed to treat (NNT). This is a measure of the number of patients receiving treatment to avoid one case of metastatic disease. Here are the statistics compared to active surveillance: prostatectomy NNT = 27; radiotherapy NNT = 33; either prostatectomy or radiotherapy NNT = 9.
• Incontinence. Three years after treatment, the rates of urinary incontinence were 7 percent in high-dose-rate brachytherapy; 5.4 percent in low-dose-rate brachytherapy; and 2.7 percent in EBRT. The rates of erectile dysfunction were 72 percent in high-dose-rate brachytherapy, 36 percent in low-dose-rate brachytherapy, and 68 percent in EBRT.

The researchers point out the importance of recording a patient’s baseline functions and quality of life before treatment begins.

The Scandinavian Prostate Cancer Group study supports the ProtecT findings. Researchers followed 695 men with early prostate cancer who were randomly assigned to one of two groups: radical prostatectomy or watchful waiting.

Researchers followed the men for 23 years. Sixty-three of the RT patients and 99 of the watchful waiting patients died of prostate cancer. They calculated that there was a 44 percent lower relative risk of death from the disease with RP compared to watchful waiting. Younger men and those with intermediate-risk prostate cancer saw the biggest benefits.

Conflicting evidence, however, comes from the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Researchers concluded radical prostatectomy (RP) does not significantly reduce the risk of death from prostate cancer or other causes (5.8 percent) compared with active surveillance (8.4 percent). This difference was deemed to be statistically insignificant. RP did reduce the risk of death from all causes in men with higher PSA levels (higher than 10 ng/ml) and in men with higher-risk tumors.

Cleveland Clinic researchers reported the results of a study of 1,989 patients who underwent brachytherapy. They found that the overall five-year survival rate was 93.7 percent and the 10-year survival rate was 76.1 percent. They concluded that “prostate brachytherapy, as monotherapy, is an effective treatment for low-risk and low-intermediate-risk prostate cancer and appears promising as a treatment for high-intermediate-risk and high-risk prostate cancer. Significant long-term toxicities are rare when brachytherapy is performed as monotherapy.”

In younger men with high-grade prostate cancer, surgery may be the better option, suggests a 2019 study in the Journal of Urology. Researchers found that, in men younger than 60 diagnosed with high-grade cancer, those treated initially with surgery rather than radiation had lower rates of death in general and specifically from prostate cancer.

However, this was an observational study and can’t really tell us for sure whether it was surgery or some other, as-yet unknown factor that was responsible for the improvements in survival. As the researchers noted, “Future prospective randomized trials are needed to confirm the long-term outcomes of these treatment approaches.”

Focal Therapy

Focal therapy, also known as “male lumpectomy,” selectively targets the areas of the prostate affected by cancer. Focal therapies for prostate cancer include high-intensity focused ultrasound (HIFU). The aim of focal therapy is to reduce the complications seen in more invasive open surgery. The research is not conclusive, with some studies showing outcomes comparable to surgery and/or radiation therapy in the short term and fewer long-term side effects.

One limitation of focal therapy is that prostate cancer is often, by its nature, multifocal, appearing in multiple locations in the prostate. Another problem is that cancerous tumors are difficult to pick up on ultrasound or MRI, which are used to guide focal therapy.

AUA treatment guidelines do not generally support the use of focal therapies, saying, “These treatment options lack robust evidence of efficacy.” There is, however, hope that further refinement of focal techniques may prove to be useful in the future.

High-Intensity Focused Ultrasound (HIFU)

HIFU uses precisely targeted doses of ultrasound energy to heat and destroy cancerous prostate tissue.

Procedure. In performing a HIFU procedure, the doctor inserts an ultrasound probe into the rectum, then focuses high-intensity sound waves onto the cancerous areas of the gland. These beams create focused heat that destroys tissue in seconds. HIFU is performed under spinal or general anesthesia and can be done on an outpatient basis.

HIFU has fewer side effects than surgery and radiotherapy, but there is inadequate research on outcomes.

While HIFU has been used for years in Europe and Canada to treat prostate cancer, it is not widely available in the United States, and some health insurance companies won’t cover the procedure. In 2015, the FDA approved HIFU for “prostate tissue ablation”—not specifically for cancer treatment.

Potential Complications. Erectile dysfunction and irritating urinary symptoms (including burning pain while urinating) are common.

Cryotherapy

Cryotherapy, which is conditionally approved by the AUA for local prostate cancer, is the targeted freezing of the prostate to destroy cancer cells. It is also known as cryosurgery or cryoablation. Cryotherapy can be used as a whole-gland treatment or a focal therapy approach.

Procedure. A surgeon uses thin, needle-like probes to enter the prostate through the perineum, and then injects liquid nitrogen into the prostate, freezing and destroying (ablating) cells. Catheterization may be needed for up to a week. The procedure is not widely available.

Good Candidates. The American Urological Association guidelines state that cryotherapy may be considered in men with intermediate-risk localized prostate cancer when radical prostatectomy or radiation therapy are inappropriate due to other health problems. It can also be used to treat cancer that has recurred after primary treatment with surgery or radiation.

Certain men are not good candidates for cryotherapy, including those who have undergone transurethral resection of the prostate (TURP) for benign prostatic enlargement, those with a very large prostate, and those with inflammatory bowel disease.

Outcomes. Cryotherapy can be used to treat the entire prostate gland or as focal therapy to ablate part of the prostate and potentially reduce complications. Some research suggests that local cancer control with cryotherapy is not quite as good as with surgery. Also, unlike surgery, cryotherapy and radiation therapy do not allow for a pathological review of the prostate tissue. Cryotherapy can be combined with ADT, but there is no consensus as to whether this improves outcomes. It is less invasive than surgery and recovery is faster; however, as with radiation, the whole prostate cannot be assessed to accurately determine staging and grading of the disease.

Potential Complications. Complications may be severe, from erectile dysfunction (up to 90 percent) to urinary incontinence (5 percent). Irritation and obstructive urinary problems are common side effects. Rectal fistula also may occur: This is an unpleasant condition where a false connection occurs between the rectum and the perineum (skin between rectum and scrotum), allowing uncontrollable leakage of feces.

A study published in the Journal of Endourology followed 300 men with high-grade prostate cancer after cryotherapy. The study’s researchers looked at whether PSA stayed low (biochemical progression-free survival, or BPFS), and found a two-year BPFS rate of 77 percent and five-year BPFS rate of 59.1 percent. At a 12-month follow-up, 90.5 percent were completely continent and 17 percent were fertile. Rectourethral fistulae occurred in 1.3 percent of patients and severe urinary retention in 3.3 percent.

Androgen-Deprivation Therapy (ADT)

Because prostate cancer originates mainly in the hormone-sensitive glandular cells of the prostate, testosterone and other male sex hormones (androgens) fuel prostate cancer. It makes sense, then, that androgen-deprivation therapy—which reduces levels of androgens in the body and in tumor cells—can slow the progression of cancer, but not cure it. ADT, also called hormonal therapy, can be used alone or in combination with other treatments.

Benefits of Hormone Therapy

ADT can reduce the size of a cancer, reduce symptoms and pain, and may extend life. However, ADT is not a cure, and over time the cancer may begin to grow again, despite the low testosterone.

In men with advanced prostate cancer that is aggressive or has spread beyond the prostate, a combination of hormone (ADT) and radiation therapy reduces the risk of dying by nearly 30 percent compared to radiation alone. Some clinicians use a protocol with intermittent ADT treatment to reduce side effects. PSA levels are monitored and ADT is started when levels creep up; treatment is stopped when PSA drops. In men at intermediate risk, this combination therapy is considered a viable alternative to radical prostatectomy.

ADT Options. Therapies used to reduce androgen levels and slow the progression of prostate cancer include:

• LHRH agonists. Available in one-month, three-month, or six-month injections or annual depots (implant under skin). These drugs stimulate the pituitary gland to produce LH (luteinizing hormone). This causes an initial rise in testosterone, followed by an abrupt decline. Drugs include goserelin (Zoladex), leuprolide (Eligard, Lupron Depot), triptorelin (Trelstar), and the implant histrelin (Vantas).
• LHRH antagonist. Available in a one-month depot. This type of drug blocks the production of gonadotropin-releasing hormone (GnRH) by the pituitary gland, which ultimately decreases production of testosterone in the testes. The drug prevents signals from the pituitary gland to the testicles, thus preventing production of testosterone. The drug of this type currently available in the United States is degarelix (Firmagon).
• Anti-androgens. Also known as androgen antagonists or testosterone blockers, these drugs suppress the action or production of androgens like testosterone. They’re taken in a tablet form. Current anti-androgens in use include apalutamide (Erleada), bicalutamide (Casodex), darolutamide (Nubeqa), enzalutamide (Xtandi), flutamide (Eulexin), and nilutamide (Nilandron). Abiraterone (Zytiga) with prednisone: Abiraterone blocks production of testosterone in prostate cancer cells. It’s taken along with prednisone, a potent anti-inflammatory medication.
• LHRH agonist or antagonist with an oral antiandrogen. This combination of drugs creates a complete androgen blockade.
• Bilateral orchiectomy. This surgery removes both testicles and replaces them with prosthetic ones. Once a common procedure, it is now rarely used.

Good Candidates for ADT

The National Comprehensive Cancer Network and the European Association of Urology recommend androgen deprivation therapy to treat advanced prostate cancer when local therapy has failed. The aim of treatment is to shrink the cancer or slow its growth and give palliative relief (meaning a reduction in severity, even if the condition can’t be cured).

ADT can also help to reduce urinary outlet obstruction and, in lower-risk men, to shrink cancer prior to surgery or radiation. Over time, most cancers stop responding to ADT and progression resumes. Standard treatment lasts 24 to 36 months.

Potential Side Effects. Low androgen levels can cause some unpleasant side effects and seriously affect quality of life. Among them:

• Feeling weak and unwell due to fatigue, anemia, and reduced muscle mass.
• Breast enlargement (gynecomastia).
• Hot flashes.
• Decreased libido and erectile dysfunction (usually improves when treatment stops).
• Increased risk of metabolic syndrome (high blood pressure, high blood sugar, abdominal obesity, and abnormal blood lipids), which increases the risk of cardiovascular disease, stroke, and diabetes.
• Psychological changes and ­cognitive impairment (forgetfulness, inattention, and depression are common).
• Increased risk of diabetes. The relative risk is 30 to 40 percent higher. Monitoring of blood glucose and lipids is advised.
• Increased risk of cardiovascular death. In one study, risk increased to 4.2 percent five years after therapy (1.5 percent in controls) and 13.5 percent 10 years after therapy (5.8 percent in controls).
• Pulmonary edema, or fluid on the lungs, which results in shortness of breath and cough.
• Increased risk of colorectal cancer and liver failure.
• Gastrointestinal tract disturbances, including diarrhea.
• Increased risk of acute kidney injury (5.5 per 1,000 person years), a rare condition with a 50 percent mortality rate.
• Osteoporosis and an increased risk of fractures.

Reducing ADT Side Effects

Cardiovascular Health. Baseline testing of blood glucose and cholesterol should be done. Eating a healthy diet can reduce the risk of obesity, diabetes, and high cholesterol. Regular exercise (with medical supervision) can reduce muscle and bone loss, improve balance, reduce the risk of falls and improve cardiovascular health. One study found that men who exercise when starting androgen deprivation therapy report fewer sexual side effects, less fatigue, and better mood. Cigarette smoking is discouraged, as it increases the risk of many of the complications.

Bone Health. Men with advanced prostatic cancer are at high risk of bone disease. Hormone treatment (ADT) causes osteoporosis and makes some men frail and more prone to falling and fracturing bones.

Drugs such as zoledronic acid (Reclast), denosumab (Prolia), and others may protect against fractures. They are given with calcium and vitamin D. Baseline bone health should be measured before treatment.

Bisphosphonates, such as zoledronic acid (Zometa) and pamidronate disodium (Aredia), may help reduce osteoporosis. These drugs attack osteoclasts—a type of cell that breaks down bone tissue.

Bone metastases (malignant growths in the bone) cause weakness and thinning of the bone, fractures, spinal compression, and pain. Some men require radiation to reduce growth of the metastases and surgery to stabilize weak or fractured bone, and many need pain medication.

Prostate cancer bone metastases are unpleasant and painful, and may lead to pathological fractures. Two drugs, however, have been found to help:

• Denosumab (Xgeva and Prolia) may prevent bone erosion and reduce the impact of cancer spread to bones by blocking RANK-Ligand, a substance that activates osteo­clasts.
• Radium-223 dichloride (Xofigo) is a radioactive drug that emits radiation (alpha particles) into bone metastases. Side effects include low blood counts, nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot.

Men taking these drugs need to be aware of a rare but serious side effect called osteonecrosis of the jaw. Make sure you discuss your medications with your dentist before starting these treatments or having any dental work.

Chemotherapy

The chemotherapy drug docetaxel (Taxotere) has been found to prolong survival among men with advanced prostate cancer. It may be used along with or after hormone therapy. Doctors administer docetaxel intravenously and in cycles. If docetaxel fails to help, a newer drug, cabazitaxel (Jevtana), may be used. Both prolong survival equally but Jevtana appears to be less toxic.

Chemotherapy can harm normal cells and cause hair loss, nausea, vomiting, anemia, infections, kidney failure, numbness and tingling, fatigue, infertility, excessive bleeding, headaches, and joint pain. Bone marrow suppression is a serious risk, but close monitoring can pre-empt this.

A study in the New England Journal of Medicine followed 790 men with metastatic, hormone-sensitive prostate cancer and concluded that “six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.” Men treated with the ADT-docetaxel regimen survived an average of 57.6 months, compared to 44 months for those on ADT alone.

Hormonal Therapy (ADT) with Chemotherapy

In men with metastatic cancer, hormonal therapy may be combined with chemotherapy. A study published in The Lancet randomized 385 men with metastatic cancer to two treatment groups.

The first received ADT alone, the second ADT plus docetaxel (chemotherapy). Men given ADT alone lived, on average, 44 months; those treated with the ADT/chemotherapy combination lived an average 58 months. Improvements were best in the more advanced cancers.

Close monitoring of men on the combined treatment is necessary as it can damage the bone marrow and liver.

Managing Treatment Side Effects. All treatments have side effects. Prostate cancer treatment options run the risk of chronic urinary or sexual health problems. Thankfully there are some treatments that can help.

Immunotherapy (Cancer Vaccines)

Prostate cancer vaccines are designed to help your immune system target and kill cancer cells. Rather than priming your body to kill an infectious disease, these vaccines teach your body how to kill cancer cells.

One such vaccine is sipuleucel-T (Provenge). During the procedure, the patient’s own white blood cells are collected and exposed in the lab to a protein specific to prostate cancer. These activated white cells are then reinfused into the bloodstream, where they begin to attack the cancer cells. Three doses are given intravenously over a month. It is approved for use in men with metastatic disease who no longer respond to ADT, a group in which immunotherapy has been shown to improve life expectancy by about four months.

Other prostate cancer immunotherapies are under study.

The Future: Biomarkers

Biomarkers are specific molecules that indicate a process, normal or abnormal, taking place in your body. PSA is the standard biomarker for prostate cancer; the big problem is that it isn’t specific or accurate enough. Current screening techniques may overdiagnose men with insignificant cancers and miss others with advanced or aggressive disease. Research aims to find biomarkers that can precisely predict clinically significant prostate cancer and accurately guide treatment.

Biomarkers can be measured in blood serum, urine, and tissues. They measure proteins, fragments of proteins, enzymes, DNA, and RNA.

It is likely that what will emerge are several biomarkers—some for diagnosis and some to guide therapy. Urine biomarkers may turn out to be useful, as urine is easily collected and passes through the prostate as it travels along the urethra.

Remarkable stories have been published of dogs that are able to detect cancers—from prostate to lung to breast—with incredible accuracy, suggesting that they’re picking up a particular odor, which may turn out to be a valuable biomarker.

The post 2. Prostate Cancer appeared first on University Health News.

Prostate-specific antigen (PSA) is measured in nanograms per milliliter, or ng/mL. Higher amounts of PSA in the blood have been linked to higher risk for prostate cancer. Levels below 3 ng/mL are basically considered normal, but there is a big grey area because PSA levels can be higher or lower due to conditions that aren’t related to prostate cancer. For example, urinary tract infections, or an enlarged or inflamed prostate gland can result in higher PSA. Other factors may lower PSA and mask a potentially cancerous condition; these include obesity, smoking, recent ejaculation, and the use of medications, including some common high blood pressure and cholesterol-lowering drugs.

The case for PSA screening is that the test may detect prostate cancer before it starts causing symptoms, and thus is easier to treat and often cure. The disadvantage is that it also finds small tumors that are very slow growing and may never cause a problem. In some cases, this has led to unnecessary treatments, which come with potential risks, such as urinary leakage and sexual dysfunction.

In general, however, if PSA is over 10 ng/mL, it’s likely due to cancer. Conversely and rarely, some men with a low PSA level may still have cancer. Therefore, many experts advocate for the use of formulas and risk calculators which incorporate PSA and other clinical factors to compile an individual’s risk assessment.

Key Clinical Data

With early-stage prostate cancer there are three factors that are critical to know, according to urologist Christopher Saigal, MD, professor of urology at UCLA Medical Center. The first is knowing your PSA at diagnosis.

“In men with prostate cancer PSA is overproduced in the blood. The more of it you make, the greater the chance of recurrence after treatment,” explains Dr. Saigal. “The second most important is the Gleason score, a measure of how aggressive the cancer looks on slides. The T-stage or tumor stage is also critical. In a physical exam you might not feel anything abnormal, but if you can feel a bump that is an indication of a higher T score.”

Most men diagnosed with prostate cancer have localized and low-risk or intermediate disease. Management options include radiation, radical prostatectomy, brachytherapy (surgically implanted radiation), and many choose active surveillance.

Advances in Treatment

Technical advances have improved upon external radiation treatment, significantly cutting down on the time commitment required for treatment. This newer type of radiation, known as stereotactic body radiotherapy, is a form of external beam radiation therapy that reduces the duration of treatment from 45 days to four to five days. The approach has been in use since 2000, but has not yet been widely adopted because of concerns over how safe and effective this approach would be in the long term. A recent UCLA-led study showed that men can safely undergo higher doses of radiation over a significantly shorter period of time and still have the same, successful outcomes as from a much longer course of treatment.

“We’ve found that using stereotactic body radiotherapy, which has a higher dose of radiation, can safely and effectively be done in a much shorter timeframe without additional toxicity or compromising any chance of a cure,” says the study’s lead author, Amar Kishan, MD, researcher at the UCLA Jonsson Comprehensive Cancer Center.

Researchers followed study participants for about seven years and discovered that recurrence rates for the disease were identical to recurrence rates found using more conventional forms of radiation.

Consider Your Options

With a prostate cancer diagnosis you have time to decide what’s best for you. Studies show there’s no difference in outcomes between immediate treatment and waiting six months. If possible, consider going to a medical center that has a prostate cancer program. Those centers provide more robust options that include caring for patients’ pelvic, urinary, sexual, and psychological needs. Men with higher-risk cancer are often eligible for prostate clinical trials, and centers with prostate cancer programs tend to have those available.

The post Update on Prostate Cancer Screening and Treatments appeared first on University Health News.

The Middle Ground. Focal laser ablation (FLA) is a targeted procedure that uses magnetic resonance imaging and laser technology to precisely identify and remove only the cancerous prostate tissue and a small margin around it instead of the whole prostate gland. This outpatient procedure is performed under anesthesia and takes from 60 to 250 minutes. Patients can return to work as early as the next day.

Putting It to the Test. In a study published in March in the Journal of Vascular and Interventional Radiology, researchers reported that it’s also highly effective. In a group of 120 men who underwent an FLA procedure, only 17% needed additional cancer treatment one year later. Not one of them reported problems with incontinence or sexual dysfunction. Complications included one case of urinary tract infection, two rectourethral fistulas, and blood in the urine of nine patients.

A subset of 16 patients with higher-risk cancer underwent a more extensive procedure called hemiablation. Only 6% of them had evidence of cancer one year later—but the more extensive procedure did significantly reduce sperm count.

FLA for Low to Medium Risk. The researchers concluded that FLA can be recommended in patients with low- to intermediate-risk cancer with tumors that are smaller than 1.5 milliliter (mL) or that take up less than 20% of the prostate. If the tumor is localized to one hemigland, slightly larger tumors can be treated with FLA.

Low-risk cancer means that it hasn’t spread beyond the prostate gland, that the prostate-specific antigen (PSA) level is less than 10 nanograms per millileter (ng/mL) and that the patient has a Gleason score of 6. The Gleason score represents the amount of cellular mutation in a prostate tumor. Grade 1 cells are normal, while grade 5 cells are highly mutated. The Gleason score adds the grades of the top and second most common cells.

Medium- or intermediate-risk cancer refers to cancer with a Gleason score of 7, a PSA level from 10 to 20 ng/mL, and a tumor that has grown through the capsule surrounding the prostate. FLA is not recommended for high-risk patients who have a Gleason score of 8 to 10, a PSA level higher than 20 ng/ml, or for whom cancer has spread to other parts of the body.

Long-Term Uncertainty. While the short-term outcomes are promising, the procedure hasn’t been used long enough to fully understand how it compares to traditional treatment. Cancer recurs within five to 10 years in up to one-third of patients who have the prostate completely removed. If cancer does recur, however, focal therapy can be repeated, and the procedure doesn’t limit the option to have additional treatment at a later time.

The post Targeted Prostate Cancer Treatment appeared first on University Health News.

The risk of prostate cancer increases dramatically with age. Six out of 10 cases are in men over 65, and the average age at diagnosis is 66. Prostate cancer was responsible for an estimated 29,430 deaths in 2018, according to the American Cancer Society. It is rare in younger men, but when it does occur, it tends to be more aggressive.

One last interesting statistic is that at autopsy, up to two-thirds of older men have prostate cancer but aren’t aware of it.

Screening for prostate cancer is controversial In the majority of men diagnosed with prostate cancer, the disease is slow growing and not life threatening. For these men diagnosis may lead to considerable stress, unnecessary investigations, and treatment, not to mention the stress of ­living under the shadow of a cancer diagnosis. It’s like going for a walk in the woods: Even if there are hundreds of snakes and spiders lurking near the path, the chances are that they will leave you alone. Once someone tells you there are hundreds of snakes and spiders lurking by the path, you begin to get anxious and panicky. The risk is the same, but now you know about it!

Pathology

The prostate is particularly susceptible to gene mutations. Some 95 percent of prostate cancers begin in the semen-producing glandular cells and are classed as adenocarcinomas. Four percent arise in the prostatic urethra’s transitional cells—the lining of the urethra as it passes through the prostate. In fact, changes begin there with cellular gene mutations years before cancer is detected. Over time, fast-growing mutations may develop, forming clusters of abnormal cells, tumors, and eventually cancer. Less than 1 percent are squamous cell carcinomas (normally seen on skin), most often occurring after radiation or hormone treatment.

Seventy percent arise in the peripheral zone, 15 to 20 percent in the central zone, and 10 to 15 percent in the transitional zone. At biopsy, the majority of cancers are found to be affecting multiple zones.

Local Spread

As clusters of cancer cells enlarge, they begin to invade the local tissue. Tumors arising in the transitional zone spread to the nearby bladder neck. Those arising in the peripheral zone creep into the ejaculatory ducts and seminal vesicles. Later in the process, they may reach, and breach, the prostatic capsule.

Distant Spread (Metastasis)

Sometimes prostatic cancers spread beyond the prostate, forming distant cancers or metastases (plural of metastasis). The most common sites for prostatic metastases are in bone, the lung, the liver, and adrenal glands.

Measuring Severity

The severity of prostate cancer is measured using two metrics:

• Grading: The Gleason score defines types of cells, and the level of abnormality (histology).
• Staging: The TNM Classification (Tumor-Node-Metastases) describes how widespread the cancer is.

At diagnosis, the majority of prostate cancers have low levels of cell abnormality, and spread is localized within the prostate. These cancers tend to be slow growing and have good outcomes. The cancers with the worst outcomes tend to have significant cell abnormalities and have spread beyond the capsule of the prostate.

Symptoms of Prostate Cancer

What are the symptoms of prostate cancer? Clinical presentation data provide a picture:

• 47 percent present with no symptoms; cancer is detected during screening.
• 38 percent present with increased urinary frequency, especially at night.
• 10 percent present with urinary urgency.
• 23 percent present with a decreased urine stream.
• 1 percent present with blood in urine (hematuria) or semen.
• Prostate cancer that has spread may present with:
• Reduced appetite and unexplained weight loss
• Bone pain, with or without pathologic fracture
• Feet or ankle pain and swelling
• Kidney failure.

Causes and Risk Factors

The cause of prostate cancer is complex and not fully understood. We do know that the glandular tissue of the prostate is prone to genetic mutations that may be triggered by a variety of factors. In many men, the disease seems to be random, and a cause remains elusive.

The term “risk factors” refers to attributes or exposures that increase the odds of getting the disease. For prostate cancer, there are many risk factors. Let’s consider the common ones.

Age

The most significant risk factor for developing prostate cancer is one we can’t help: aging. Sixty percent of all prostate cancers are diagnosed in men over the age of 65.

Genetic Factors

Genetics are at play in the 5 to 10 percent of prostate cancer patients who have a strong family history. A man with a first-degree relative (brother or father) with prostate cancer has double the risk of developing the disease and presents six to seven years earlier than other men.

The National Cancer Institute explains that the following factors are suggestive of genetic risk:

• Multiple affected first-degree relatives with prostate cancer, including three successive generations with prostate cancer on the mother’s or father’s side.
• A relative with early-onset prostate cancer (age ≤55 years).
• Family history of prostate cancer and other cancers (e.g., breast, ovarian, pancreatic).

Genetic researchers have so far discovered more than 100 gene variations or mutations associated with prostate cancer. Certain clusters of gene variations are helpful for predicting risk and outcome, and some mutations are linked to more aggressive cancers.

Notable culprits are the BRCA1 and BRCA2 mutations, also linked to breast cancer risk in women. A recent study presented at the American Urological Association annual meeting showed that BRCA2 carriers who developed prostate cancer were more likely to develop aggressive disease, with advanced staging at diagnosis, higher rates of metastases, and poorer survival rates. The team of researchers also found that the BRCA1 and BRCA2 genes are more commonly found in African-American men with prostate cancer, a possible explanation for why this group has poorer outcomes.

Significance of Genetic Risk

Herein lies a common dilemma in medicine: What do we do when someone is identified with a genetic risk? There is a danger that this knowledge may cause unnecessary panic and needless investigation and treatment. While prostate cancer is very common, most patients do not die from it. Genetic testing—when used prudently—can help identify men with aggressive cancers earlier and save lives. Genetic testing is increasingly used for targeting treatment.

Epigenetics

Doctors used to believe that your genes were your destiny. However, the fast-emerging field of epigenetics is proving that this is far from true: Lifestyle and environmental factors can alter the inheritance and expression of genes. What this means for people with an increased genetic risk of prostate cancer is that by improving lifestyle and environment, the risk of prostate cancer may be reduced, along with the risk of many other chronic illnesses.

Racial Factors

Data from the Centers for Disease Control and Prevention and from the National Cancer Institute show that there are racial differences in the incidence of prostate cancer. In one study, African American men were found to have the highest rates of prostate cancer, followed by white, Hispanic, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander (A/PI) men.

Black men have twice the risk of any other racial group, here in the United States and in the United Kingdom and the Caribbean. Research reveals that this is likely due in part to genetic factors and hormonal differences. However, diet, income, education, and health-care access may also play a role. African American men also tend to get prostate cancer earlier and in a more aggressive form than other races, with death rates being significantly higher.

Lifestyle Factors

One of the likely causes of prostate cancer is inflammation, and there is an established link to lifestyle. The Western lifestyle, with its sedentary habits and poor diet, is a major cause of inflammation in the body and a significant risk factor for many chronic diseases, including cancer, heart disease, and diabetes.

According to Cancer.org, “Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe, and the lowest rates being in southeastern and south-central Asia and northern Africa.”

Added to this is the evidence that Asian men who migrate soon take on the risk rate of the country they move to—a significant smoking gun (implicating lifestyle and environmental triggers) if ever there was one!

The human body is a highly complex, interconnected organism. No organ exists in isolation, so what is good for the body in general is likely good for the prostate. The body has a remarkable ability to heal itself and maintain a healthy equilibrium, but sometimes our actions push it to the limit, and disease is the result.

There is some research on lifestyle and prostate cancer risk, but the largest body of research into lifestyle and health has focused largely on coronary artery disease (CAD), the biggest cause of death in the Western world.

Due to the complex nature of disease and of lifestyle, it can be difficult to prove that one particular lifestyle factor causes or protects against a specific disease. For example, men who are obese have an increased risk of prostate cancer, but is this because they are obese or because they have a poorer diet and are less likely to exercise? Likewise, men who are vegan have a lower risk of prostate cancer, but is this because they eat no animal products or because they are more likely to be non-smokers and lead active lifestyles?

Diet and Nutrition

The link between diet, general health, disease prevention, and longevity is becoming increasingly compelling. Large longitudinal studies—where subjects are followed for years (such as the Framingham Heart Study and the Nurses’ Health Study)—provide strong evidence.

Diet is complex. Important factors include:

• Number of calories consumed
• The quality of food (macronutrients, micronutrients, non-nutrient dietary constituents)
• The variety of foods consumed
• Beverages
• Eating habits

One example of a healthy diet is the Mediterranean diet, which is high in fruits and vegetables, nuts, grains, olive oil, and lean sources of protein and low in factory-produced, processed foods. A comprehensive review of research, published in the journal Cancer Medicine, showed that strict adherence to the Mediterranean diet only slightly lowered the risk of mortality from prostate cancer but had a significant effect on the risk of some other cancers (like gastric, liver, pancreatic, and lung cancer).

A study by the American Association for Cancer Research looked at diet following diagnosis. Researchers compared the Western diet (higher intake of processed and red meats, high-fat dairy, and refined grains) to a prudent pattern (higher intake of vegetables, fruits, fish, legumes, and whole grains). They concluded that a “Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality.”

Obesity and Metabolic Syndrome

Obesity increases the risk of prostate cancer, research tells us. One study found that “men with a higher BMI and waist circumference had an increased risk of high-grade prostate cancer, an aggressive form of the disease.” A 2017 study showed that obesity at age 21 was associated with an increased risk of fatal prostate cancer.

The mechanism for the increased risk of prostate cancer is thought to lie with insulin levels. Insulin is a growth factor, so when high, it promotes cell division in abnormal cells. Further research, from The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, reported that men who are “taller and who have greater adiposity (that is, are overweight) have an elevated risk of high-grade prostate cancer and prostate cancer death.”

Metabolic syndrome is a group of risk factors including obesity, high blood pressure, cholesterol abnormalities, high triglycerides, and insulin resistance. It is thought to be a precursor for cardiovascular disease and type 2 diabetes. Research published in 2017 in the International Journal of Cancer suggests that metabolic syndrome may increase the risk of prostate cancer and result in a more aggressive cancer.

Other Factors

Also linked to prostate cancer are dietary supplements, heart disease, exercise, and smoking, among other factors.

Dietary Supplements

Many men take dietary supplements to improve health, and assume that supplements cause no harm. But troubling research suggests this is not so. Several studies have linked supplements to increased risk of prostate cancer:

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT) reported that when vitamin E was given alone, it was found to increase the risk of prostate cancer by 17 percent.
• A study from Boston University concluded “long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk of prostate cancer.”
• University of Southern California (USC) researchers found that folic acid supplements, when taken regularly, doubled the risk of prostate cancer.
• There is conflicting evidence as to whether vitamin D supplements lower or increase the risk.

While this research is not conclusive, it does suggest that if you want to reduce your prostate cancer risk, you would be better off improving your diet than taking supplements.

Heart Disease

Heart disease is the most common cause of death in men. When two diseases are very common, it’s hard to tease out whether one causes the other. Heart disease and prostate cancer share similar risk factors—including poor diet, obesity, smoking, and inactivity—but we cannot say with certainty that heart disease causes prostate cancer.

Smoking

There is no doubt that smoking is bad for health. It increases the risk of all chronic illnesses, and prostate cancer is no exception. A meta-analysis (combining data from 24 studies) found that the risk of prostate cancer was related to the number of cigarettes smoked. Researchers concluded “the heaviest smokers had a 24 to 30 percent greater risk of death from prostate cancer than did nonsmokers.”

Alcohol Consumption

No surprise here: Moderate to severe alcohol consumption is bad for our overall health, and that includes prostate health. A meta-analysis in the American Journal of Public Health reported that there was a “dose-dependent relationship between alcohol intake and risk of prostate cancer, starting with low-volume consumption.”

Exercise

While there is solid evidence that regular exercise is good for general health, there is limited evidence of an impact on prostate cancer risk. However, one Harvard study reported that men who engaged in three hours a week of vigorous exercise were 61 percent less likely to die from prostate cancer than men who did less than one hour a week.

Testosterone

Male hormones—testosterone and other androgens—are known to promote prostate cancer growth, but the link is hard to define. Males castrated before puberty and those with androgen insensitivity syndromes do not develop prostate cancer. Beyond these extreme cases, there is not a linear relationship between testosterone levels and prostate cancer risk.

Studies show that men with the top 25 percent of testosterone levels are 2.34 times more likely to develop prostate cancer than men with the lowest 25 percent of testosterone levels. Put simply, high levels of testosterone appear to make prostate cancer more aggressive.

Testosterone replacement treatment is used medically to treat hypogonadism (low testosterone), and also illegally used in bodybuilding and performance enhancement. Medical treatment is not thought to increase the risk of prostate cancer, because it is correcting naturally low testosterone. The jury is out on the risks for men taking testosterone without prescription.

Ejaculation Frequency

Research in the journal European Urology suggests that frequent ejaculation lowers the risk of prostate cancer. Researchers concluded that there was “a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa [prostate cancer], particularly for low-risk disease.” The study included nearly 32,000 men who answered questions on ejaculation frequency in 1992 and then were monitored for the next 18 years.

Vasectomy

Half a million American men have a vasectomy each year, so it’s prudent to ask: Does vasectomy increase the risk of prostate cancer? The American Urological Association reviewed the research on the link between vasectomy and prostate cancer risk and concluded that based on the results of two meta-analyses, vasectomy is not associated with prostate cancer. A 2017 review in JAMA Internal Medicine confirmed that vasectomy had an insignificant impact on aggressive prostate cancer risk.

Prevention of Prostate Cancer

The development of prostate cancer is complicated, and it is unlikely it can be prevented altogether. What the risk factors above do tell us is that while you can’t change your age, your race, or your family history, you still may be able to influence your risk. Compelling evidence, as noted earlier, tells us that a healthy lifestyle reduces your risk of most illnesses.

A Closer Look at Lifestyle

If you want to take control of your health and potentially reduce your risk of prostate cancer, here are some strategies that may help.

Improve your diet. Eat more fruits and vegetables, eat lean protein, and reduce intake of red meat cooked at high temperatures (processed, grilled, fried, or broiled).

• Tomatoes and cruciferous vegetables (high in carotenoids) draw particular attention, including broccoli, Brussels sprouts, and cauliflower.
• Eat a wide variety of fruits and vegetables of different colors so you get plenty of micronutrients.

Eat antioxidant-rich foods like blueberries, watermelon, garlic, and arugula; these may reduce DNA damage.

Food allergies and insensitivities are increasingly common: Listen to your body and avoid foods that make you feel unwell, even if they are on the “healthy” list.

• Limit dairy intake.
• Moderate amounts of tea and coffee may be beneficial for prostate health.
• Consider eating more soy, but make sure it’s organic.
• Eat more healthy fats. Switch processed fats for olive, avocado oil or seed oils. Eat oily fish like salmon two to three times a week.

Exercise regularly. This will improve your overall health and may reduce your prostate cancer risk. Starting to exercise when you are young is especially protective.

Drugs and medications. Some medications coincidentally may reduce the risk of prostate cancer:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin or ibuprofen.
• Metformin, used in the treatment of type 2 diabetes.
• Statins, used to lower bad LDL cholesterol.
• 5-ARIs, used to treat benign prostatic hyperplasia, have been shown to reduce the risk of prostate cancer by about one-fourth. However, they may increase the risk of more aggressive cancers. If you are at high risk, you may wish to discuss the use of these drugs as a preventative measure with your clinician.

Diagnostic Evaluation

There are two stages to diagnostic evaluation:

• Screening is defined as the testing of individuals with no symptoms in an attempt to catch early disease.
• Investigations are assessments and tests done in individuals with symptoms or where screening has identified a potential problem.

Let’s begin by talking about the PSA test that’s both a screening and diagnostic test.

What Is PSA?

Prostate-specific antigen (PSA) is a blood test commonly used in two scenarios:

• A screening test (men with no symptoms)
• A diagnostic test (men with symptoms)

PSA is a protein made by the prostate to maintain semen’s liquid form, so that sperm can move freely from the male to the female reproductive system during natural conception. Small quantities of PSA make their way into the bloodstream, allowing for measurement in the PSA blood test.

Over a billion PSA tests have been done since it was approved by the FDA in 1986 to monitor treatment response and disease recurrence and in 1994 as a screening and diagnostic test. A 2014 study published in the journal Prostate International confirmed that PSA is a useful test, concluding that there is “a strong correlation of PSA level with tumor diagnosis, tumor aggressiveness, and bone metastasis.”

The PSA test is controversial as a screening test but is extremely useful as a diagnostic test and has saved millions of lives, picking up aggressive cancers so that men can receive early treatment.

Understanding the PSA Test

The PSA test measures tiny quantities of PSA in the blood. The scale used is ng/ml or nanograms (one-billionth of a gram) per milliliter (one-thousandth of a liter).

• A PSA test result under 4 ng/ml traditionally has been considered “normal.” There is, however, a caveat: Some aggressive cancers have a PSA in this range. The Prostate Cancer Prevention Trial (PCPT) warns there is no PSA level at which the prostate cancer risk is zero.
• For the general male population, a PSA level between 4.1 and 10 carries a 47 percent risk of prostate cancer.
• PSA over 10 carries a 58 percent risk of prostate cancer, and thereafter the risk is closely correlated to PSA level.

Advanced PSA Measurements

Researchers have not given up on the PSA test as a prostate-cancer screening tool and are continually working to refine and improve it.

Screening

Screening for asymptomatic men (showing no symptoms) for prostate cancer involves the PSA test and a digital rectal examination (DRE). Routine prostate cancer screening is controversial for two main reasons:

• The risks of screening healthy men may outweigh the potential benefits.
• Prostate cancer is often not life threatening. In fact, in many cases prostate cancers are so slow-growing that they can almost be considered benign.

The goal of prostate cancer screening, therefore, is to detect high-risk tumors while they are treatable and potentially curable.

Digital Rectal Examination (DRE)

This simple test is performed during a physical examination. The patient lies on his side and the doctor inserts a lubricated, gloved finger (digit) into the rectum. The prostate lies in front of the rectum, and the doctor palpates for size, texture, lumps, and pain.

While the DRE can be embarrassing and a little uncomfortable, it is a useful screening test and is over in a couple of minutes.

Like the much-maligned PSA test, it is a crude and unreliable test, but doctors believe it is still worth doing in the absence of more definitive screening. It can also detect problems with other organs in the pelvic region, including the bladder and bowel.

To Screen or Not to Screen?

Screening tests are those done on people who feel well, with the aim of detecting serious disease before symptoms arise and before the disease is advanced, thus allowing early treatment and improving outcomes.

All screening tests have their pros and cons. Even a simple test like routine blood pressure monitoring can have a downside: Sometimes blood pressure is elevated due to anxiety about visiting the doctor (white coat syndrome) and testing may cause unwarranted alarm and further unnecessary testing. It’s important to weigh the advantages and disadvantages of any screening test before you make a decision.

Advantages of PSA Screening

As is the case with most cancers, the earlier prostate cancer is detected, the greater the odds of a cure. Proponents argue that screening is the only way to catch prostate cancer at an early stage. They also point to the fact that death rates from prostate cancer have decreased significantly since widespread screening began in the early 1990s.

The great news is that screening has dramatically increased the detection of prostate cancer while it is still localized to the prostate, a significant factor in improved outcomes.

It is now rare for men to be first diagnosed with prostate cancer when it is advanced. Deaths from prostate cancer have significantly declined in the last 20 years, which is great news by any standard.

The Disadvantages of PSA Screening

While the drop in deaths from prostate cancer is cause for celebration, opponents of PSA testing suggest that this has little to do with screening and more to do with treatment advances: The survival rate was already improving in the United States, and survival rates have improved in countries that do not screen.

The case against screening points to these potential problems:

False negatives: The PSA test misses some cancers. Around 20 percent of men confirmed to have prostate cancer have normal PSA levels (less than 4 ng/ml). False negatives give a false sense of security.

Other causes of low PSA: Unfortunately, there are factors that naturally reduce PSA levels, further complicating the interpretation of results. These include:

• Cigarette smoking (past or present).
• Obesity: Greater blood volumes may dilute PSA.
• Medications:
  • BPH treatments: 5-alpha reductase inhibitors like finasteride (Proscar) and dutasteride (Avodart), although they may improve the PSA test’s accuracy.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen (Advil, Motrin).
  • Diuretics for high blood pressure; examples: chlorothiazide (Diuril) and hydrochlorothiazide (Microzide, Dyazide, Maxzide).
  • Statins for high cholesterol, such as atorvastatin (Lipitor) and simvastatin (Zocor).

False positives: Some 70 to 80 percent of men with elevated PSA levels do not have cancer. For these men, a positive test leads to a cascade of testing that often results in the man being told he doesn’t have cancer. That would be fine—if testing caused no harm. However, being told that you have a positive result may cause severe psychological stress for weeks or months.

And when a PSA test result raises suspicions of prostate cancer, the next test is prostate biopsy, which may cause complications such as infection, blood in the semen and/or urine, urinary symptoms, and, possibly, erectile dysfunction. (See page 24 for more about prostate biopsies.)

Other causes of high PSA: Unfortunately, there are factors that naturally increase PSA levels, further complicating the interpretation of results. These include:

• Prostatitis (non-cancerous inflammation), benign prostatic hypertrophy, and urine infections can all increase PSA, further confusing the issue.
• Tests or surgery on the prostate, including DRE.
• Recent ejaculation, especially in older men.
• Exercise, most notably bicycle riding (doctors advise not to ride your bicycle for 24 hours before PSA testing).
• Hepatitis.
• Bypass surgery.

The unpredictability of positives: Statistically speaking, a very high PSA level is closely correlated to aggressive prostate cancer. But, when PSA is mildly elevated, the results are less clear-cut. Some men with high PSA turn out to have no cancer or a very slow-growing type, while some men with a low level of PSA turn out to have aggressive cancer. Research published in the journal Prostate International shows this latter scenario to be alarmingly common.

Number needed to treat: Statistics have measured the number of patients who need to be treated in order to prevent one extra bad outcome. In 2012, the European Randomized Study of Screening for Prostate Cancer trial (ERSPC 2012) showed that “to prevent one prostate cancer death, 935 men would need to be screened and 37 cancers would need to be detected.” Some researchers considered this rate to be unacceptably high.

PSA Screening: The Research

Two major studies have fueled the debates about prostate cancer screening.

PLCO Trial

The National Cancer Institute sponsored the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial in the U.S. They followed 77,500 men, all of them between ages 55 and 74, who had no history of prostate, lung, or colorectal cancer. Men were randomized into one of two groups:

• The intervention arm received trial screening, chest x-rays, flexible sigmoidoscopy, PSA blood tests, and digital rectal exams
• The control arm received standard care.

Enrollment began in 1993, participants were screened through 2006, and data were collected through 2015. Researchers reported that seven to 13 years later, “there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.”

In other words, the very costly screening program statistically had little effect on outcomes. However, the study has been heavily criticized for several flaws, paramount of which is the fact that 52 percent of the control group was in fact screened at some stage.

European Randomized Study of Screening for Prostate Cancer

The ERSPC, which involved eight European countries, is the largest ever prostate cancer screening study. A total of 182,000 men (162,000 of them between ages 55 and 69) were randomized into the intervention and control groups. Those in the intervention arm were offered PSA blood tests every two or four years. Those with a PSA level of more than 3.0 ng/ml were offered biopsy. Patient follow-up was extended to 11 years and is ongoing.

In recent analysis the researchers concluded “a man who undergoes PSA testing will have his risk of dying from prostate cancer reduced by 29 percent.”

The major down side, as they discovered, was that there were high rates of false positives: 30 percent of those with detected cancers did not have progressive disease. The “number needed to treat” (NNT, or number treated to avoid one death) was 48, which is considered to be high.

Professor Fritz Schroeder, the study coordinator, concluded “screening programs for prostate cancer will not be feasible until the medical communities can confidently balance the risk of reducing death from prostate cancer with these unacceptably high levels of overdiagnosis and overtreatment.”

PSA Screening: The Guidelines

The controversy over screening creates a dilemma for clinicians and patients alike. Many clinicians turn to guidelines from major medical organizations, including:

• U.S. Preventive Services Task Force
• American Cancer Society
• National Comprehensive Cancer Network
• American Urological Association
• European Society for Medical Oncology

The guidelines vary, so it falls to the individual clinician to decide which one(s) to follow. Patients should then be well informed so that a shared decision-making process can occur.

U.S. Preventive Services Task Force (USPSTF)

In 2012, the USPSTF recommended against routine prostate screening in all men. However, in May 2018, the task force reversed its controversial stance and now advises that men ages 55 to 69 discuss the pros and cons of PSA screening with their physicians. The task force recommended against screening for men age 70 and older and men “who do not express a preference for screening.”

American Cancer Society (ACS)

The ACS offers the following recommendations about prostate cancer screening.

• Step 1: Screening information to be provided to the following groups, so that an informed decision can be made:
  • Men 50 and over with average risk.
  • Men aged 45 to 50 with high risk, including African Americans and men with a first-degree relative (father, brother, son) diagnosed before age 65.
  • Men aged 40 to 45 with highest risk (more than one first-degree relative diagnosed at an early age).
• Step 2: Men who opt for screening should be tested with a PSA test and DRE. If the man is unsure, he can ask his doctor to make the decision on his behalf.
  • If PSA is below 2.5 ng/ml, a rescreening every two years is advised.
  • For those with a higher PSA, annual screening is advised.

National Comprehensive Cancer Network (NCCN)

NCCN screening guidelines rec­ommend:

• Step 1: Baseline history and physical examination, with a discussion of the risks and benefits of a baseline DRE and PSA.
• Step 2: Patient opts for a baseline DRE, which is normal. Then the following should be offered:
  • Baseline PSA testing:  Men ages 45 to 49.
  • PSA is below 1.0 ng/ml: Retest every two to four years.
  • PSA is 1.0 ng/ml or higher: Annual or biannual testing.
  • If DRE is normal, PSA is below
    3 ng/ml, and man’s age is 50 to 70: Retest every one to two years.
  • Beyond the age of 75, only a select few should be screened.

American Urological Association (AUA)

The AUA’s 2013 screening guidelines recommend screening for men aged 55 to 69 who have been fully informed and have made a shared decision with the clinician to go ahead with screening. Screening is recommended at intervals of at least two years.

Screening is not recommended for men in the following groups:

• Any man with a life expectancy of less than 10 to 15 years
• Men under 40 years or over 70
• Men between ages 40 to 54 years at average risk.

European Society for Medical Oncology (ESMO)

The ESMO’s PSA screening guidelines recommend no screening for:

• Population-based PSA screening
• Asymptomatic men over 70 years old
• Men with a life expectancy of less than 15 years

PSA testing should be offered to these higher risk men:

• Over 50
• Over 45 with a positive family history
• African Americans over 45
• 40-year-old with a PSA level over 1 ng/ml
• 60-year-old with a PSA level over 2 ng/ml

Diagnostic Investigations

If you have prostatic symptoms or a high PSA or abnormal DRE results, your doctor will take you through some or all of the following steps.

• Full medical history, including symptoms, surgeries, medications, and family history.
• Full physical examination of all body systems, including a DRE.
• Symptoms assessment, such as the AUA Symptom Index.
• Urine test to look for infection, blood and glucose.

Blood test for:

• General health markers (blood count and chemistry).
• PSA, advanced PSA testing (free PSA, PSA velocity, Prostate Health Index, 4Kscore, or prostate cancer antigen 3 (PCA3).

Transrectal ultrasound (scans via the rectum, using a probe) to look for abnormalities or lesions.

Transrectal Ultrasound (TRUS) Biopsy

During a TRUS-guided biopsy an ultrasound probe is inserted into the rectum and a spring-loaded needle takes multiple tiny samples (core needle biopsy). These samples are sent to the laboratory to look for cancerous cells. Performed under local anesthetic in the urologist’s office, the biopsy takes about 15 minutes and is mildly uncomfortable. Sometimes, a biopsy fails to detect cancer when there is a high level of suspicion, so a repeat biopsy may be needed.

Potential complications of a biopsy include bleeding, lower urinary tract symptoms, urinary tract infection, and prostate infection (prostatitis). Some men report worsening of erectile dysfunction. The risk of infection can be reduced by giving prophylactic antibiotics before the biopsy. Men should avoid taking nonsteroidal anti-inflammatory drugs (like aspirin or ibuprofen) and fish oils prior to biopsy, to reduce bleeding risk.

The image-guided targeted fusion biopsy is one of several techniques being used to improve accuracy of biopsy. First the patient undergoes an MRI, during which abnormal areas are flagged. Then an ultrasound-guided biopsy takes samples from these targeted areas.

Post-Diagnosis Investigations

If you have a confirmed diagnosis of prostate cancer, your doctor may want to perform further tests to determine the severity and to check whether it has spread (metastasized). Prostate cancer can be tiny when it first presents, and its spread is unpredictable, so these tests are very useful.

Investigations may include:

• Pelvic ultrasound to look for local spread beyond the prostate.
• Bone scan to look for bone metastases.
• Chest x-ray to look for lung and chest wall metastases.
• Scans—CT scans (computed tomography), MRIs (magnetic resonance imaging), and PET scans (positron emission tomography)—which may be used to look for signs of spreading to the lymph nodes, pelvis, or beyond.
• Lymph node biopsy to look for spread to lymph nodes.
• Genomic testing to help determine which cancers are benign and low-risk, and which are aggressive and life-threatening. Examples include Oncotype DX Genomic Prostate Score (GPS), ProMark, Decipher, and Prolaris.

The results of these tests can be used to guide decisions regarding treatment.

Biopsy Results: Histology

Biopsy samples are evaluated for changes in cells. Changes are seen on a continuum.

High-grade prostatic intraepithelial neoplasia (HGPIN or PIN): As with other cancers, prostate cancer starts with precancerous changes that may be discovered via biopsy. PIN is divided into low-grade (mild dysplasia) and high-grade prostatic intraepithelial neoplasia (HGPIN, or severe dysplasia). HGPIN are abnormal cells that have not become invasive and are found in 80 to 100 percent of prostates with carcinoma. This finding suggests that they are a precursor to carcinoma in some men. It should be noted, however, that these cells are detected in up to a quarter of men, most of whom do not go on to develop cancer. In those who do develop carcinoma, PIN predates malignancy by 10 or more years. A small body of evidence suggests that when PIN is found in multiple sites, there is an increased risk of prostate cancer. If PIN is detected, a six-month follow-up biopsy may be recommended.

Atypical small acinar proliferations (atypia or ASAP): Atypia is a more significant finding than PIN, as approximately 50 percent predate cancer. It is found at biopsy in 2 to 5 percent of men. In atypia, there are abnormal cells; however, they are few in number, they don’t quite look like cancer cells, plus other features (such as inflammation) may confuse the picture. Some clinicians describe atypia as “suspicious” or “highly suspicious for cancer” and recommend rebiopsy in six months, with more extensive sampling.

Cancer: If cancer cells are found at biopsy, they will be “graded” to see how abnormal they are. Low-grade cancers most resemble normal tissue and may have only just begun to invade locally. The clinician will also look for evidence of spread beyond the prostate gland.

Measuring Cancer Severity

Clinicians use three main criteria to determine the severity of cancer:

• Blood tests: May include PSA levels, advanced PSA tests, and biomarkers.
• Grading: The Gleason score, which defines types of cells (histology).
• Staging: TNM Classification (tumor node metastases), which defines where cancer is found.

The Gleason Score

This is the most commonly used grading score for prostate cancer. First developed in 1966, the Gleason score has been refined several times since then. It is based purely on the “architecture” or histology of the cells—that is, how they look in the laboratory. It has been found to be a good indicator of how cancer will progress and, thus, is a useful guide for treatment.

The Gleason Score is composed of two scores, both using a scale of 1 to 5. A score of 1 means the cells are very close to normal; a score of 5 means the cells are very abnormal. The scores are added to get a final score between 2 and 10.

Modified Gleason Score (ISUP)

Some clinicians use the 2- to 10-point Gleason score. Others are shifting over to the new International Society of Urological Pathology (ISUP) Score:

• Gleason scores ≤ 6: ISUP grade 1 (least aggressive)
• Gleason score 3 + 4 = 7: ISUP grade 2
• Gleason score 4 + 3 = 7: ISUP grade 3
• Gleason score 8: ISUP grade 4
• Gleason score 9 to 10: ISUP grade 5 (most aggressive)

A study published in European Urology reported that the new system provides these benefits: “more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.” The hope is that it will lead to a reduction in the overtreatment of benign, slow-growing cancers.

Staging Prostate Cancer

TNM Classification was developed by the American Joint Committee on Cancer (AJCC) in 1992. The tumor node metastases, or TNM, staging system is used to define a prostate cancer progression. It has three components: primary tumor (T), lymph node (N) involvement, and metastasis (M: spread to other organs). The staging is summarized in the box on page 27.

Risk Group

Having completed the necessary investigations, your doctor will determine your risk group. This, in turn, will help predict prognosis and guide treatment.

The search for new, more reliable assessments is ongoing.

Enhanced Screening: New Developments

Genetic Screening

The link between genes and cancer is fascinating. Genetic mutations are occurring all the time in our bodies, but most result in no harm to the individual and the mutation line dies out. When mutations occur in certain genes, disease may occur.

Somatic mutations.The most common type of mutation, “somatic mutations,” involve genes responsible for cell growth, cell repair, and cell division. Somatic mutations can lead to abnormal or uncontrollable cell division, with the result being a tumor.

Somatic mutations are not passed down to future generations. Most prostate cancers are due to these sporadic somatic mutations and are therefore not hereditary or detectable on genetic screening.

Germline mutations. Less common are “germline mutations” that affect every cell in the body. They are usually triggered by lifestyle and environmental factors and changes in other genes. Germline mutations can be inherited.

Inherited genes implicated in prostate cancer include BRCA1, BRCA2, and HOXB13. BRCA1 and BRCA2 repair damaged DNA and suppress tumors, keeping cell division at a normal level.

Gene fusion. Gene fusion is a hybrid gene formed from two previously separate genes. The fusion occurs due to DNA damage, when damaged pieces of DNA attach to other damaged pieces of DNA, creating new genes.

Generalized inflammation and environmental factors are implicated in this process. (The study of gene alteration due to environment, as discussed earlier, is known as epigenetics.)

In as many as 50 percent of men with prostate cancer, there is gene fusion of TMPRSS2 (androgen regulator) and ERG. ERG is a gene responsible for transcribing DNA for the cancer-causing gene ETS (erythroblast transformation-specific).

Other genetic markers implicated in prostate cancer include: TP53, AR, PTEN, PIK3CA, RB1, APC, CHD1, MYC, and ATM.

The aim of current research is to identify more genes involved in prostate cancer, understand the mode of action, and develop therapies to reduce the burden of disease.

“Liquid” Biopsies

Liquid biopsies take a urine or blood sample and look for evidence of cancer cells, DNA, or fragments of cancer. They can be used to help detect early cancer, develop a treatment plan, and track progress of treatment. The advantage is that liquid biopsies are far less invasive than repeated prostate biopsies.

Examples of liquid biopsies:

ExoDx Prostate IntelliScore measures exosome (fragments of cells) biomarkers in urine.

The Stockholm-3 (STHLM3) blood test screens several forms of PSA, other protein biomarkers, and germline genetic markers and clinical variables. Recently, promising research from Sweden suggests that use of the STHLM3 could reduce the number of biopsies by nearly one-third and the number of benign biopsies by 44 percent, according to the researchers.

IsoPSA is another blood test that’s showing promise. A 2017 study reported in European Urology concluded that “IsoPSA demonstrated a 48 percent reduction in false-positive biopsies… (and a) 45 percent reduction in the false-positive rate.”

Still another new blood test showing promise is the surface-enhanced Raman scattering (SERS) in combination with the support vector machine (SVM). This technique involves the use of a new analysis tool that looks at the chemical composition of blood serum. It produces a diagnostic accuracy of 98.1 percent.

Prostate Cancer Treatment

It’s normal to feel shocked and overwhelmed by a diagnosis of prostate cancer. But unlike many other cancers, the majority of prostate cancers are slow-growing and not life-threatening. The five-year survival rate for all prostate cancers is 99 percent. This statistic, while reassuring, hides the fact that if, at diagnosis, the prostate cancer has spread beyond the prostate and into the pelvis or into other organs, the five-year survival rate is only 29 percent.

If you receive a prostate cancer diagnosis, listen carefully to the information your clinical team gives you and take your time to process it. If you’re uncertain about something, ask for clarification either at the time or at a later date. Get as much information as you can in writing, so that you can learn more when the initial shock has died down.

Myriad treatment options exist for prostate cancer. There is no one-size-fits-all: Deciding on the best treatment protocol is a complicated process. Prostate cancer treatments involve complex trade-offs, and each treatment has its own risks and benefits.

The big dilemma in prostate cancer is whether to treat it in “low-risk” cases. Some slow-growing cancers pose little immediate risk to health, and there are significant complications to treatment.

The aim of treatment should be to improve longevity and quality of life. A younger man—one who potentially has decades of life ahead of him—may decide that living with cancer and the uncertainty it brings will warrant aggressive treatment with a high chance of a cure. An older man who has other health problems may decide to hold off on treatment until his doctor tells him it’s urgent.

Shared Decision-Making

The American Urological Association (AUA) offers useful guidelines for doctors on how to treat prostate cancer. They recommend beginning with an initial assessment, followed by counseling and then shared discussion regarding treatment options. These options are geared around the following factors:

Risk category: Determined by the characteristics of the tumor, its aggressiveness, and its spread, as assessed via these procedures:

• Blood tests (PSA levels, advanced PSA tests, and biomarkers)
• Grading the types of cancer cells (Gleason score)
• Staging the spread of the cancer (TNM classification)

Life expectancy: Determined by current age and general health. This may be overwhelming to discuss, but it’s important. As you have learned, many prostate cancers are so slow-growing that they may take decades before they are problematic.

Current level of functioning and lifestyle: It’s important to assess your baseline quality of life, including work, family, love life, leisure time, and so on.

Expected post-treatment function: Consider expectations surrounding your sex life. It’s important to look ahead, too. What would you like your life to look like in five or 10 years?

Your values and preferences: Consider the importance of issues like recovery time, side effects, and distance you’re willing to travel for treatment.

Your clinician’s preference and expertise: Many of the treatments discussed later in this chapter are not offered by every doctor. Outcomes are better when the doctor is an expert in a particular technique. As a general rule look for an experienced surgeon who is completing at least 40 radical prostatectomies each year, as they tend to have better outcomes, with lower complication rates. Ask about your physician’s outcomes and complication rates.

Lifestyle: Your clinical team should also talk to you about your modifiable risk factors—smoking, obesity, and diet, for example. This is particularly important in low-risk cancers, where lifestyle changes may have an impact on your risk of cancer progression and also may improve your quality of life, general health, and well-being.

Specialists: You may also be referred to a range of specialists (like medical oncologists, radiologists, and surgeons) who can advise you on the various treatment options. You may also be informed of your eligibility to take part in ongoing clinical trials for new therapies.

Research with care. We live in an age when access to medical information is at our fingertips 24/7. It’s great to research and become an expert on your own condition, as then you can make informed decisions and advocate for yourself. There is a down side, however, to personal research. First, you may become frightened or obsessed while reading information that isn’t designed for the public. Plus, there’s a lot of inaccurate information on the Internet, and with it comes the potential to make bad decisions. That said, there are some excellent sites that are reliable, among them the National Comprehensive Cancer Network, Cancer.org and Cancer.gov. You may also want to access professionally run community groups and support groups. Also, be extremely wary of getting advice from friends and family: They are biased, don’t understand your clinical picture, and may feed you dubious advice. Your health is too precious to leave to anyone who isn’t a medical professional.

AUA Treatment Guidelines

Low-Risk Prostate Cancer

The American Urological Association recommended protocol for treatment of low-risk cancer:

• Active surveillance or watchful waiting: Preferred approach for men with very low-risk and most men with low-risk prostate cancer.
• Radical prostatectomy or radiation therapy: For those at higher risk of progression, including younger men with strong family history of prostate cancer and gene markers.
• Hormone therapy (androgen deprivation therapy/ADT): Used when brachytherapy (radiological seed implantation) is planned and the patient’s prostate size needs to be reduced.
• Cryotherapy and high-intensity focused ultrasound (HIFU): Both are available, although HIFU has not been approved in the U.S. specifically for prostate cancer treatment.

Many men on active surveillance have poor compliance with follow-up, so it’s important to confirm the diagnosis with a repeat biopsy or MRI scan before they enter active surveillance. Up to one in three men, given a low-risk diagnosis, turn out to have cancers that are more advanced, and in rare cases they go on to die of an aggressive cancer. Misdiagnosis is most common in African-American men.

Intermediate-Risk Cancer

Protocol recommended:

• CT or MRI scan: To accurately determine staging.
• Radical prostatectomy (RP) or radiation therapy, plus hormone therapy: Standard treatment.
• Cryosurgery: May be considered in some men who are not suitable for RP or radiation therapy.
• Active surveillance: May be an option for some who understand and are willing to accept the higher risk of metastases.
• Watchful waiting: May be an option for older men whose life expectancy is less than five years.
• High-intensity Focused Ultrasound (HIFU): Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking.

High-Risk Prostate Cancer

Protocol recommended:

• CT or MRI scan plus bone scan: To accurately determine staging.



• Radical prostatectomy or radiation therapy, plus hormone therapy: Standard treatment.
• Watchful waiting: May be an option for older men who are symptom-free or who have a life expectancy of less than five years.
• Cryosurgery, focal therapy, and HIFU treatments: Not recommended as standard, but may be included in a clinical trial.
• Hormone therapy alone: Not recommended except in men with a life expectancy of less than five years plus local symptoms.
• Genetic counseling: For the patient and close family, especially if there is a history of other cancers—breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma.

In high-risk prostate cancer, there is more urgency about making treatment decisions. The earlier the treatment is initiated, the better the outcome.

Metastatic Prostate Cancer

Protocol recommended:

• Hormone therapy: Standard treatment.
• Pain relief as needed.
• Palliative care, if this becomes necessary.

What Is Radical Prostatectomy?

Retropubic radical prostatectomy is the most common surgery for prostate cancer. It produces excellent outcomes, especially in younger men or healthy older men.

Procedure

Prior to surgery, the bowel is evacuated and cleansed to open up space in the pelvis. The surgery is done under general or spinal anesthetic in the operating room. The surgeon accesses the prostate via an incision in the abdomen or the perineum (the area between the scrotum and anus). The entire prostate gland and seminal vesicles are removed—thus the word “radical.” Local lymph nodes are often removed as a precaution.

Surgery is most effective in men with disease isolated to the prostate (stages T1 and T2), who are healthy, and who are under age 70. A hospital stay of one to three days is usual, but it may take several weeks to feel back to normal. Catheterization for at least a week is recommended, to allow the urethra to heal.

During surgery, the surgeon has to weigh certainty against the risk of complications. Removing more tissue and lymph nodes increases the certainty that all of the cancer has been removed, but increases the risk of damaging the nerves to the penis, leading to impotence, and increases the risk of damaging the urethral sphincter, leading to urinary incontinence.

Techniques

There are several radical prostatectomy techniques, including:

Open: Abdominal incision above the pubic bone or perineum. This gives the surgeon an excellent view of the prostate and surrounding organs in the pelvis and the ability to biopsy local lymph nodes (lymph node dissection). This is the preferred technique for more advanced cancers.

Laparoscopic: A flexible laparoscope is inserted via a small incision in the abdomen, suprapubic area, or perineum, and the prostate is removed. Technically, this is much more difficult, requiring expert training. Lymph nodes cannot be dissected.

Robotic: Robotic procedures now account for 60 percent of RP surgeries in the U.S. Three to four incisions are made for robotic arms or laparoscopes. One arm carries a laparoscopic video camera, the other surgical tools. The surgeon sits at a screen and operates the robotic arms with a joystick and pedals. Advantages: Improved accuracy, shorter hospital stay, and less blood loss (and, consequently, a lower transfusion rate). Survival rates are similar to open surgery.

Nerve-sparing radical prostatectomy: This is a prostatectomy with an added technique that attempts to preserve the neurovascular bundles—the nerves and blood vessels that allow the penis to become erect. These are dissected and spared from removal, with the aim to preserve erectile function and lessen urinary problems. This procedure is delicate and time-consuming. The results cannot be guaranteed, and it takes several months for function to begin to recover.

The perineal incision approach is rarely used but has the advantage of being easier in overweight men and causing less bleeding and pain. The disadvantage is that lymph nodes cannot be biopsied and nerve damage is more common.

Research: One study followed 483 low-risk patients for 10 years after surgery. Researchers found that recurrence and survival rates were similar in robotic and open prostatectomy. Robotic surgery resulted in shorter hospital stays, fewer blood transfusions, and a small improvement in sexual function. There was, however, an increased incidence of urinary and other complications, plus post-operative expenses were higher.

Outcomes: For men with localized cancer, radical prostatectomy has a high cure rate. For those with cancer that has spread beyond the prostate, radiation or androgen therapy may also be needed.

The three main techniques have similar outcomes, so the decision as to which technique to use should be determined by the surgeon’s expertise and the patient’s preference.

Potential Complications: Early complications, which usually settle in during the first two weeks after surgery, include bleeding, infection (in scar, urine, or prostate), swelling of the penis and scrotum, lymphadenopathy, and heart problems.

Persistent complications include nerve damage and erectile dysfunction (20 to 70 percent) and urinary incontinence (50 percent). It should be noted that some untreated men also develop these complications during active surveillance, but at less than half of that following surgery.

There is reassuring evidence that urinary control and sexual function can improve, with time, after surgery. Another study asked 3,187 men about symptoms post-prostatectomy. They found that in those with incontinence at 12 months post-op, good urinary function was restored at two years in 30 percent; at three years in 49 percent; and at four years in 59 percent. For those with impotence at 12 months post-op, erectile function was restored at two years in 22 percent; at three years in 32 percent; and at four years in 40 percent.

The 2016 ProtecT Trial of 391 post-prostatectomy men found that there were no surgery-related deaths, but nine men had thromboembolic (blood clot) or cardiovascular events, 14 required blood transfusion (over three units), one had a rectal injury, and nine developed anastomoses (abnormal connection between two organs). Read more about the ProtecT Trial on page 34.

Benefits of Surgery

Surgery removes a lot of uncertainty. Research shows that in men with disease isolated to the prostate, 90 percent are alive and cancer-free 10 years after surgery. A coincidental benefit is that you will never develop benign prostatic hyperplasia, a benign but troublesome condition affecting half of men over the age of 60. Open surgery has the advantage of allowing biopsy of lymph nodes to improve certainty over staging and guide further treatment.

Postsurgical Therapy

Some men will be offered radiation or hormone therapy following surgery. It may be recommended in the following situations:

• Adjuvant therapy: For high-risk patients, where cancer was seen on the outer margin of the removed tissue or where cancer had spread to the seminal vesicles. This is usually performed soon after surgery.
• Salvage therapy: For “biochemical recurrence.” A rise in PSA in the months following surgery is seen in 25 to 30 percent of patients. External-beam radiation is usually offered, but some clinicians prefer hormone therapy.

In the post-op period, the Decipher genomic test can calculate the risk of prostatic cancer recurrence or metastasis and is useful in steering treatment decisions.

Pre-RP Lymph Node Biopsy

In order to be certain of staging, some surgeons perform lymph node biopsy to rule out lymph node involvement and steer treatment.

Radiation

Radiation is a viable alternative to radical prostatectomy, with the potential for cure in localized prostate cancer. It carries with it its own set of risks and benefits. There are two forms of radiation therapy commonly used to treat prostate cancer: external-beam radiation therapy (EBRT) and brachytherapy (the insertion of radioactive seeds into the prostate gland).

What Is External-Beam Radiation Therapy (EBRT)?

EBRT can be used as a primary treatment for localized cancers, or following surgery, where biopsy reveals spreading beyond the prostatic capsule, or if PSA rises in the postoperative months.

Procedure: Currently the most widely used radiation therapy, this treatment uses focused high-energy x-rays over multiple sessions to destroy the cancer. It can also be used on diseased lymph nodes. The major disadvantage is that EBRT is time-consuming: The patient receives radiation therapy for about 15 minutes each day, five days a week, for about two months. Straps are used to prevent movement and lead shields protect surrounding organs (testicles and penis).

Good candidates: EBRT is a good option for older men with other health problems in whom cancer has spread outside of the prostatic capsule (Stage 3) and in men who have already had TURP (transurethral resection of prostate) for benign prostatic hyperplasia. It can also be used in advanced cancers to help reduce the size of the prostate and reduce symptoms.

Advanced EBRT: Technological advances with high-dose EBRT have led to improved precision of this technique:

• 3-dimensional conformal radiation therapy (3D-CRT): The radiation beam is shaped to match the tumor. Beams of radiation come from several directions to precisely match the tumor’s height, width, and depth.
• Intensity-modulated radiation therapy (IMRT): This treatment uses state-of-the-art, targeted, high-dose radiation, minimizing damage and side effects. A 3D map of the tumor is created and high-intensity radiation beams are targeted at the affected areas.
• Hypofractionated radiation: This newer technique is gaining popularity. It uses higher doses of radiation over four to five weeks. It has a similar side effect and outcome profile to standard EBRT.
• Stereotactic body radiation therapy, or SBRT: Offered as an alternative to conventional radiation fractionation for low-risk patients, but for intermediate- and high-risk patients it should be offered in a clinical trial setting. These techniques (for example, CyberKnife, Gamma­Knife, or TomoTherapy) speed up the process further, into just five days. They deliver high-dose radiation with pinpoint accuracy. Early results are promising but suggest that side effects may be higher. SBRT may be useful for men whose cancer has spread beyond the capsule or for men who have had a TURP. It is available at only a limited number of centers.
• Proton beam therapy (PBT): Another newer treatment uses protons instead of photons (x-rays). Protons are charged particles that radiate energy. Photon beams are narrow and easier to target, scatter less, and may cause less damage to healthy tissue. Early results are showing similar outcomes to EBRT, but gastrointestinal complications are more common. PBT is not available in all centers, and it may not be covered by insurance, although it may be available as part of a clinical trial.

Outcomes: Some evidence suggests that survival rates may be slightly lower than in radical prostatectomy and brachytherapy.

Potential complications: EBRT has different complications from surgery. Because the beam cannot discern healthy from cancerous tissue, there’s a chance healthy tissue will be damaged. Common complications include:

• Cystitis (inflammation of bladder), blood in urine, urinary retention, and urinary incontinence.
• Proctitis (inflammation of rectum) and enteritis (inflammation of small intestine), which leads to diarrhea, blood in stool, bloating, rectal leakage, and rectal pain. Bowel symptoms can persist for months.
• Impotence takes time to develop after radiation therapy; five years after treatment is at a similar level to surgery.
• Fatigue may develop during treatment and last weeks or months after treatment has stopped.
• Lymphedema is the swelling of the legs or genitals. It can occur when the lymph nodes—which normally help drain fluid from an area—are damaged by radiotherapy. It can cause significant discomfort.
• Secondary cancers (bladder, colon, and rectum) are a potential but rare complication.

Complication rates vary between technique and dose used. They also depend on pre-treatment function.

Gastrointestinal (GI) complications are most common with proton-beam therapy, while brachytherapy has the lowest risk of GI problems. In an attempt to reduce GI damage, researchers have developed “tissue spacers” to reduce rectal exposure to radiation.

The SpaceOAR (Spacing Organs At Risk) System is an FDA-approved hydrogel that is injected as a liquid, quickly solidifying to create a cushion between the rectum and prostate.

Secondary cancers may be slightly higher after EBRT. A study published in The BMJ found that EBRT—but not brachytherapy—potentially increased the risk of certain cancers. Researchers found that the odds varied from 0.1 to 3.8 percent for bladder cancer, 0.3 percent to 4.2 percent for colorectal cancer, and 0.3 percent to 1.2 percent for rectal cancers. They concluded that these “absolute rates were low,” and that “further studies with longer follow-up are required to confirm these findings.” It would be hard to prove categorically that a secondary cancer was due to radiation, and that the cancer wouldn’t have occurred anyway.

Benefits: Radiation therapy is pain-free, and recovery time is much shorter than with surgery. Plus, there is no anesthesia or surgical wound from which to recover. Compared to surgery, immediate complications are less common.

Brachytherapy (BT) or Seed Therapy

Brachytherapy is also known as internal radiation therapy or interstitial radiation therapy.

Procedure: An outpatient procedure, BT takes about 60 minutes to complete. It requires either general or spinal anesthesia. An ultrasound or MRI-guided needle inserts 50 to 150 “seeds”—pellets the size of a grain of rice—throughout the prostate. It’s like having a mini-x-ray machine embedded into the prostate; it works continuously until it runs out of energy, after about a year.

Good candidates: For standard brachytherapy, men with low-risk cancer and a small prostate are better candidates. For high-dose brachytherapy, intermediate- and high-risk patients are better candidates.

Outcomes: BT survival rates are similar to surgery. However, quality of life tends to be a little better, as urinary incontinence and sexual problems are less common. Research also suggests that survival rates and quality of life are better after brachytherapy than after EBRT.

Complications: Radiation travels only a few millimeters and thus has little effect on the organs external to the prostate. However, the urethra—which lies in the center of the prostate—may be damaged during radiation, leading to urinary problems in most men. Some men require temporary catheterization during treatment. Physical exercise may reduce urinary symptoms. Rarely, bowel symptoms occur, for a month or so. There is a small radiation risk to people around you, so it is advised that pregnant women and children under 18 should avoid sitting on your lap for extended periods, at least in the first two months. In the first two weeks, the seeds can be ejaculated (in 1 percent of patients), so sex should be avoided; later, a condom should be worn during sex. Urine remains radioactive and toxic for months.

Benefits of brachytherapy: Most men recover quickly from the insertion procedure and are pain-free. There is no abdominal or perineal wound to heal. Compared to EBRT, the time commitment is much lower—one procedure and you’re done.

Which Treatment Is Best?

Several studies have compared the outcomes for the main treatment options: radical prostatectomy, EBRT, brachytherapy, and active surveillance. The findings show that each option has its own long-term side-effect profile. Here’s a summary of recent research.

One study reported in Cancer Medicine in 2017 measured quality of life 15 years after prostate cancer treatment, comparing RP, EBRT, and BT. Findings:

• Impairments in urinary irritation/obstruction: Worse in EBRT or BT.
• Decrease in bowel function: Worse in EBRT. However, newer techniques are improving this.
• Long-term change in urinary incontinence: Worse for patients treated with RP compared to BT.

A study in Radiotherapy Oncology looked at quality of life changes 48 months after treatment in the cases of 907 men. Researchers looked at RP, BT, and IMRT. Findings:

• RP: More urinary incontinence, but less urinary irritation and obstruction than radiotherapy. Very low levels of bowel dysfunction.
• Brachytherapy and IMRT: Better sexual function than in those who had surgery, although all groups had symptoms.

The ProtecT Trial was a large randomized study. Researchers followed patients for 10 years and compared surgery (RP), radiotherapy, and active surveillance. Findings:

Prostate cancer–specific mortality: At a similar level in all groups—around 1 percent after 10 years. All-cause mortality was similar in all groups at around 10 percent. Risk of death from cancer was 6.6 percent lower after RP compared to active surveillance at eight years follow-up, and 11 percent lower at 23 years.

Disease progression and metastases: RP and radiotherapy progression rates were less than half those of active surveillance.

Active monitoring: Forty-four percent of the patients who were assigned to active monitoring did not receive radical treatment and avoided side effects. Fifty-six percent went on to need treatment over the 10-year period.

Number needed to treat (NNT): This is a measure of the number of patients receiving treatment to avoid one case of metastatic disease. Here are the statistics compared to active surveillance: prostatectomy NNT = 27; radiotherapy NNT = 33; either prostatectomy or radiotherapy NNT = 9.

Incontinence: Three years after treatment, the rates of urinary incontinence were 7 percent in high-dose-rate brachytherapy; 5.4 percent in low-dose-rate brachytherapy; and 2.7 percent in EBRT. The rates of erectile dysfunction were 72 percent in high-dose-rate brachytherapy, 36 percent in low-dose-rate brachytherapy, and 68 percent in EBRT.

The researchers point out the importance of recording a patient’s baseline functions and quality of life before treatment begins.

The Scandinavian Prostate Cancer Group study supports the ProtecT findings. Researchers followed 695 men with early prostate cancer who were randomly assigned to one of two groups: radical prostatectomy or watchful waiting.

Researchers followed the men for 23 years. Sixty-three of the RT patients and 99 of the watchful waiting patients died of prostate cancer. They calculated that there was a 44 percent lower relative risk of death from the disease with RP compared to watchful waiting. Younger men and those with intermediate-risk prostate cancer saw the biggest benefits.

Conflicting evidence, however, comes from the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Researchers concluded radical prostatectomy (RP) does not significantly reduce the risk of death from prostate cancer or other causes (5.8 percent) compared with active surveillance (8.4 percent). This difference was deemed to be statistically insignificant. RP did reduce the risk of death from all causes in men with higher PSA levels (higher than 10 ng/ml) and in men with higher-risk tumors.

Cleveland Clinic researchers reported the results of a study of 1,989 patients who underwent brachytherapy. They found that the overall five-year survival rate was 93.7 percent and the 10-year survival rate was 76.1 percent. They concluded that “prostate brachytherapy, as monotherapy, is an effective treatment for low-risk and low-intermediate-risk prostate cancer and appears promising as a treatment for high-intermediate-risk and high-risk prostate cancer. Significant long-term toxicities are rare when brachytherapy is performed as monotherapy.”

Androgen-Deprivation Therapy (ADT)

Because prostate cancer originates mainly in the hormone-sensitive glandular cells, androgens fuel prostate cancer. It makes sense, then, that androgen-deprivation therapy—which reduces levels of androgens—can slow the progression of cancer, but not cure it. ADT can be used alone or in combination with other treatments. The primary androgen is testosterone.

Types of ADT include the following.

LHRH agonists: Available in one-month, three-month, or six-month injections or annual depots (implant under skin). These drugs stimulate the pituitary gland to produce LH (luteinizing hormone); this causes an initial elevation in testosterone, followed by an abrupt decline. Drugs include goserelin (Zoladex), leuprolide (Eligard, Lupron), triptorelin (Trelstar), and the implant histrelin (Vantas).

• LHRH antagonist: Available in a one-month depot. This type of drug prevents signals from the pituitary gland to the testicles, thus preventing production of testosterone. Drugs include degarelix (Firmagon).
• LHRH agonist or antagonist with an oral antiandrogen: This type of drug creates a complete androgen blockade.
• Nonsteroidal antiandrogen monotherapy: These bind to testosterone receptors in the prostate, inhibiting or suppressing androgen production. They’re taken in a tablet form and include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron).
• Bilateral orchiectomy: This simple surgery removes both testicles and replaces them with prosthetic ones. Once a common procedure, it is now rarely used. It can be useful if there is spinal cord compression due to metastases. The surgery is irreversible.

Good Candidates for ADT

The National Comprehensive Cancer Network and the European Association of Urology (EAU) recommend androgen deprivation therapy for treatment of patients with advanced prostate cancer when local therapy has failed. The aim of treatment is to shrink the cancer or slow its growth and give palliative relief (meaning a reduction in severity, even if the condition can’t be cured).

ADT can also help with reduction of urinary outlet obstruction and, in lower-risk men, to shrink cancer prior to surgery or radiation. Over time, most cancers stop responding to ADT and progression resumes. Standard treatment lasts 24 to 36 months.

Potential side effects: Low androgen levels can cause some unpleasant side effects and seriously affect quality of life. Among them:

• Feeling weak and unwell due to fatigue, anemia, and reduced muscle mass.
• Breast enlargement (gynecomastia).
• Psychological changes and cognitive impairment (forgetfulness, inattention, and depression are common).
• Decreased libido and erectile dysfunction (usually improves when treatment stops).
• Hot flashes.
• Increased risk of metabolic syndrome (high blood pressure, high blood sugar, abdominal obesity, and abnormal blood lipids), which increases the risk of cardiovascular disease, stroke, and diabetes.
• Osteoporosis and an increased risk of fractures.
• Increased risk of diabetes. The relative risk is 30 to 40 percent higher. Monitoring of blood glucose and lipids is advised.
• Increased risk of cardiovascular death. Risk increased to 4.2 percent five years after therapy (1.5 percent in controls) and 13.5 percent 10 years after therapy (5.8 percent in controls).
• Pulmonary edema, or fluid on the lungs, which results in shortness of breath and cough.
• Gastrointestinal tract disturbances, including diarrhea.
• Increased risk of colorectal cancer and liver failure.
• Increased risk of acute kidney injury (5.5 per 1,000 person years), a rare condition with a 50 percent mortality rate.

One study found that men who exercise when starting androgen deprivation therapy report fewer sexual side effects, more fatigue, and better mood.

Reducing ADT Side Effects

Bone health: Osteoporosis and fractures cause significant disability. Drugs such as zoledronic acid (Reclast), denosumab (Prolia), and others may protect against fractures. They are given with calcium and vitamin D. Baseline bone health should be measured before treatment.

Cardiovascular health: Baseline testing of blood glucose and cholesterol should be done. Eating a healthy diet can reduce the risk of obesity, diabetes, and high cholesterol. Regular exercising (with medical supervision) can reduce muscle and bone loss, improve balance, reduce the risk of falls and improve cardiovascular health. Cigarette smoking is discouraged, as it increases the risk of many of the complications.

Benefits of Hormone Therapy

ADT can reduce the size of a cancer, reduce symptoms and pain, and may extend life. Sadly, ADT is not a cure, and over time the cancer may begin to grow again, despite the low testosterone.

Combination Hormone and Radiation Therapy

In men with advanced prostate cancer that is aggressive or has spread beyond the prostate, a combination of hormone (ADT) and radiation therapy is standard. This combination reduces the risk of dying by nearly 30 percent compared to radiation alone. Some clinicians use a protocol with intermittent ADT treatment to reduce side effects. PSA levels are monitored and ADT is started when levels creep up; treatment is stopped when PSA drops.

In men at intermediate risk, this combination therapy is considered a viable alternative to radical prostatectomy.

Cryotherapy

Cryotherapy is a procedure that involves the controlled freezing of the prostate to destroy cancer cells. It is also known as cryosurgery or cryoablation.

Procedure: A surgeon uses thin, needle-like probes to enter the prostate through the perineum, and then injects liquid nitrogen into the prostate, freezing and destroying (ablation) cells. Catheterization may be needed for up to a week. The procedure is not widely available.

Good candidates: The American Urological Association recommends cryotherapy for patients with intermediate-risk localized prostate cancer, where RP or radiotherapy are inappropriate due to other health problems. It can also be used in biological recurrence (high PSA after primary treatment). Certain men are not good candidates for cryotherapy: those who have undergone transurethral resection of the prostate (TURP) for benign prostatic enlargement, those with a very large prostate, and those with inflammatory bowel disease.

Outcomes: Cryotherapy can be used to treat the entire prostate gland or as focal therapy to ablate part of the prostate and potentially reduce complications. Some research suggests that local cancer control with cryotherapy is not quite as good as with surgery. Also, unlike surgery, cryotherapy and radiation therapy do not allow for a pathological review of the prostate tissue. Cryotherapy can be combined with ADT, but there is no consensus as to whether this improves outcomes. It is less invasive than surgery and recovery is faster; however, as with radiation, the whole prostate cannot be assessed to accurately determine staging and grading of the disease.

Potential complications: Complications may be severe, from erectile dysfunction (up to 90 percent) to urinary incontinence (5 percent). Irritation and obstructive urinary problems are common side effects. Rectal fistula also may occur: This is an unpleasant condition where a false connection occurs between the rectum and the perineum (skin between rectum and scrotum), allowing uncontrollable leakage of feces.

A study published in Journal of Endourology followed 300 men with high-grade prostate cancer after cryotherapy. The study’s researchers looked at whether PSA stayed low (biochemical progression-free survival, or BPFS), and found a two-year BPFS rate of 77 percent and five-year BPFS rate of 59.1 percent. At a 12-month follow-up, 90.5 percent were completely continent and 17 percent were fertile. Rectourethral fistulae occurred in 1.3 percent of patients and severe urinary retention in 3.3 percent.

Chemotherapy

The chemotherapy drug docetaxel (Taxotere) has been found to prolong survival among men with advanced prostate cancer. It may be used along with or after hormone therapy. Doctors administer docetaxel intravenously and in cycles.

Potential side effects: Chemotherapy can harm normal cells and cause men to feel unwell with such symptoms as hair loss, nausea, vomiting, anemia, infections, kidney failure, numbness and tingling, fatigue, infertility, tendency to bleed, headaches, and joint pain. Bone marrow suppression is a serious risk, but close monitoring can pre-empt this.

A study in New England Journal of Medicine followed 790 men with metastatic, hormone-sensitive prostate cancer and concluded that “six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.” Men treated with the ADT-docetaxel regimen survived an average of 57.6 months, compared to 44 months for those on ADT  alone.

If docetaxel fails to help, a newer drug, cabazitaxel (Jevtana), may be used.

Hormonal Therapy (ADT) and Chemotherapy

In men with metastatic cancer, hormonal therapy may be combined with chemotherapy. A study published in The Lancet  randomized 385 men with metastatic cancer to two treatment groups:

The first received ADT alone, the second ADT plus docetaxel (chemotherapy). Men given ADT alone lived, on average, 44 months; those treated with the ADT/chemotherapy combination lived an average 58 months. Improvements were best in the more advanced cancers.

Close monitoring of men on the combined treatment is necessary as it can damage the bone marrow and liver.

Cancer Vaccines/Immunotherapy

Prostate cancer vaccines are designed to help your immune system target and kill cancer cells. Rather than priming your body to kill an infectious disease, these vaccines teach your body how to kill cancer cells.

One such vaccine is sipuleucel-T (Provenge). During the procedure, the patient’s own white blood cells are collected and exposed in the lab to a protein specific to prostate cancer. These activated white cells are then reinfused into the bloodstream, where they begin to attack the cancer cells. Three doses are given intravenously over a month. It is approved for use in men with metastatic disease who no longer respond to ADT, a group in which it has been shown to improve life expectancy by about four months.

Other prostate cancer immunotherapies are under study.

Treatment for Bone Metastasis

Prostate cancer bone metastases are unpleasant and painful, and may lead to pathological fractures. Two drugs, however, have been found to help:

• Denosumab (Xgeva) may reduce the impact of cancer spread to bones.
• Radium-223 dichloride (Xofigo) is a radioactive drug that emits radiation (alpha particles) into bone metastases. Side effects include low blood counts, nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot.

High-Intensity Focused Ultrasound (HIFU)

Procedure: In performing a HIFU procedure, the doctor inserts an ultrasound probe into the rectum, then focuses high-intensity sound waves onto the cancerous areas of the gland. These beams create focused heat that destroys tissue in seconds. HIFU is performed under spinal or general anesthesia and can be done on an outpatient basis.

HIFU has fewer side effects than surgery and radiotherapy, but there is inadequate research on outcomes.

While HIFU has been used for years in Europe and Canada to treat prostate cancer, it is not widely available in the United States, and some health insurance companies won’t cover the procedure. In 2015, the FDA approved HIFU for “prostate tissue ablation”—not specifically for cancer treatment.

Potential complications: Erectile dysfunction and irritating urinary symptoms (including burning pain while urinating) are common.

Focal Therapy

Focal therapy, also known as “male lumpectomy,” selectively targets only affected areas of the prostate using cryotherapy, HIFU, and photodynamic therapy. The aim is to reduce complications. The research is not conclusive, with some studies showing comparable outcomes in the short term and fewer long-term side effects.

Part of the problem is that prostate cancer is often, by its nature, multifocal, appearing in more than one of the three prostate lobes at once. Another problem is that cancerous areas are difficult to pick up on ultrasound or MRI. The AUA does not support the use of focal therapies, saying, “these treatment options lack robust evidence of efficacy.” There is, however, hope that further refinement of focal techniques may prove to be useful in the future.

Managing Side Effects of Treatment

Sadly, all treatments have side effects. Most treatment options run the risk of chronic urinary or sexual health problems. Thankfully there are some treatments that can help.

Bone Disease

Men with advanced prostatic cancer are at high risk of bone disease. Hormone treatment (ADT) causes osteoporosis and makes some men frail and more prone to falling and fracturing bones. Furthermore, bone metastases (malignant growths in the bone) cause weakness and thinning of the bone, fractures, spinal compression, and pain. Some men require radiation to reduce growth of the metastases and surgery to stabilize weak or fractured bone, and many need pain medication.

Bisphosphonates, such as zoledronic acid (Zometa) and pamidronate disodium (Aredia), may help reduce osteoporosis. These drugs attack osteoclasts—a type of cell that breaks down bone tissue.

Denosumab (Xgeva) is a drug that prevents bone erosion by blocking RANK-Ligand, a substance that activates osteo­clasts. Men taking these drugs need to be aware of a rare but serious side effect called osteonecrosis of the jaw. Make sure you discuss your medications with your dentist before starting these treatments or having any dental work.

Looking to the Future: Biomarkers

Biomarkers are specific molecules that indicate a process, normal or abnormal, taking place in your body. PSA is the standard biomarker for prostate cancer; the big problem is that it isn’t specific or accurate enough. Current screening techniques may overdiagnose men with insignificant cancers and miss others with advanced or aggressive disease. Research aims to find biomarkers that can precisely predict clinically significant prostate cancer and accurately guide treatment.

Biomarkers can be measured in blood serum, urine, and tissues. They measure proteins, fragments of proteins, enzymes, DNA, and RNA.

It is likely that what will emerge are several biomarkers—some for diagnosis and some to guide therapy. Urine biomarkers may turn out to be useful, as urine is easily collected and passes through the prostate as it travels along the urethra.

Remarkable stories have hit the news of dogs that are able to detect cancers—from prostate to lung to breast—with incredible accuracy, suggesting that they’re picking up a particular odor, which may turn out to be a valuable biomarker.

The post 2. Prostate Cancer appeared first on University Health News.

To keep things in perspective, however, it is also one of the most survivable cancers: It’s responsible for only one in 39 male deaths and its incidence and death rates have been in steady decline for more than 25 years. The spectrum of disease is very broad, and most men fall at the benign end and require no active treatment. It is said that “You are more likely to die with prostate cancer than from it”—if it has not spread, that is.

The risk of prostate cancer increases dramatically with age. Six out of 10 cases are in men over 65, and the average age at diagnosis is 66. Annually, it is responsible for approximately 27,000 deaths. It is rare in younger men, but when it does occur, it tends to be more aggressive.

One last interesting statistic is that at autopsy, up to two-thirds of older men have prostate cancer but aren’t aware of it.

Screening for prostate cancer is controversial, as in many men it is very slow-growing, even without treatment. This means that often, a diagnosis leads to considerable stress, unnecessary investigations, and treatment, not to mention the stress of living under the shadow of a cancer diagnosis when there is little risk to life. It’s like going for a walk in the woods: Even if there are hundreds of snakes and spiders lurking near the path, the chances are that they will leave you alone. Once someone tells you there are hundreds of snakes and spiders lurking by the path, you begin to get anxious and panicky. The risk is the same, but now you know about it!

Pathology

The prostate is particularly susceptible to gene mutations. Some 95 percent of prostate cancers begin in the semen-producing glandular cells; they’re called adenocarcinomas. Four percent arise in the prostatic urethra transitional cells—the lining of the urethra as it passes through the prostate. In fact, changes begin there with cellular gene mutations years before cancer is detected. Over time, fast-growing mutations may develop, forming clusters of abnormal cells, tumors, and eventually cancer. Less than 1 percent are squamous cell carcinomas (normally seen on skin), most often occurring after radiation or hormone treatment.

Seventy percent arise in the peripheral zone, 15 to 20 percent in the central zone, and 10 to 15 percent in the transitional zone. At biopsy, the majority of cancers are found to be affecting multiple zones.

Local Spread

As clusters of cancer cells enlarge, they begin to invade the local tissue. Tumors arising in the transitional zone spread to the nearby bladder neck. Those arising in the peripheral zone creep into the ejaculatory ducts and seminal vesicles. Later in the process, they may reach, and breach, the prostatic capsule.

Distant Spread (Metastasis)

Sometimes prostatic cancers spread beyond the prostate, forming distant cancers or metastases (plural of metastasis). The most common sites for prostatic metastases are bone, lung, liver, and adrenal glands.

Measuring Severity

The severity of prostate cancer is measured with two parameters:

• Grading: The Gleason score, which defines types of cells, and the level of abnormality (histology)
• Staging: The TNM Classification (Tumor-Node-Metastases) describes how widespread the cancer is.

At diagnosis, the majority of prostate cancers have low levels of cell abnormality and spread is localized within the prostate: These cancers tend to be slow growing and have good outcomes. The cancers with the worst outcomes tend to have significant cell abnormality and have spread beyond the capsule of the prostate.

Symptoms of Prostate Cancer

What are the symptoms of prostate cancer? Clinical presentation data provides a picture:

• 47 percent present with no symptoms; cancer is detected during screening.
• 38 percent present with increased urinary frequency, especially at night.
• 10 percent present with urinary urgency.
• 23 percent present with a decreased urine stream.
• 1 percent present with blood in urine (hematuria) or semen.

Prostate cancer that has spread may present with:

• Reduced appetite and unexplained weight loss
• Bone pain, with or without pathologic fracture
• Feet or ankle pain and swelling
• Kidney failure.

Causes and Risk Factors

The cause of prostate cancer is not fully understood. We do know that the glandular tissue of the prostate is prone to genetic mutations and that there are many factors that influence this. In many men, the disease seems to be rather random, and a cause remains elusive. Risk factors are attributes or exposures that increase the odds of getting the disease.

For prostate cancer, there are many risk factors. Let’s consider the common ones.

Age

The most significant risk factor for developing prostate cancer is one we can’t help: aging. Sixty percent of all prostate cancers are diagnosed in men over the age of 65. According to the Prostate Cancer Foundation, the risk of diagnosis changes dramatically with age:

• 1 in 10,000 for men under 40
• 1 in 39 for men aged 40 to 59
• 1 in 14 for men aged 60 to 69

Genetic Factors

About 5 to 10 percent of prostate cancer patients have a strong family history, pointing to a genetic susceptibility. A man with a first-degree relative (brother or father) with prostate cancer has double the risk of developing the disease and presents six to seven years earlier than other men.

The National Cancer Institute explains that the following factors are suggestive of genetic risk:

• Multiple affected first-degree relatives with prostate cancer, including three successive generations with prostate cancer on the mother’s or father’s side.
• A relative with early-onset prostate cancer (age ≤55 years).
• Family history of prostate cancer and other cancers (e.g., breast, ovarian, pancreatic).

More than 100 gene variations or mutations have been associated with prostate cancer, according to 2016 data. Many men will carry a small number of gene variants, which turn out to be insignificant. Certain clusters of gene variation are helpful for predicting risk and outcome. Some mutations are linked to more aggressive cancers.

Notable culprits are the BRCA1 and BRCA2 mutations, also linked to breast cancer risk in women. A recent study presented at the American Urological Association showed that BRCA2 carriers who developed prostate cancer were more likely to develop aggressive disease, with advanced staging at diagnosis, higher rates of metastases, and poorer survival rates. They also presented research that showed that the BRCA1 and BRCA2 genes are more commonly found in African American men with prostate cancer, a possible explanation for why this group has poorer outcomes.

Significance of Genetic Risk

Herein lies a common dilemma in medicine: What do we do when someone is identified with a genetic risk? There is a danger that this knowledge may cause unnecessary panic and needless investigation and treatment. While prostate cancer is very common, most patients do not die from it. Genetic testing—when used prudently—can help identify men with aggressive cancers earlier and save lives. Genetic testing is increasingly used for targeting treatment.

Routine screening of the public and commercial genetic tests are not currently recommended as the risks significantly outweigh the rewards.

Epigenetics

The medical profession used to believe that our genes were our destiny. However, the fast-emerging field of epigenetics is proving that this is far from true: Lifestyle and environmental factors can alter the inheritance and expression of genes. What this means for people with an increased genetic risk of prostate cancer is that by improving lifestyle and environment, they might be able to reduce the risk of prostate cancer, along with many other chronic illnesses.

Racial Factors

Data from the Centers for Disease Control and Prevention and from the National Cancer Institute show that there are racial differences in the incidence of prostate cancer. Over a five-year study, African American men had the highest rates of prostate cancer, followed by white, Hispanic, American Indian/Alaska Native (AI/AN), and Asian/Pacific Islander (A/PI) men.

African American men have twice the risk of any other racial group. This trend is also seen in the United Kingdom and the Caribbean. Research reveals that this is likely due in part to genetic factors and hormonal differences but that diet, income, education, and healthcare access may also play a role. African American men also tend to get prostate cancer earlier and in a more aggressive form than other races, with death rates being significantly higher.

As with the genetic risk factor, it is hard to know what to do with this knowledge. Mass screening of African American men would cause more harm than good.

Lifestyle Factors

One of the likely causes of prostate cancer is inflammation, and there is an established link to lifestyle. The Western lifestyle, with its sedentary habits and poor diet, is a major cause of inflammation in the body and a significant risk factor for many chronic diseases, including cancer, heart disease, and diabetes.

According to Cancer.org, “Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe, and the lowest rates being in southeastern and south-central Asia and northern Africa.”

Added to this is the evidence that Asian men who migrate quickly take on the risk rate of the country they move to—a significant smoking gun (implicating lifestyle and environmental triggers) if ever there was one!

The human body is a highly complex, interconnected organism. No organ exists in isolation, so what is good for the body in general is good for the prostate. The body has a remarkable ability to heal itself and maintain a healthy equilibrium, but sometimes our actions push it to the limit, and disease is the result.

There is some research on lifestyle and prostate cancer risk, but the largest body of research into lifestyle and health has focused largely on coronary artery disease (CAD), the biggest cause of death in the Western world.

Due to the complex nature of disease and of lifestyle, it can be difficult to prove that one particular lifestyle factor causes or protects against a specific disease. For example, men who are obese have an increased risk of prostate cancer, but is this because they are obese or because they have a poorer diet and are less likely to exercise? Likewise, men who are vegan have a lower risk of prostate cancer, but is this because they eat no animal products or because they are often non-smokers and lead more active lifestyles?

Diet and Nutrition

The link between diet, general health, disease prevention, and longevity is becoming increasingly compelling. Large longitudinal studies—where subjects are followed for years (such as the Framingham Heart Study and the Nurses Health Study)—provide strong evidence.

Diet is complex. Important factors include:

• Number of calories consumed
• The quality of food (macronutrients, micronutrients, non-nutrient dietary constituents)
• The variety of foods consumed
• Beverages
• Eating habits

One example of a healthy diet is the Mediterranean diet, which is high in fruits and vegetables, nuts, grains, olive oil, and lean sources of protein and low in factory-produced, processed foods. A comprehensive review of research, published in the journal Cancer Medicine, showed that strict adherence to the Mediterranean diet slightly lowered the risk of mortality from prostate cancer but had a significant effect on the risk of some other cancers (like gastric, liver, pancreatic, and lung cancer).

A 2015 study by the American Association for Cancer Research looked at diet following diagnosis. They compared the Western diet (higher intake of processed and red meats, high-fat dairy, and refined grains) to a Prudent pattern (higher intake of vegetables, fruits, fish, legumes, and whole grains). They concluded that a “Western dietary pattern was associated with higher prostate cancer-specific and all-cause mortality.”

Obesity and Metabolic Syndrome

Obesity, research tells us, increases the risk of prostate cancer. A study presented to the European Obesity Summit in 2015 found that “men with a higher BMI and waist circumference had an increased risk of high-grade prostate cancer, an aggressive form of the disease.” A 2017 study showed that obesity at age 21 was associated with an increased risk of fatal prostate cancer.

The mechanism for the increased risk of prostate cancer is thought to lie with insulin levels. Insulin is a growth factor, so when high, it promotes cell division in abnormal cells. Further research, from The European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, reported in 2016 that men who are “taller and who have greater adiposity (that is, are overweight) have an elevated risk of high-grade prostate cancer and prostate cancer death.”

Metabolic syndrome is a group of risk factors including obesity, high blood pressure, cholesterol abnormalities, high triglycerides, and insulin resistance. It is thought to be a precursor for cardiovascular disease and diabetes. Research published in 2017 in the International Journal of Cancer suggests that metabolic syndrome may increase risk of prostatic cancer and result in a more aggressive cancer.

Other Factors

Also linked to prostate cancer include dietary supplements, heart disease, exercise, and smoking, among other factors.

Dietary Supplements

Many men take dietary supplements to improve health, and many assume that supplements cause no harm. But troubling research suggests this is not so. Several small studies have linked supplements to increased risk of prostate cancer:

• The Selenium and Vitamin E Cancer Prevention Trial (SELECT) reported that when vitamin E was given alone, it was found to increase the risk of prostate cancer by 17 percent.
• A study from Boston University concluded that “long-term zinc intake from multivitamins or single supplements was associated with a doubling in risk of prostate cancer.”
• University of Southern California (USC) researchers found that folic acid supplements, when taken regularly, doubled the risk of prostate cancer.
• There is conflicting evidence as to whether vitamin D supplements lower or increase the risk.

While this research is not conclusive, it does suggest that if you want to reduce your prostate cancer risk, you would be better off improving your diet than taking artificial supplements.

Heart Disease

Heart disease is the most common cause of death in men. When two diseases are very common, it’s hard to tease out whether one causes the other. Heart disease and prostate cancer share similar risk factors—including poor diet, obesity, smoking, and inactivity—but we cannot say with certainty that heart disease causes prostate cancer.

Smoking

There is no doubt that smoking is bad for health. It increases the risk of all chronic illnesses, and prostate cancer is no exception. A 24-study meta-analysis (combining data from multiple studies) in 2010 found that the risk of prostate cancer was related to the number of cigarettes smoked. They concluded that “the heaviest smokers had a 24 to 30 percent greater risk of death from prostate cancer than did nonsmokers.”

Alcohol Consumption

No surrpise here: Moderate to severe alcohol consumption is bad for our overall health, and that includes prostate health. A 2016 meta-analysis in the American Journal of Public Health reported that there was a “dose-dependent relationship between alcohol intake and risk of prostate cancer, starting with low-volume consumption.”

Exercise

While the evidence that regular exercise is good for general health is solid, there is limited evidence of an impact on prostate cancer risk. However, a Harvard study reported that men who engaged in three hours a week of vigorous exercise were 61 percent less likely to die from prostate cancer than men who did less than one hour a week.

The Reykjavik Study in Iceland concluded that “extensive physical activity beginning in early adulthood may reduce the risk of advanced prostate cancer.”

Testosterone

Male hormones—testosterone and other androgens—are known to promote prostate cancer growth, but the link is hard to define. Males castrated before puberty and those with androgen insensitivity syndromes do not develop prostate cancer. Beyond these extreme cases, there is not a linear relationship between testosterone levels and prostate cancer risk.

Studies show that men with the top 25 percent of testosterone levels are 2.34 times more likely to develop prostate cancer than men with the lowest 25 percent of testosterone levels. Put simpy, high levels of testosterone appear to make prostate cancer more aggressive.

Testosterone replacement treatment is used medically to treat hypogonadism (low testosterone), and also illegally in bodybuilding and performance enhancement. Medical treatment is not thought to increase the risk of prostate cancer, because it is correcting naturally low testosterone. The jury is out on the risks for men taking testosterone without prescription. In 2016 the American Urological Association reported that “current evidence does not provide any definitive answers regarding the risks of testosterone therapy on prostate cancer.”

Ejaculation Frequency

Research in the journal European Urology suggests that frequent ejaculation lowers the risk of prostate cancer. They concluded that there was “a beneficial role of more frequent ejaculation throughout adult life in the etiology of PCa (prostate cancer), particularly for low-risk disease.” The study included 31,925 men “who answered questions on ejaculation frequency on a 1992 questionnaire and followed through to 2010,” the study authors noted.

Vasectomy

Half a million American men have a vasectomy each year, so it’s prudent to ask: Does vasectomy increase the risk of prostate cancer? The American Urological Association reviewed the research on the link between vasectomy and prostate cancer risk and concluded that “based on the results of the two meta-analyses, vasectomy is not associated with prostate cancer.” A 2017 review in JAMA Internal Medicine confirmed that vasectomy had an insignificant impact on aggressive prostate cancer risk.

Prevention of Prostate Cancer

The development of prostate cancer is complicated, and it is unlikely it can be prevented altogether. What the risk factors above do tell us it that while you can’t change your age, your race, or your family history, you still may be able to influence your risk. Compelling evidence, as noted earlier, tells us that a healthy lifestyle reduces your risk of most illnesses.

The problem with prevention is that people live busy, chaotic lives. A healthy lifestyle takes time, energy, and often money (especially in terms of diet), and the results are not guaranteed. We have all heard of health nuts who die of a heart attack in their 40s and chain-smoking alcoholics who live well into their 80s. A sensible approach is to focus on overall health, rather than just one specific disease, thus shifting the balance of risk in your favor.

A Closer Look at Lifestyle

If you want to take control of your health and potentially reduce your risk of prostate cancer, here are some strategies that may help.

Improve your diet. Eat more fruits and vegetables, eat lean protein, and reduce intake of red meat cooked at high temperatures (processed, grilled, fried, or broiled).

• Tomatoes and cruciferous vegetables (high in carotenoids) draw particular attention, including broccoli, Brussels sprouts, and cauliflower.
• Eat a wide variety of fruits and vegetables of different colors so you get plenty of micronutrients.

Eat antioxidant-rich foods like blueberries, watermelon, garlic, and arugula; these reduce DNA damage.

Food allergies and insensitivities are increasingly common: Listen to your body and avoid foods that make you feel unwell, even if they are on the “healthy” list.

• Limit dairy intake.
• Moderate amounts of tea and coffee are beneficial for prostate health.
• Consider eating more soy, but make sure it’s organic.
• Eat more healthy fats. Switch processed fats for olive, avocado oil or seed oils. Eat oily fish like salmon two to three times a week or take a fish oil supplement.

Exercise regularly. This will improve your overall health and may reduce your prostate cancer risk. Starting to exercise when you are young is especially protective.

Drugs and medications. Some medications coincidentally reduce the risk of prostate cancer:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin or ibuprofen.
• Metformin used in treatment of type 2 diabetes.
• Statins used to lower bad LDL cholesterol.
• 5-ARIs, used to treat benign prostatic hyperplasia, have been shown to reduce the risk of prostatic cancer by 26 percent. However, they may increase the risk of more aggressive cancers. If you are at high risk, you may wish to discuss the use of these drugs as a preventative measure, with your clinician.

Diagnostic Evaluation

There are two stages to diagnostic evaluation:

• Screening is defined as the testing of individuals with no symptoms in an attempt to catch early disease.
• Investigations are assessments and tests done in individuals with symptoms or where screening has identified a potential problem.

Let’s begin by talking about the PSA test that’s both screening and diagnostic test.

What Is PSA?

Prostate-specific antigen or PSA is a blood test commonly used in two scenarios:

• A screening test (men with no symptoms)
• A diagnostic test (men with symptoms)

PSA is a protein made by the prostate to maintain semen’s liquid form, so that sperm can move freely from the male to the female reproductive system during natural conception. Small quantities of PSA make their way into the bloodstream, allowing for measurement in the PSA blood test.

Over a billion PSA tests have been done since it was approved by the FDA in 1986 to monitor treatment response and disease recurrence and in 1994 as a screening and diagnostic test. A 2014 study published in the journal Prostate International confirmed that PSA is a useful test, concluding that there is “a strong correlation of PSA level with tumor diagnosis, tumor aggressiveness, and bone metastasis.”

The PSA test is controversial as a screening test but is extremely useful as a diagnostic test and has saved millions of lives, picking up aggressive cancers so that men can receive early treatment.

Understanding the PSA Test

The PSA test measures tiny quantities of PSA in the blood. The scale used is ng/ml or nanograms (one-billionth of a gram) per milliliter (one-thousandth of a liter).

• A PSA test result under 4 ng/ml is considered “normal.” There is, however, a caveat: Some aggressive cancers have a PSA in this range. The Prostate Cancer Prevention Trial (PCPT) warns there is no PSA level at which the prostate cancer risk is zero.
• For the general male population, a PSA level between 4.1 and 10 carries a 47 percent risk of prostate cancer.
• PSA over 10 carries a 58 percent risk of prostate cancer, and thereafter the risk is closely correlated to PSA level.

Age-Adjusted PSA

PSA rises naturally with age, so adjusting for age can help interpret the results. The American Urological Association recommends the following thresholds:

• 40- to 49-year-olds normal: less than 2.5
• 50- to 59-year-olds normal: less than 3.5
• 60- to 69-year-olds normal: less than 4.5
• 70- to 79-year-olds normal: less than 6.5

However, the same caveats apply as above: Low PSA may actually indicate aggressive disease.

Advanced PSA Measurements

In an effort to improve accuracy of screening, the PSA has been adapted and refined. The jury is out as to which of these tests are most useful.

Screening

Screening for asymptomatic men (showing no symptoms) for prostate cancer involves the PSA test and a digital rectal examination (DRE). Routine prostate cancer screening is controversial for two main reasons:

• Unlike some screening tests—like cervical cancer and colorectal cancer—the risks of screening healthy men may outweigh the potential benefits.
• Unlike some cancers—pancreatic and lung cancer, for example—prostate cancer is often not life-threatening. In fact, in many cases prostate cancers are so slow-growing that they can almost be considered benign.

The goal of prostate cancer screening, therefore, is to detect high-risk tumors while they are treatable and potentially curable.

Digital Rectal Examination (DRE)

This simple test is performed at a physical examination. The patient lies on his side and the doctor inserts a lubricated, gloved finger (digit) into the rectum. The prostate lies in front of the rectum and the doctor palpates for size, texture, lumps, and pain.

While the DRE can be embarrassing and a little uncomfortable, it is a useful screening test and is over in a couple of minutes.

Like the much-maligned PSA test, it is a crude and unreliable test, but doctors believe it is still worth doing in the absence of more definitive screening. It can also detect problems with other organs, including the bladder and bowel, in the pelvic region.

To Screen or Not to Screen?

Screening tests are those done on people who feel well, with the aim of detecting serious disease before symptoms arise and before the disease is advanced, thus allowing early treatment and improving outcome.

All screening tests have their pros and cons. Even a simple test like routine blood pressure monitoring can have a downside: Sometimes blood pressure is elevated due to anxiety about visiting the doctor (white coat syndrome) and testing may cause unwarranted alarm and further unnecessary testing. It’s important to weigh the advantages and disadvantages of any screening test before you make a decision.

Advantages of PSA Screening

As is the case with most cancers, the earlier prostate cancer is detected, the greater the odds of a cure. Proponents argue that screening is the only way to catch prostate cancer at an early stage. They also point to the fact that death rates from prostate cancer have decreased significantly since widespread screening began in the early 1990s.

The great news is that screening has dramatically increased the detection of prostate cancer while it is still localized to the prostate, a significant factor in improved outcomes.

It is now rare for men to be first diagnosed with prostate cancer when it is advanced. Deaths from prostate cancer have significantly declined in the last 20 years, which is great news by any standard.

The Disadvantages of PSA Screening

While the drop in deaths from prostate cancer is cause for celebration, opponents to PSA testing suggest that this has little to do with screening and more to do with treatment advances: The survival rate was already improving in the United States, and survival rates have improved in countries that do not screen.

The case against screening points to these potential problems:

False negatives: PSA misses some cancers. Around 20 percent of men confirmed to have prostate cancer have normal PSA levels (less than 4 ng/ml). False negatives give a false sense of security.

Other causes of low PSA: Unfortunately, there are factors that naturally reduce PSA levels, further complicating the interpretation of results. These include:

• Cigarette smoking (past or present).
• Obesity: Greater blood volumes may dilute PSA.
• Medications:
  • BPH treatments: 5-alpha reductase inhibitors like finasteride (Proscar) and dutasteride (Avodart), although they may improve accuracy.
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen (Advil, Motrin).
  • Diuretics for high blood pressure; examples: chlorothiazide (Diuril) and hydrochlorothiazide (Microzide, Dyazide, Maxzide).
  • Statins for high cholesterol such as atorvastatin (Lipitor) and simvastatin (Zocor).

False positives: Some 70 to 80 percent of men with elevated PSA levels do not have cancer. For these men, a positive test leads to a cascade of testing that often results in the man being told he doesn’t have cancer. That would be fine—if testing caused no harm.
However, being told that you have a positive result may cause severe psychological stress for weeks or months.

And when a clinician determines the PSA to be significant, the next test is prostate biopsy, which carries risks: One in five men develop complications and turn out to have a negative biopsy; one in 24 develops erectile dysfunction; and 1 in 56 develops urinary incontinence.

Other causes of high PSA: Unfortunately, there are factors that naturally increase PSA levels, further complicating the interpretation of results. These include:

• Prostatitis (non-cancerous inflammation), benign prostatic hypertrophy, and urine infections can all increase PSA, further confusing the issue.
• Tests or surgery on the prostate, including DRE.
• Recent ejaculation, especially in older men.
• Exercise, most notably bicycle riding (doctors advise not to ride your bicycle for 24 hours before PSA testing).
• Hepatitis.
• Bypass surgery.

The unpredictability of positives: Statistically speaking, a very high PSA level is closely correlated to aggressive prostate cancer. But, when PSA is mildly elevated, the results are less clear-cut. Some men with high PSA turn out to have no cancer or a very slow growing type, while some men with a low level of PSA turn out to have aggressive cancer. Research published in the journal Prostate International in 2014 shows this latter scenario to be alarmingly common.

Number needed to treat: Statistics have measured the number of patients who need to be treated in order to prevent one extra bad outcome. In 2012, the European Randomized Study of Screening for Prostate Cancer trial (ERSPC 2012) showed that “to prevent one prostate cancer death, 935 men would need to be screened and 37 cancers would need to be detected.” Researchers considered this rate to be unacceptably high.

PSA Screening: The Research

Two major studies have fueled the debates on prostate cancer screening.

PLCO Trial

The National Cancer Institute sponsored the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial in the U.S. They followed 77,500 men, all of them between the ages 55 and 74, who had no history of prostate, lung, or colorectal cancer. Men were randomized into one of two groups:

• The intervention arm, receiving trial screening
• The control arm, receiving standard care. The intervention arm received chest x-rays, flexible sigmoidoscopy, PSA blood tests, and digital rectal exams.

Enrollment began in 1993, participants were screened through 2006, and data was collected through 2015. Researchers reported that seven to 13 years later, “there was no evidence of a mortality benefit for organized annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care, and there was no apparent interaction with age, baseline comorbidity, or pretrial PSA testing.”

In other words, the very costly screening program statistically had little effect on outcomes. However, the study has been heavily criticized for several flaws, paramount of which is the fact that 52 percent of the control group was in fact screened at some stage.

European Randomized Study of Screening for Prostate Cancer

The ERSPC, which involved eight European countries, is the largest ever prostate cancer screening study. A total of 182,000 men (162,000 of them between the ages 55 and 69) were randomized into the intervention and control groups. Those in the intervention arm were offered PSA blood tests every two or four years. Those with a PSA level of more than 3.0 ng/ml were offered biopsy. Patient follow-up was extended to 11 years and is ongoing.

In recent analysis the researchers concluded that “a man who undergoes PSA testing will have his risk of dying from prostate cancer reduced by 29 percent.”

The major down side, as they discovered, was that there were high rates of false positives: 30 percent of those with detected cancers did not have progressive disease. The “number needed to treat” (NNT, or number screened to avoid one death) was 48, which is considered to be high.

Professor Fritz Schroeder, the study coordinator, concluded that “screening programs for prostate cancer will not be feasible until the medical communities can confidently balance the risk of reducing death from prostate cancer with these unacceptably high levels overdiagnosis and overtreatment.”

PSA Screening: The Guidelines

The controversy over screening creates a dilemma for clinicians and patients alike. Many clinicians turn to guidelines from major medical institutions, including:

• U.S. Preventive Services Task Force (USPSTF)
• American Cancer Society (ACS)
• National Comprehensive Cancer Network (NCCN)
• American Urological Association (AUA)
• European Society for Medical Oncology (ESMO)

The guidelines vary, so it falls to the individual clinician to decide which one(s) to recommend. Patients should then be well-informed so that a shared decision-making process can occur.

U.S. Preventative Task Force (USPSTF)

USPSTF’s 2012 screening guidelines take a strong stance: “The U.S. Preventive Services Task Force recommends against PSA–based screening for prostate cancer.” The organization recognizes that some men will still request screening and advises shared decision-making that weighs the benefits and risks and takes into account the patient’s preferences and values.

American Cancer Society (ACS)

The ACS’s 2010 screening guidelines advise no routine screening in any age group.

• Step 1: Screening information to be provided to the following groups, so that an informed decision can be made:
  • Men 50 and over with average risk.
  • Men aged 45 to 50 with high risk, including African Americans and men with a first-degree relative (father, brother, son) diagnosed before 65 years old.
  • Men aged 40 to 45 with highest risk (more than one first-degree relative diagnosed at an early age).
• Step 2: Men who opt for screening should be tested with a PSA test and DRE. If the man is unsure, he can ask his doctor to make the decision on his behalf.
  • If PSA is below 2.5 ng/ml, a rescreening every two years is advised.
  • For those with a higher PSA, annual screening is advised.

National Comprehensive Cancer Network (NCCN)

The NCCN screening guidelines recommend:

• Step 1: Baseline history and physical examination, with a discussion of the risks and benefits of a baseline DRE and PSA.
• Step 2: Patient opts for a baseline DRE, which is normal. Then the following should be offered:
  • Baseline PSA testing: 45- to 49-year-olds.
  • PSA is below 1.0 ng/ml: Retest every two to four years.
  • PSA is 1.0 ng/ml or higher: Annual or biannual testing.
  • If DRE is normal, PSA is below 3 ng/mL, and man is 50- to 70-years-old: Retest every one to two years.
  • Beyond the age of 75, only a select few should be screened.

American Urological Association (AUA)

The AUA’s 2013 screening guidelines recommend screening for men aged 55- to 69-years-old who have been fully informed and have made a shared decision with the clinician to go ahead with screening. Screening is recommended at intervals of at least two years.

Screening is not recommended for men in the following groups:

• Any man with a life expectancy of less than 10 to 15 years
• Men under 40 years or over 70
• Men between ages 40 to 54 years at average risk.

European Society for Medical Oncology (ESMO)

The ESMO’s PSA screening guidelines recommend no screening for:

• Population-based PSA screening
• Asymptomatic men over 70-years-old
• Men with a life expectancy of less than 15 years

PSA testing should be offered to these higher risk men:

• Over 50
• Over 45 with a positive family history
• African American over 45
• 40-year-old with a PSA level over 1 ng/mL
• 60-year-old with a PSA level over 2 ng/mL

Diagnostic Investigations

If you have prostatic symptoms or a high PSA or abnormal DRE results, your doctor will take you through some or all of the following steps.

• Full medical history, including symptoms, surgeries, medications, and family history.
• Full physical examination of all body systems, including a DRE.
• Symptoms assessment using a checklist, such as the AUA Symptom Index.
• Urine test to look for infection, blood and glucose.

Blood test for:

• General health markers (blood count and chemistry).
• PSA, advanced PSA testing (free PSA, PSA velocity, Prostate Health Index, 4Kscore, or prostate cancer antigen 3 (PCA3).

• Transrectal ultrasound (scans via the rectum, using a probe) to look for abnormalities or lesions.

Transrectal Ultrasound (TRUS) Biopsy

A TRUS-guided biopsy involves an ultrasound probe being inserted into the rectum and a spring-loaded needle taking multiple tiny samples (core needle biopsy). These samples are sent to the laboratory to look for cancerous cells. Performed under local anaesthetic in the urologist’s office, the biopsy takes about 15 minutes and is mildly uncomfortable. Sometimes, a biopsy fails to detect cancer when there is a high level of suspicion, so a repeat biopsy may be taken.

Potential complications of a biopsy include bleeding, lower urinary tract symptoms, urinary tract infection, and infection of prostate (prostatitis). Some men report worsening of erectile dysfunction. The risk of infection can be reduced by giving prophylactic antibiotics before the biopsy. Men should avoid taking nonsteroidal anti-inflammatory drugs (like aspirin or ibuprofen) and fish oils prior to biopsy, to reduce bleeding risk.

The image-guided targeted fusion biopsy is one of several techniques being developed to improve accuracy of biopsy. First the patient undergoes an MRI, during which abnormal areas are flagged. Then an ultrasound-guided biopsy takes samples from these targeted areas.

Post-Diagnosis Investigations

If you have a confirmed diagnosis of cancer, your doctor may want to perform further tests to determine the severity and to check whether it has spread (metastasized). Prostate cancer can be tiny when it first presents, and its spread is unpredictable, so these tests are very useful.

Investigations may include:

• Pelvic ultrasound to look for local spread beyond the prostate.
• Bone scan to look for bone metastases.
• Chest x-ray to look for lung and chest wall metastases.
• Scans, including CT scans (computed tomography), MRIs (magnetic resonance imaging), and PET scans (positron emission tomography), which may be used to look for signs of spreading to the lymph nodes, pelvis, or beyond.
• Lymph node biopsy to look for spread to lymph nodes.
• Genomic testing. Still in the development phase, it is hoped that genomic testing may help determine which cancers are benign and low-risk, and which are aggressive and life-threatening. Examples include Oncotype DX Genomic Prostate Score (GPS), ProMark, Decipher, and Prolaris.

The results of these tests will guide decisions regarding treatment.

Biopsy Results: Histology

Biopsy samples are evaluated for changes in cells. Changes are seen on a continuum.

High-grade prostatic intraepithelial neoplasia (HGPIN or PIN): Like many cancers, prostate cancer starts with precancerous changes that may discovered via biopsy. PIN is divided into low-grade (mild dysplasia) and high-grade prostatic intraepithelial neoplasia (HGPIN, or severe dysplasia). HGPIN are abnormal cells that have not become invasive and are found in 80 to 100 percent of prostates with carcinoma. This suggests that they are a precursor. It should be noted, however, that these cells are detected in up to a quarter of men, most of whom do not develop cancer. In those who do develop carcinoma, PIN predates a malignancy by 10 or more years. A small body of evidence suggests that when PIN is found in multiple sites, there is an increased risk of prostate cancer. If PIN is detected, a six-month follow-up biopsy may be recommended.

Atypical small acinar proliferations (atypia or ASAP): Atypia is a more significant finding than PIN, as approximately 50 percent predate cancer. It is found at biopsy in 2 to 5 percent of men. In atypia, there are abnormal cells; however, they are few in number, they don’t quite look like cancer cells, and other features (such as inflammation) may confuse the picture. Some clinicians describe atypia as “suspicious” or “highly suspicious for cancer” and recommend rebiopsy in six months’ time, with more extensive sampling.

Cancer: If cancer cells are found at biopsy, they will be “graded” to see how abnormal they are. Low-grade cancers look most like normal tissue and may have only just begun to invade locally. The clinician will also look for evidence of spread beyond the prostate gland.

Measuring Cancer Severity

Clinicians use three main criteria to determine the severity of cancer:

• Blood tests: May include PSA levels, advanced PSA tests, and biomarkers.
• Grading: The Gleason score, which defines types of cells (histology).
• Staging: TNM Classification (tumor node metastases), which defines where cancer is found.

The Gleason Score

This is the most commonly used grading score for prostate cancer. First developed in 1966, the Gleason score has been refined several times since then. It is based purely on the “architecture” or histology of the cells—that is, how they look in the laboratory. It has been found to be a good indicator of how cancer will progress and, thus, is a useful guide for treatment.

The Gleason Score is composed of two scores, both using a scale of 1 to 5. A score of 1 means the cells are very close to normal; a score of 5 means the cells are very abnormal.

Modified Gleason Score (ISUP)

Some clinicians use the 2- to 10-point Gleason score. Others are shifting over to the new International Society of Urological Pathology (ISUP) Score:

• Gleason scores ≤ 6: ISUP grade 1 (least aggressive)
• Gleason score 3 + 4 = 7: ISUP grade 2
• Gleason score 4 + 3 = 7: ISUP grade 3
• Gleason score 8: ISUP grade 4
• Gleason score 9 to 10: ISUP grade 5 (most aggressive)

A study published in European Urology in 2016 reported that the new system provides these benefits: “more accurate grade stratification than current systems, simplified grading system of five grades, and lowest grade is 1, as opposed to 6, with the potential to reduce overtreatment of PCa.” The hope is that it will lead to a reduction in the overtreatment of benign, slow-growing cancers.

Staging Prostate Cancer

TNM Classification was developed by the American Joint Committee on Cancer (AJCC) in 1992 and refined, the tumor node metastases, or TNM, staging system is used to define a prostate cancer progression. It has three components: primary tumor (T), lymph node (L) involvement, and metastasis (M: spread to other organs). The staging is summarized in the box on this page.

Risk Group

Having completed the necessary investigations, your doctor will determine your risk group. This, in turn, will help predict prognosis and guide treatment. 

Enhanced Screening: New Developments

Genetic Screening

The link between genes and cancer is fascinating. Genetic mutations are occurring all the time in our bodies, but most result in no harm to the individual and the mutation line dies out. When mutations occur in certain genes, disease may occur.

The most common type of mutation: somatic mutations, which involve genes responsible for cell growth, cell repair, and cell division. Somatic mutations can lead to abnormal or uncontrollable cell division, with the result being a tumor.

Somatic mutations are not passed down to future generations. Most prostate cancers are due to these sporadic somatic mutations and are therefore not hereditary or detectable on genetic screening.

Less common are germline mutations that affect every cell in the body. They are usually triggered by lifestyle and environmental factors and changes in other genes. Germline mutations can be inherited.

Researchers frequently find new germlines implicated in prostate cancer. When a germline mutation is discovered, it adds genetic screening arsenal for prostate cancer.

Inherited genes implicated in prostate cancer include BRCA1, BRCA2, and HOXB13. BRCA1 and BRCA2 repair damaged DNA and suppress tumors, keeping cell division at a normal level.

The HOXB13 gene is involved with making a protein that transcribes DNA, regulates activity of other genes, and suppresses tumor growth. Defects in these genes lead to uncontrollable cell division and growth.

Gene fusion is a hybrid gene formed from two previously separate genes. The fusion occurs due to DNA damage, when damaged pieces of DNA attach to other damaged pieces of DNA, creating new genes.

Generalized inflammation and environmental factors are implicated in this process. (The study of gene alteration due to environment, as discussed earlier, is known as epigenetics.)

In about 50 percent of men with prostate cancer, there is gene fusion of TMPRSS2 (androgen regulator) and ERG. ERG is a gene responsible for transcribing DNA for the cancer-causing gene ETS (erythroblast transformation-specific).

This gene fusion can lead to the overexpression of ETS, resulting in uncontrolled cell growth. This finding is never seen in normal prostate cells but is seen in precancerous (PIN) cells.

Other genetic markers implicated in prostate cancer: TP53, AR, PTEN, PIK3CA, RB1, APC, CHD1, MYC, and ATM.

The aim of current research is to identify more genes involved in prostate cancer, understand the mode of action, and develop therapies to reduce the burden of disease.

“Liquid” Biopsies

Liquid biopsies take a urine or blood sample and look for evidence of cancer cells, DNA, or fragments of cancer. They can be used to help detect early cancer, develop a treatment plan, and track progress of treatment. The advantage is that liquid biopsies are far less invasive than repeated prostate biopsies.

Examples of liquid biopsies:

ExoDx Prostate IntelliScore—which is in the development phase—measures exosome (fragments of cells) biomarkers in urine.

The Stockholm-3 (STHLM3) blood test screens several forms of PSA, other protein biomarkers, and germline genetic markers and clinical variables.vPromising research from Sweden, reported in Lancet Oncology in 2015, suggests that the “STHLM3 model could reduce the number of biopsies by 32 percent (95 percent CI 24 to39) and could avoid 44 percent (35 to 54) of benign biopsies.”

IsoPSA is another blood test that’s showing promise. A 2017 study reported in European Urology concluded that “IsoPSA demonstrated a 48 percent reduction in false-positive biopsies… (and a) 45 percent reduction in the false-positive rate.”

Still another new blood test showing promise is the surface-enhanced Raman scattering (SERS) in combination with the support vector machine (SVM). This technique involves the use of a new analysis tool that looks at the chemical composition of blood serum. It produces a diagnostic accuracy of 98.1 percent.

Screening: Making Your Decision

There are varying opinions on screening for prostate cancer, opinions that can leave you confused and wondering about which course of action is the best.

Some of the tests discussed are available only at certain centers, so your doctor will advise you on what to do. He should talk to you about the screening available and the pros and cons for each. Things you may wish to consider in the process:

• Am I at low risk? Example: You’re under 60, not African American, have no family prostate cancer history of note, and are fit and healthy.
• Am I at high risk? Example: You’re aged 60 to 70, are African American, have a strong relevant family history, or have diabetes or chronic health problems.
• What does my doctor advise?
• What would I do if I were diagnosed with slow-growing, low-risk cancer?
• How would I cope with the uncertainty of turning down the test?

Every man is different, and there is no right or wrong answer. Ultimately the decision is yours.

Prostate Cancer Treatment

It’s normal to feel shocked and overwhelmed by a diagnosis of prostate cancer. But unlike many other cancers, the majority of prostate cancers are slow-growing and not life-threatening. The five-year survival rate for all prostate cancers is 98.6 percent. This statistic, while reassuring, hides the fact that if, at diagnosis, the prostate cancer has spread beyond the prostate and into the pelvis or into other organs by way of metastasis, the five-year survival rate is only 29 percent.

If you receive a prostate cancer diagnosis, listen carefully to the information your clinical team gives you and take your time to digest it. If you’re uncertain about something, ask for clarification either at the time or at a later date. Get as much information as you can in writing, so that you can learn more when the initial shock has died down.

Myriad treatment options exist for prostate cancer. There is no one-size-fits-all: Deciding on the best treatment protocol is a complicated process. Prostate cancer treatments involve complex trade-offs, and each treatment has its own risks and benefits.

The big dilemma in prostate cancer is whether to treat it in “low-risk” cases. Some slow-growing cancers pose little immediate risk to health, and there are significant complications to treatment.

The aim of treatment should be to improve longevity and quality of life. A younger man—one who potentially has decades of life ahead of him—may decide that living with cancer and the uncertainty it brings will warrant aggressive treatment with a high chance of a cure. An older man who has other health problems may decide to hold off on treatment until his doctor tells him it’s urgent.

Shared Decision-Making

The American Urological Association (AUA) offers useful guidelines for doctors on how to treat prostate cancer. They recommend beginning with an initial assessment followed by counseling and then shared discussion regarding treatment options. These options are geared around the following factors:

• Risk category: Determined by the characteristics of the tumor, its aggressiveness, and its spread, as assessed via these procedures:
  • Blood tests (PSA levels, advanced PSA tests, and biomarkers)
  • Grading the types of cancer cells (Gleason score)
  • Staging the spread of the cancer (TNM classification)
• Life expectancy: Determined by current age and general health. This may be overwhelming to discuss, but it’s important. As you have learned, many prostate cancers are so slow-growing that they may take decades before they are problematic.
• Current level of functioning and lifestyle: It’s important to assess your baseline quality of life, including work, family, love life, leisure time, and so on.
• Expected post-treatment function: Consider expectations surrounding your sex life. It’s important to look ahead, too. What would you like your life to look like in five or 10 years?
• Your values and preferences: Consider the importance of issues like recovery time, side effects, and distance you’re willing to travel for treatment.
• Your clinician’s preference and expertise: Many of the treatments discussed later in this chapter are not offered by every doctor. Outcomes are better when the doctor is an expert in a particular technique. An experienced surgeon will be completing at least 40 radical prostatectomies each year.
• Lifestyle: Your clinical team should also talk to you about your modifiable risk factors—smoking, obesity, and diet, for example. This is particularly important in low-risk cancers, where lifestyle changes may have an impact on your risk of cancer progression and also may improve your quality of life, general health, and well-being.
• Specialists: You may also be referred to a range of specialists (like oncologists, radiologists, and surgeons) who can advise you on the the various treatment options. You may also be informed of your eligibility to take part in ongoing clinical trials for new therapies.
• Research with care: We live in an age when access to medical information is at our fingertips 24/7. It’s great to research and become an expert on your own condition, as then you can make informed decisions and advocate for yourself. There is a down side, however, to personal research. First, you may become frightened or obsessed while reading information that isn’t designed for the public. Plus, there’s a lot of inaccurate information on the Internet, and with it comes the potential to make bad decisions. That said, there are some excellent sites that are reliable, among them the National Comprehensive Cancer Network, Cancer.org and Cancer.gov. You may also want to access professionally run community groups and support groups. Also, be extremely wary of getting advice from friends and family: They are biased, don’t understand your clinical picture, and may feed you dubious advice. Your health is too precious to leave to a game of Chinese Whispers.

AUA Treatment Guidelines

Low-Risk Prostate Cancer

The American Urological Assocition recommended protocol for treatment of low-risk cancer:

• Active surveillance or watchful waiting: Standard approach in most men.
• Radical prostatectomy or radiation therapy: For those at higher risk of progression, including younger men with strong family history of prostate cancer and gene markers.
• Hormone therapy (androgen deprivation therapy/ADT): When brachytherapy (radiological seed implantation ) is planned and the patient’s prostate size needs to be reduced.
• Cryosurgery and HIFU (high-intensity focused ultrasound): Still in research phase, these are not recommended in low-risk patients.

Many men on active surveillance have poor compliance with follow-up, so it’s important to confirm the diagnosis with a repeat biopsy or MRI scan before they enter active surveillance. Up to 1 in 3 men, given a low-risk diagnosis, turn out to have cancers that are more advanced, and in rare cases they go on to die of an aggressive cancer. Misdiagnosis is most common in African-American men.

Intermediate-Risk Cancer

Protocol recommended:

• CT or MRI scan: To accurately determine staging.
• Radical prostatectomy (RP) or radiation therapy, plus hormone therapy: Standard treatment.
• Cryosurgery: May be considered in some men who are not suitable for RP or radiation therapy.
• Active surveillance: May be an option for some who understand and are willing to accept the higher risk of metastases.
• Watchful waiting: May be an option for older men whose life expectancy is less than five years.
• High-intensity Focused Ultrasound (HIFU): May be considered in some men.

High-Risk Prostate Cancer

Protocol recommended:

• CT or MRI scan plus bone scan: To accurately determine staging.
• Radical prostatectomy or radiation therapy, plus hormone therapy: Standard treatment.
• Watchful waiting: May be an option for older men who are symptom-free or who have a life expectancy of less than five years.
• Cryosurgery, focal therapy, and HIFU treatments: Not recommended as standard, but may be included in a clinical trial.
• Hormone therapy alone: Not recommended except in men with a life expectancy of less than five years plus local symptoms.
• Genetic counseling: For the patient and close family, especially if there is a history of other cancers—breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma.

In high-risk prostate cancer, there is more urgency about making treatment decisions. The earlier the treatment is initiated, the better the outcome.

Metastatic Prostate Cancer

Protocol recommended:

• Hormone therapy: Standard treatment.
• Pain relief as needed.
• Palliative care, if this becomes necessary.

What Is Radical Prostatectomy?

Retropubic radical prostatectomy is the most common surgery for prostate cancer. It produces excellent outcomes especially in younger men or healthy older men.

Procedure: Prior to surgery, the bowel is evacuated and cleansed to open up space in the pelvis. The surgery is done under general or spinal anaesthetic in the operating room. The surgeon accesses the prostate via an incision in the abdomen or the perineum (the area between the scrotum and anus). The entire prostate gland and seminal vesicles are removed—thus the word “radical.” Local lymph nodes are often removed as a precaution.

Surgery is most effective in men with disease isolated to the prostate (stages T1 and T2), who are healthy, and who are under age 70. A hospital stay of one to three days is usual, but it may take several weeks to feel back to normal. Catheterization for at least a week is recommended, until the urethra heals.

During surgery, the surgeon has to weigh certainty against the risk of complications. Removing more tissue and lymph nodes increases the certainty that all of the cancer has been removed, but increases the risk of damaging the nerves to the penis, leading to impotence, and increases the risk of damaging the urethral sphincter, leading to urinary incontinence.

Techniques: There are several radical prostatectomy techniques, including:

• Open: Abdominal incision above the pubic bone or perineum. This gives the surgeon an excellent view of the prostate and surrounding organs in the pelvis and the ability to biopsy local lymph nodes (lymph node dissection). This is the preferred technique for more advanced cancers.
• Laparoscopic: A flexible laparoscope is inserted via a small incision in the abdomen, suprapubic area, or perineum, and the prostate is removed. Technically, this is much more difficult, requiring expert training. Lymph nodes cannot be dissected.
• Robotic: Robotic procedures now account for 60 percent of RP surgeries in the U.S. Three to four incisions are made for robotic arms or laparoscopes. One arm carries a laparoscopic video camera, the other surgical tools. The surgeon sits at a screen and operates the robotic arms with a joystick and pedals. Advantage: Improved accuracy, shorter hospital stay, and less blood loss (and, consequently, a lower transfusion rate). Survival rates are similar to open surgery.
• Nerve-sparing radical prostatectomy: This is a prostatectomy with an added technique that attempts to preserve the neurovascular bundles—the nerves and blood vessels that allow the penis to become erect. These are dissected and spared from removal, with the aim to preserve erectile function and lessen urinary problems. This procedure is delicate and time-consuming. The results cannot be guaranteed, and it takes several months for function to begin to recover.

The perineal incision approach is rarely used but has the advantage of being easier in overweight men and causing less bleeding and pain. The disadvantage is that lymph nodes cannot be biopsied and nerve damage is more common.

Research

A 2015 study followed 483 low-risk patients for 10 years after surgery. Researchers found that recurrence and survival rates were similar in robotic and open prostatectomy. Robotic surgery resulted in shorter hospital stays, fewer blood transfusions, and a small improvement in sexual function. There was, however, an increased incidence of urinary and other complications, plus post-operative expenses were higher.

Outcomes

For men with cancer that is localized, radical prostatectomy has a high cure rate. For those with cancer that has spread beyond the prostate, radiation or androgen therapy may also be needed.

The three main techniques have similar outcomes, so the decision as to which technique to use should be determined by the surgeon’s expertise and the patient’s preference.

Expert surgeons usually perform 40 prostatectomies annually, and they tend to have better outcomes, with lower complication rates.

Potential Complications

Early complications, which usually settle in during the first two weeks after surgery, include bleeding, infection (in scar, urine, or prostate), swelling of penis and scrotum, lymphadenopathy, and heart problems.

Persistent complications include nerve damage and erectile dysfunction (20 to 70 percent) and urinary incontinence (50 percent). It should be noted that some untreated men also develop these complications during active surveillance, but at less than half of that following surgery.

There is reassuring evidence that urinary control and sexual function can improve, with time, after surgery. A 2015 study asked 3,187 men about symptoms post-prostatectomy. They found that in those with incontinence at 12 months post-op, good urinary function was restored at two years in 30 percent; at three years in 49 percent; and at four years in 59 percent. For those with impotence at 12 months post-op, erectile function was restored at two years in 22 percent; at three years in 32 percent; and at four years in 40 percent.

Comparing Techniques

• Radical prostatectomy surgery causes more urinary and sexual problems in the first few months postoperatively than does radiation therapy.
• Perineal surgery has an increased risk of fecal incontinence.
• Postoperative bleeding is reduced in perineal, laparoscopic, and robotic surgeries, compared to open prostatectomy.
• Nerve sparing techniques are associated with better erectile function recovery compared to non-nerve sparing.
• Older men experience a higher incidence of erectile dysfunction and urinary incontinence, compared to younger men.
• Some men can still orgasm after surgery but they are unable to ejaculate, will be infertile after surgery, and may leak urine.

The 2016 ProtecT Trial of 391 post-prostatectomy men found that there were no surgery-related deaths, but nine men had thromboembolic (blood clot) or cardiovascular events, 14 required blood transfusion (over three units), one had a rectal injury, and nine developed anastomoses (abnormal connection between two organs).

Benefits of Surgery

Surgery removes a lot of uncertainty. Research shows that in men with disease isolated to the prostate, 90 percent are alive and cancer-free 10 years after surgery. A coincidental benefit is that you will never develop benign prostatic hyperplasia, a benign but troublesome condition affecting half of men over the age of 60. Open surgery has the advantage of allowing biopsy of lymph nodes to improve certainty over staging and guide further treatment.

Postsurgical Therapy

Some men will be offered radiation or hormone therapy following surgery. It may be offered as adjuvant therapy soon after surgery or as salvage therapy months later. It may be recommended in the following situations:

• Adjuvant therapy: For high-risk patients, where cancer was seen on the outer margin of the removed tissue or where cancer had spread to the seminal vesicles.
• Salvage therapy: For “biochemical recurrence.” A rise in PSA in the months following surgery is seen in 25 to 30 percent of patients. External-beam radiation is usually offered, but some clinicians prefer hormone therapy.

In the post-op period, the Decipher genomic test can calculate the risk of prostatic cancer recurrence or metastasis and is useful in steering treatment decisions.

Pre-RP Lymph Node Biopsy

In order to be certain of staging, some surgeons perform lymph node biopsy to rule out lymph node involvement, which can dramatically change the treatment options.

Radiation

Radiation is a viable alternative to radical prostatectomy, with the potential for cure in localized prostate cancer. It carries with it its own set of risks and benefits. There are two forms of radiation therapy commonly used to treat prostate cancer: external-beam radiation therapy (EBRT) and brachytherapy (the insertion of radioactive seeds into the prostate gland).

What Is External-Beam Radiation Therapy (EBRT)?

EBRT can be used as a primary treatment for localized cancers or following surgery, where biopsy reveals spreading beyond the prostatic capsule, or if PSA rises in the postoperative months.

Procedure: Currently the most widely used radiation therapy, this treatment uses focused high-energy x-rays over multiple sessions to destroy the cancer. It can also be used on diseased lymph nodes. The major disadvantage is that EBRT is time-consuming: The patient receives radiation therapy for about 15 minutes each day, five days a week, for about two months. Straps are used to prevent movement and lead shields protect surrounding organs (testicles and penis).

Good candidates: EBRT is a good option for older men with other health problems, where cancer has spread outside of the prostatic capsule (Stage 3) and in men who have already had TURP (transurethral resection of prostate) for benign prostatic hyperplasia. It can also be used in advanced cancers to help reduce the size of the prostate and reduce symptoms.

Advanced ERBT: Technological advances with high-dose EBRT have led to improved precision of this technique:

• 3-dimensional conformal radiation therapy (3D-CRT): The radiation beam is shaped to match the tumor. Beams of radiation come from several directions to precisely match the tumor’s height, width, and depth.
• Hypofractionated radiation: This newer technique is gaining popularity. It uses higher doses of radiation over a few days or weeks. It has a similar side effect and outcome profile to standard ERBT.
• Stereotactic body radiation therapy, or SBRT: Still in the research phase, these techniques (for example, CyberKnife, GammaKnife, or TomoTherapy) speed up the process further, into just five days. They deliver high-dose radiation with pinpoint accuracy. Early results are promising but suggest that side effects may be higher. SBRT may be useful for men whose cancer has spread beyond the capsule or for men who have had a TURP. It is available at only a limited number of centers.
• Intensity-modulated radiation therapy (IMRT): This new treatment uses state-of-the-art, targeted, high-dose radiation, minimizing damage and side effects. A 3D map of the tumor is created and high-intensity radiation beams are targeted at the affected areas. Most research points to better outcomes, but it is not conclusive.
• Proton beam therapy (PBT): Another new research treatment using protons instead of photons (x-rays). Protons are charged particles that radiate energy. Photon beams are narrow and easier to target, scatter less, and may cause less damage to healthy tissue. Early results are showing similar outcomes to ERBT, but gastrointestinal complications are more common. PBT is not available in all centers and it may not be covered by insurance, although it may be available as part of a clinical trial.

Outcomes: Survival rates using ERBT tend to be slightly lower than in radical prostatectomy and brachytherapy. Outcomes for newer therapies are unclear, but ongoing research will clarify.

Potential complications: EBRT has different complications than surgery. Because the beam cannot discern healthy from cancerous tissue, there’s a chance healthy tissue will be damaged. Common complications include:

• Cystitis (inflammation of bladder), blood in urine, urinary retention, and urinary incontinence.
• Proctitis (inflammation of rectum) and enteritis (inflammation of small intestine), which leads to diarrhea, blood in stool, bloating, rectal leakage, and rectal pain. Bowel symptoms can persist for months.
• Impotence takes time to develop after radiation therapy; five years after treatment is at a similar level to surgery.
• Fatigue may develop during treatment and last weeks or months after treatment has stopped.
• Lymphedema is the swelling of the legs or genitals. It can occur when the lymph nodes—which normally help drain fluid from an area—are damaged by radiotherapy. It can cause significant discomfort.
• Secondary cancers (bladder, colon, and rectum) are a potential but rare complication.

Complication rates vary between technique and dose used. They also depend on pre-treatment function.

Gastrointestinal (GI) complications are most common with proton-beam therapy, while brachytherapy has the lowest risk of GI problems. In an attempt to reduce GI damage, researchers have developed “tissue spacers” to reduce rectal exposure to radiation.

The SpaceOAR (Spacing Organs At Risk) System is an FDA-approved hydrogel that is injected as a liquid, quickly solidifying to create a cushion between the rectum and prostate.

Secondary cancers may be slightly higher after ERBT. A study published in The BMJ (formerly called The British Medical Journal) in 2016 found that ERBT—but not brachytherapy—potentially increased the risk of certain cancers. Researchers found that the odds varied from 0.1 to 3.8 percent for bladder cancer, 0.3 percent to 4.2 percent for colorectal cancer, and 0.3 percent to 1.2 percent for rectal cancers. They concluded that these “absolute rates were low,” and that “further studies with longer follow-up are required to confirm these findings.” It would be hard to prove categorically that a secondary cancer was due to radiation, and that the cancer wouldn’t have occurred anyway.

Benefits: Radiation therapy is pain-free, and recovery time is much shorter than with surgery. Plus, there is no anesthesia or surgical wound from which to recover. Compared to surgery, complications are less common.

Brachytherapy (BT) or Seed TherapyBT Variation

Temporary high-dose-rate (HDR-BT) brachytherapy involves temporary source implantation, whereby higher-dose seeds are implanted but later removed. An inpatient treatment, it usually involves three treatments of 15 minutes over a few days.

Brachytherapy is also known as internal radiation therapy or interstitial radiation therapy.

Procedure: An outpatient procedure, BT that takes about 60 minutes to complete. It requires either general or spinal anesthesia. An ultrasound or MRI-guided needle inserts 50 to 150 “seeds”—pellets the size of a grain of rice—throughout the prostate. It’s like having a mini-x-ray machine embedded into the prostate; it works continuously until it runs out of energy, after about a year.

Good candidates: For standard brachytherapy, men with low-risk cancer and a small prostate are better candidates. For high-dose brachytherapy, intermediate- and high-risk patients are better candidates.

Outcomes: BT survival rates are similar to surgery. However, quality of life tends to be a little better, as urinary complications and sexual problems are less common. Research also suggests that survival rates and quality of life are better after brachytherapy than after EBRT.

Complications: Radiation travels only a few millimeters and thus has little effect on the organs external to the prostate. However, the urethra—which lies in the center of the prostate—may be damaged during radiation, leading to urinary problems in most men. Some men require temporary catheterization during treatment. Physical exercise may reduce urinary symptoms. Rarely, bowel symptoms occur, for a month or so. There is a small radiation risk to people around you, so it is advised that pregnant women and children under 18 should avoid sitting on your lap for extended periods, at least in the first two months. In the first two weeks, the seeds can be ejaculated (in 1 percent of patients), so sex should be avoided; later, a condom should be worn during sex. Urine remains radioactive and toxic for months.

Benefits of brachytherapy: Most men recover quickly from the insertion procedure and are pain-free. There is no abdominal or perineal wound to heal. Compared to ERBT, the time commitment is much lower—one procedure and you’re done.

Which Treatment Is Best?

Several studies have compared the outcomes for the main treatment options: radical prostatectomy, EBRT, bracytherapy, and active surveillance. The findings show that each option has its own long-term side-effect profile. Here’s a summary of recent research.

One study reported in Cancer Medicine in 2017 measured quality of life 15 years after prostate cancer treatment, comparing RP, EBRT, and BT. Findings:

• Impairments in urinary irritation/obstruction: Worse in EBRT or BT.
• Decrease in bowel function: Worse in EBRT. However, newer techniques are improving this.
• Long-term change in urinary incontinence: Worse for patients treated with RP compared to BT.

A 2016 study in Radiotherapy Oncology looked at quality of life changes 48 months after treatment in the cases of 907 men. Researchers looked at RP, BT, and IMRT (intensity-modulated radiation therapy—a new form of EBRT). Findings:

• RP: More urinary incontinence, but less urinary irritation and obstruction than radiotherapy. Very low levels of bowel dysfunction.
• Brachytherapy and IMRT: Better sexual function than in those who had surgery, although all groups had symptoms.
• The ProtecT Trial was a large randomized study that reported its findings in 2016. Researchers followed patients for 10 years and compared surgery (RP), radiotherapy, and active surveillance. Findings:
• Prostate cancer–specific mortality: At a similar level in all groups—around 1 percent after 10 years. All-cause mortality was similar in all groups at around 10 percent. Risk of death from cancer was 6.6 percent lower ater RP compared to active surveillance at eight years follow-up, and 11 percent lower at 23 years.
• Disease progression and metastases: RP and radiotherapy progression rates were less than half in those under active surveillance.
• Active monitoring: Forty-four percent of the patients who were assigned to active monitoring did not receive radical treatment and avoided side effects. Fifty-six percent went on to need treatment over the 10-year period.
• Number needed to treat (NNT): This is a measure of the number of patients receiving treatment to avoid one case of metastatic disease. Here are the statistics compared to active surveillance: prostatectomy NNT = 27; radiotherapy NNT = 33; either prostatectomy or radiotherapy NNT = 9.
• Incontinence: Three years after treatment, the rates of urinary incontinence were 7 percent in high-dose-rate brachytherapy; 5.4 percent in low-dose-rate brachytherapy; and 2.7 percent in EBRT. The rates of erectile dysfunction were 72 percent in high-dose-rate brachytherapy, 36 percent in low-dose-rate brachytherapy, and 68 percent in EBRT.

The researchers point out the importance of recording a patient’s baseline functions and quality of life before treatment begins.

The Scandinavian Prostate Cancer Group study supports the ProtecT findings. Researchers followed 695 men with early prostate cancer who were randomly assigned to one of two groups: radical prostatectomy or watchful waiting.

Researchers followed the men for 23 years. Sixty-three of the RT patients and 99 of the watchful waiting patients died of prostate cancer. They calculated that there was a 44 percent lower relative risk of death from the disease with RP compared to watchful waiting. Younger men and those with intermediate-risk prostate cancer saw the biggest benefits.

Conflicting evidence, however, comes from the Prostate Cancer Intervention Versus Observation Trial (PIVOT). Researchers concluded Radical prostatectomy (RP) does not significantly reduce the risk of death from prostate cancer or other causes (5.8 percent) compared with active surveillance (8.4 percent). There is a difference, but PIVOT’s researchers deemed it not to be statistically significant. RP did reduce the risk of death from all causes in men with higher PSA levels (higher than 10 ng/ml) and in men with higher-risk tumors.

Cleveland Clinic researchers in 2015 reported the results of a study of 1,989 patients who underwent brachytherapy. They found that the overall five-year survival rate was 93.7 percent and the 10-year survival rate was 76.1 percent. They concluded that “prostate brachytherapy, as monotherapy, is an effective treatment for low-risk and low-intermediate-risk prostate cancer and appears promising as a treatment for high-intermediate-risk and high-risk prostate cancer. Significant long-term toxicities are rare when brachytherapy is performed as monotherapy.”

Androgen-Deprivation Therapy (ADT)

Because prostate cancer mainly originates in the hormone-sensitive glandular cells, androgens fuel prostate cancer. It makes sense, then, that androgen-deprivation therapy—which reduces levels of androgens—can slow the progression of cancer.

ADT does not cure cancer. ADT can be used alone or in combination with other treatments. The primary androgen is testosterone.

Types of Androgen-Deprivation Therapy include the following.

• LHRH agonists: Available in one-month, three-month, or six-month injections or annual depots (implant under skin). These drugs stimulate the pituitary gland to produce LH (luteinising hormone); this causes an initial elevation in testosterone, followed by an abrupt decline. Drugs include goserelin (Zoladex), leuprolide (Eligard, Lupron), triptorelin (Trelstar), and the implant histrelin (Vantas).
• LHRH antagonist: Available in a one-month depot. This type of drug prevents signals from the pituitary gland to the testicles, thus preventing production of testosterone. Drugs includes degarelix (Firmagon).
• LHRH agonist or antagonist with an oral antiandrogen: This type of drug creates a complete androgen blockade.
• Nonsteroidal antiandrogen monotherapy: These bind to testosterone receptors in the prostate, inhibiting or suppressing androgen production. They’re taken in a tablet form and include bicalutamide (Casodex), flutamide (Eulexin), and nilutamide (Nilandron).
• Bilateral orchiectomy: This simple surgery removes both testicles and replaces them with prosthetic ones. Once a common procedure, it is now rarely used. It can be useful if there is spinal cord compression due to metastases. The surgery is irreversible.

Good Candidates for ADT

The National Comprehensive Cancer Network and the European Association of Urology (EAU) recommend androgen deprivation therapy for treatment of patients with advanced prostate cancer when local therapy has failed. It is useful to shrink the cancer or slow its growth and give palliative relief (meaning a reduction in severity, even if the condition can’t be cured).

ADT can also help with reduction of urinary outlet obstruction and, in lower-risk men, to shrink cancer prior to surgery or radiation. Over time, most cancers stop responding to ADT and progression resumes. Standard treatment lasts 24 to 36 months.

Potential side effects: Low androgen levels can cause some unpleasant side effects and seriously affect quality of life. Among them:

• Feeling weak and unwell due to fatigue, anemia, and reduced muscle mass
• Breast enlargement (gynaecomastia)
• Psychological changes and cognitive impairment (forgetfulness, inattention, and depression are common).
• Decreased libido and erectile dysfunction (usually improves when treatment stops)
• Hot flashes
• Increased risk of metabolic syndrome (high blood pressure, high blood sugar, abdominal obesity, and abnormal blood lipids), which increases the risk of cardiovascular disease, stroke, and diabetes.
• Osteoporosis and an increased risk of falls, which lead to an increased risk of fractures
• Increased risk of diabetes. The relative risk is 30 to 40 percent higher. Monitoring of blood glucose and lipids is advised.
• Increased risk of cardiovascular death. Risk increased to 4.2 percent five years after therapy (1.5 percent in controls) and 13.5 percent 10 years after therapy (5.8 percent in controls).
• Pulmonary edema, or fluid on the lungs, which results in shortness of breath and cough.
• Gastrointestinal tract disturbances, including diarrhea
• Increased risk of colorectal cancer and liver failure.
• Increased risk of acute kidney injury (5.5 per 1,000 person years), a rare condition with a 50 percent mortality rate.

An interesting 2015 study found that men who exercise when starting androgen deprivation therapy report fewer sexual side effects, more fatigue, and better mood.

Reducing ADT Side Effects

Bone health: Osteoporosis and fractures cause significant disability. Two drugs may protect against fractures: zoledronic acid [Reclast] and denosumab [Prolia]. They are given with calcium and vitamin D. Baseline bone health should be measured before treatment.

Cardiovascular health: Baseline testing of blood glucose and cholesterol should be done. Eating a healthy diet can reduce the risk of obesity, diabetes, and high cholesterol. Regular exercising (with medical supervision) can reduce muscles and bone loss, improve balance, reduce the risk of falls and improve cardiovascular health. Cigarette smoking is discouraged, as it increases the risk of many of the complications.

Benefits of Hormone Therapy

ADT can reduce the size of a cancer, reduce symptoms and pain, and may extend life. Sadly, they are not a cure, and over time the cancer may begin to grow again, despite the low testosterone.

Combination Hormone and Radiation Therapy

In men with advanced prostate cancer that is aggressive or has spread beyond the prostate, a combination of hormone (ADT) and radiation therapy is standard. This combination reduces the risk of dying by nearly 30 percent compared to radiation alone. Some clinicians use a protocol with intermittent ADT treatment to reduce side effects. PSA levels are monitored and ADT is started when levels creep up; treatment is stopped when PSA drops.

In men with intermediate risk, this combination therapy is considered a viable alternative to radical prostatectomy.

Cryotherapy

Cryotherapy is a procedure that involves the controlled freezing of the prostate to destroy cancer cells. It is also known as cryosurgery or cryoablation.

Procedure: A surgeon uses thin, needle-like probes to enter the prostate through the perineum, and then injects liquid nitrogen into the prostate, freezing and destroying (ablation) cells. Catheterization may be needed for up to a week. It is not widely available.

Good candidates: The American Urological Association recommends cryotherapy for patients with intermediate-risk localized prostate cancer, where RP or radiotherapy are inappropriate due to other health problems. It can also be used in biological recurrence (high PSA after primary treatment). Certain men are not good candidates for cryotherapy: those who have undergone transurethral resection of the prostate (TURP) for benign prostatic enlargement, those with a very large prostate, and those with inflammatory bowel disease.

Outcomes: Cryotherapy is gaining popularity as research begins to show its effectiveness. Ablation of just part of the prostate is showing promising results in reducing complications while preserving good survival outcomes. Early indications are that outcomes are not as effective as surgery but are similar to external beam radiation therapy (EBRT). Cryotherapy can be combined with ADT therapy but there is no consensus as to whether this improves outcomes. It is less invasive than surgery and recovery is faster; however, as with radiation, because tissue is destroyed, the whole prostate cannot be assessed to accurately determine staging and grading of the disease.

A 2016 study published in Journal of Endourology followed 300 men with high-grade prostatic cancer after cryotherapy. The study’s researchers looked at whether PSA stayed low (biochemical progression-free survival, or BPFS), and found a two-year BPFS rate of 77 percent and five-year BPFS rate of 59.1 percent. At a 12-month follow-up, 90.5 percent were completely continent and 17 percent were fertile. Rectourethral fistulae (an abnormal hole that forms between the rectum and the uretha) occurred in 1.3 percent of patients and severe urinary retention in 3.3 percent.

Potential complications: Complications may be severe, from erectile dysfunction (up to 90 percent) to urinary incontinence (5 percent). Irritative and obstructive urinary problems are common side effects. Rectal fistula also may occur: This is an unpleasant condition where a false connection occurs between the rectum and the perineum (skin between rectum and scrotum), allowing uncontrollable leakage of feces.

Chemotherapy

New to the arsenal of treatments for prostate cancer is the chemotherapy drug docetaxel (Taxotere). Given at the same time as hormone therapy, it has been found to prolong survival. Docetaxel is used to treat advanced cancer, as it targets rapidly dividing cells. Doctors administer docetaxel intravenously and in cycles.

Potential side effects: Chemotherapy can harm normal cells and cause men to feel unwell with such symptoms as hair loss, nausea, vomiting, anemia, infections, kidney failure, numbness and tingling, fatigue, infertility, tendency to bleed, headaches, and joint pain. Bone marrow suppression is a serious risk, but close monitoring can pre-empt this.

A 2015 study in New England Journal of Medicine followed 790 men with metastatic, hormone-sensitive prostate cancer and concluded that “six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.” Men treated with the ADT-docetaxel regimen survived an average of 57.6 months, compared to 44 months for those on ADT alone.

If docetaxel fails to help, an even newer drug Cabazitaxel (Jevtana) may be used.

Hormonal Therapy (ADT) and Chemotherapy

In men with metastatic cancer, hormonal therapy may be combined with chemotherapy. A study published in The Lancet in 2013 randomized 385 men with metastatic cancer to two treatment groups:

The first received ADT alone, the second ADT plus docetaxel (chemotherapy). Men given ADT alone lived, on average, 44 months; those treated with the ADT/chemotherapy combination lived an average 58 months. Improvements were best in the more advanced cancers.

Close monitoring of men on the combined treatment is necessary as it can damage the bone marrow and liver.

Cancer Vaccines/Immunotherapy

Cancer vaccines represent an exciting new hope in the fight against prostate cancer. Rather than priming your body to kill an infectious disease, these vaccines teach your body how to kill cancer cells.

One such vaccine is sipuleucel-T (Provenge). During the procedure, the patient’s own white blood cells are collected and exposed in the lab to a protein specific to prostate cancer. These activated white cells are then reinfused into the bloodstream, where they begin to attack the cancer cells. Three doses are given intravenously over a month. It is approved for use in men with metastatic disease who no longer respond to ADT, a group in which it has been shown to improve life expectancy by about four months.

Treatment for Bone Metastasis

Bone metastases are unpleasant and painful, and may lead to pathological fractures. Two drug, however, have been found to help:

• Denosumab (Xgeva) may reduce the impact of cancer spread to bones.
• Radium-223 dichloride (Xofigo) is a radioactive drug that emits radiation (alpha particles) into bone metastasis. Side effects include low blood counts, nausea, diarrhea, vomiting, and swelling of the leg, ankle, or foot.

High-Intensity Focused Ultrasound (HIFU)

Procedure: In performing a HIFU procedure, the doctor inserts an ultrasound probe into the rectum, then focuses sound waves beams onto the cancerous areas of the gland. These beams create focused heat that destroys tissue in seconds. HIFU is performed under spinal or general anesthetic and can be done on an outpatient basis.

HIFU has fewer side effects than surgery and radiotherapy, but there is inadequate research on outcomes. In fact, the American Urological Association states that “these treatment options lack robust evidence of efficacy.”

While HIFU has been used for years in Europe and Canada to treat prostate cancer, it is not widely available in the United States, and some health insurance companies won’t cover the procedure. In 2015, the FDA reluctantly approved HIFU for “prostate tissue ablation”—not specifically for cancer treatment.

Potential complications: Erectile dysfunction and irritating urinary symptoms (including burning pain while urinating) are common.

Focal Therapy

Focal therapy, also known as “male lumpectomy,” selectively targets only affected areas of the prostate using cryotherapy, HIFU, and photodynamic therapy. The aim is to reduce complications. The research is not conclusive, with some studies showing comparable outcomes in the short term and fewer long-term side effects.

Part of the problem is that prostate cancer is often, by its nature, multifocal, appearing in more than one of the three prostate lobes at once. Another problem is that cancerous areas are difficult to pick up on ultrasound or MRI. The AUA fails to support the use of focal therapies, saying that “these treatment options lack robust evidence of efficacy.” There is, however, hope that further refinement focal techniques may prove to be useful in the future.

Managing Side Effects of Treatment

Sadly, all treatments have side effects. Most treatment options run the risk of chronic urinary or sexual health problems. Thankfully there are some treatments that can help.

Bone Disease

Men with advanced prostatic cancer are at high risk of bone disease. Hormone treatment (ADT) causes osteoporosis and makes some men frail and more prone to falling and fracturing bones. Furthermore, bone metastases (malignant growths in the bone) cause weakness and thinning of the bone, fractures, spinal compression, and pain. Some men require radiation to reduce growth of the metastases and surgery to stabilize weak or fractured bone, and many need pain medication.

Bisphosphonates, such as Zoledronic acid (Zometa) and pamidronate disodium (Aredia), may help reduce osteoporosis. These drugs attack osteoclasts cells—a type of cell that breaks down bone tissue.

Denosumab (Xgeva) is a new drug that prevents bone erosion by blocking RANK-Ligand, a substance that activates osteoclasts. Men taking these drugs need to be aware of a rare but serious side effect called osteonecrosis of the jaw. Make sure you discuss your medications with your dentist before starting these treatments or having any dental work.

Looking to the Future: Biomarkers

Biomarkers are specific molecules that indicate a process, normal or abnormal, taking place in your body. PSA is the standard biomarker for prostate cancer; the big problem is that it isn’t specific or accurate enough. Current screening techniques are known to be very problematic—overdiagnosing many men with insignificant disease and missing others with advanced or aggressive disease. Research aims to find biomarkers that can precisely predict clinically significant prostate cancer and accurately guide treatment.

Biomarkers can be measured in blood serum, urine, and tissues. They measure proteins, fragments of proteins, enzymes, DNA, and RNA.

It is likely that what will emerge are several biomarkers—some for diagnosis and some to guide therapy. Urine biomarkers may turn out to be useful, as urine is easily collected and passes through the prostate as it travels along the urethra.

Remarkable stories have hit the news of dogs that are able to detect cancers—from prostate to lung to breast—with incredible accuracy, suggesting that they’re picking up a particular odor, which may turn out to be a valuable biomarker.

The post 2. Prostate Cancer appeared first on University Health News.

Scientists, however, continue to piece together the mosaic of genetic and lifestyle factors that seem to play a role in prostate cancer’s development. Their efforts are identifying not only whether your genetic code may place you at higher risk for the disease, but also potential avenues for how to avoid prostate cancer.

What Causes Prostate Cancer: Genetic Contributors

As with many cancers, the answer to the question of what causes prostate cancer lies partly in genetics. Prostate cancer appears to develop along a number of molecular and genetic pathways. Although having a genetic predisposition to prostate cancer doesn’t necessarily guarantee that you’ll get the disease, it does increase the likelihood.

A family history of prostate cancer—e.g., your father or brother had the disease—more than doubles the odds that you’ll develop the disease, too. Your risk may be even greater if you’ve had several family members who’ve had prostate cancer, especially if they were younger when they developed the disease.

You might inherit an increased risk of prostate cancer not only from your male relatives, but also from your female ones. If a woman in your family developed breast cancer caused by mutations in the BRCA1 and BRCA2 genes, you may face a greater risk of prostate cancer. Additionally, some evidence suggests that men with BRCA-related prostate cancers, especially those tied to BRCA2, are more likely to present with more advanced and aggressive disease, and they also may have worse survival outcomes after prostate cancer surgery.

Another inherited genetic abnormality, Lynch syndrome, which increases the risk of colorectal cancer and other cancers, also may be linked to a greater likelihood of developing prostate cancer. (Keep in mind, though, that these inherited genetic disorders account for a relatively minute percentage of prostate cancers.)

Genetics also may explain, at least in part, racial differences in prostate cancer risk. Prostate cancer occurs more commonly in African-American men and less so in Asian-American and Hispanic men. Rates of fatal prostate cancer also are significantly higher among African-Americans. However, exactly what causes prostate cancer to be more common and deadly in African-Americans and less common in other racial groups remains unclear.

If you have received a prostate cancer diagnosis, your doctor will want to ascertain the grade (or Gleason score) and stage of your cancer. The grade and stage will determine treatment, which could include active surveillance. [Illustration: Dreamstime.com]

How Your Lifestyle May Influence Your Risk

In their ongoing search for what causes prostate cancer, researchers have raised suspicions that certain modifiable factors may raise prostate cancer risk, increase the odds of having more aggressive disease, and worsen your overall prognosis.

Studies suggest that being obese is associated with a greater likelihood of high-grade prostate cancer and death from the disease, as well as poorer outcomes after prostate cancer treatment. One potential reason for this finding is that obese men tend to have larger prostates, and since it’s more difficult to find cancer in a larger prostate, these men may be more likely to have their cancer identified at a later stage.

Also, men who are obese have, on average, lower levels of prostate-specific antigen (PSA) found in the blood test used to screen for prostate cancer. As a result they may be less likely to have a potentially dangerous prostate cancer diagnosed early on.

Obesity has been tied to chronic inflammation, the body’s response to infection or injury. Fat cells in the abdomen produce an array of inflammatory substances, including insulin-like growth factor, which has been associated with prostate cancer growth. Scientists have found pockets of inflammation in cancerous prostate cells, leading them to theorize that inflammation caused by an infection and/or dietary and hereditary factors may contribute to gene alterations that cause prostate cancer.

Evidence suggests a potential role of diet in prostate cancer, but exactly how your eating habits affect your risk of the disease remains unclear. Researchers have yet to prove conclusively if any individual food or food group causes or prevents the disease. Rather, your overall dietary pattern seems to influence your prostate cancer risk.

How to Reduce Your Risk of Prostate Cancer

Many experts consider a heart-healthy eating plan—rich in fruits, vegetables, whole grains, and healthful protein and fat sources, and low in saturated fat, added sugars, sodium, and processed foods—to be beneficial for prostate health, as well. For example, rates of prostate cancer are lower in Asia, but when Asians immigrate to the United States and other countries that follow a typical Western-style diet, their risk of the disease increases.

One study (Cancer Prevention Research, June 2015) found that men who adhered to a Western-style diet (abundant in red and processed meats, high-fat dairy, and refined grains) were nearly three times more likely than those who ate a more heart-healthy diet to die from prostate cancer.

Still, researchers are unsure whether the increased risk of prostate cancer is a result of consuming these unhealthy foods or the fact that people who follow a Western-style diet tend to eat fewer fruits, vegetables, and other foods containing nutrients that may protect against prostate cancer.

Some research suggests that other factors may be on the list of what causes prostate cancer or results in poorer outcomes from the disease, but further studies are necessary to confirm these associations:

• Smoking: Research generally does not support a link between smoking and developing prostate cancer, but some studies suggest that smoking may increase the likelihood of dying from prostate cancer or experiencing a return of the disease.
• Sleep problems: One study found that men who had problems falling asleep or staying asleep were more likely to develop prostate cancer. One possible connection between sleep and prostate cancer is the hormone melatonin, which plays a key role in the sleep-wake cycle. Sleep problems can reduce melatonin production. In one study (European Urology, February 2015), researchers reported that men with sleep problems generally had lower melatonin levels in the morning, and below-average melatonin levels were associated with a greater risk of advanced prostate cancer.
• Vasectomy: Some research suggests that this common contraceptive surgery may increase the risk of high-grade or lethal/metastatic prostate cancer, but other investigations have not supported this association.

Originally published in 2016, this post is regularly updated.

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