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Prostate Cancer

BREAKTHROUGH: High Intensity Focused Ultrasound for Prostate Cancer-Noveltry or Innovation?
JAMA June 28, 2016: 315(24); p. 2659-60
Non-invasive High Intensity Focused Ultrasound offers T-1 and T-2 prostate cancer men an equally effective, safe, less costly procedure with less down time, less recovery, with less erectile issues. In the Editor's opinion, one-third of prostate surgery can be avoided using HIFU. See the   JAMA article for more details.

[Editor]:Recent articles from Morganthaler and Journal of Urology 2015 show the safety of use of testosterone replacement therapy in men with low, moderate and high risk prostate surgery after identification and destructive procedures.

The Merck Manual Home Edition
"Prostate Cancer:
*The risk of prostate cancer increases as men age.
*Symptoms, such as difficulty urinating, a need to urinate frequently and urgently, and blood in the urine, usually occur only after the cancer is advanced.
*The cancer can spread, usually to the bone,lymph nodes, or spine.
*Screening tests are controversial, but doctors may do a digital rectal examination and a blood test to check for prostate cancer in men without symptoms.
*If cancer is suspected, ultrasonography and a biopsy of prostate tissue are done.
*Treatment may involve active surveillance, removal of the prostate gland, radiation therapy, or hormonal or newer drugs to slow cancer growth.

Among men in the United States, prostate cancer is the most common cancer and one of the most common causes of cancer death. Every year, more than 238,000 new cases are diagnosed and about 30,000 people die of prostate cancer. The chance of developing prostate cancer increases with age and is greater for:
*Men who are black or Hispanic
*Men whose close relatives had the disease

Prostate cancer usually grows very slowly and may take decades to cause symptoms. Thus, particularly because it occurs more often in older men, far more men have prostate cancer than die from it. Many men with prostate cancer die from other causes without ever knowing that the cancer was present.

Prostate cancer begins in a small area of the gland. Most prostate cancers grow very slowly and never cause symptoms. Some, however, grow rapidly or spread outside the prostate. The cause of prostate cancer is not known.

Prostate cancer usually causes no symptoms until it reaches an advanced stage. Sometimes, symptoms similar to those of benign prostatic hyperplasia (BPH) develop, including difficulty urinating and a need to urinate frequently or urgently. However, these symptoms do not develop until after the cancer grows large enough to compress the urethra and partially block the flow of urine. Later, prostate cancer may cause bloody urine or a sudden inability to urinate.

In some men, symptoms of prostate cancer develop only after it spreads (metastasizes). The areas most often affected by cancer spread are bones (typically the pelvis, ribs, or vertebrae). Bone cancer tends to be painful and may weaken a bone enough for it to easily fracture.

Commonly, spread to the spine affects the spinal cord and can cause pain, numbness, weakness, or urinary incontinence. After the cancer spreads, anemia is common.

Many men with prostate cancer die of other causes without ever knowing that they had the cancer. [Editor]80% of men who die after 80 years of age have a small prostate cancer.

Some prostate cancers grow so slowly that they may not require treatment. Others are aggressive and grow and spread quickly. Doctors cannot always tell which prostate cancers will be aggressive.

Doctors may suspect prostate cancer based on the symptoms, the results of a digital rectal examination, or the results of screening blood tests. The screening blood test is a measurement of prostate-specific antigen (PSA) levels. PSA is a substance produced only by prostate gland tissue.

If results of these tests suggest cancer, ultrasonography is usually done. In men with prostate cancer, ultrasonography may or may not reveal the cancer but is used to guide biopsy of the prostate.

If the results of a digital rectal examination or PSA test suggest prostate cancer, tissue samples from the prostate are taken and analyzed (biopsy). When doing a biopsy, doctors usually first obtain images of the prostate by inserting an ultrasound probe (transducer) into the rectum (transrectal ultrasonography). Doctors then insert a needle through the probe and use the needle to obtain tissue samples several times (transrectal ultrasound-guided prostate biopsy). Usually, 5 or 6 samples are taken from each side of the prostate to increase the likelihood of finding a small cancer. This procedure takes only a few minutes, and men are usually given local anesthesia.

Grading and staging help doctors determine the likely course and the best treatment of the cancer.

The Gleason scoring system is the most common way to grade prostate cancer. Based on the microscopic examination of tissues obtained from the biopsy, a number between 1 and 5 is assigned based on how distorted the cells appear. Because cancer cells often vary in their appearance, the number score for the most common abnormal cells is added to the number for the next most common abnormal cells to give a total score from 2 to 10. Scores between 6 and 7 are most common. The higher the number (high grade), the more aggressive the cancer is and the more likely it is that the cancer will spread.

Prostate cancers are staged according to three criteria:
*How far the cancer has spread within the prostate
*Whether the cancer has spread to lymph nodes in areas near the prostate
*Whether the cancer has spread to organs far from the prostate (metastatic cancer)

Testing to stage the cancer is often done when cancer is diagnosed. However, such testing may not be necessary when the likelihood of spread beyond the prostate is extremely low. Likelihood of spread is low when cancers have a Gleason score of 7 or less, the PSA level is less than 10 ng/mL, and the cancer has not penetrated the surface of the gland. Results of the digital rectal examination, ultrasonography, and biopsy reveal how far the cancer has spread within the prostate.

If likelihood of spread is not low, doctors usually do computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen and pelvis. Sometimes MRI is done using a special coil inserted in the rectum. A bone scan may be done in people who have pain in their bones or who have a very high PSA or Gleason score.

If spread to the brain or spinal cord is suspected, CT or MRI of those organs is done.

Because prostate cancer is common and sometimes fatal, and because symptoms may not develop until the cancer has become advanced, many doctors offer screening tests to men with no symptoms. Screening has the advantage of finding aggressive cancers early—when they might be cured. However, because screening tests are positive in many men who do not have cancer and because some prostate cancers grow so slowly that they may not require treatment, experts disagree about whether and when screening is helpful.

Screening is considered in men older than 50 and in those older than 40 who have risk factors, such as being black or having a family history of prostate cancer. Benefits of screening may decrease with age. For example, one professional organization recommends against screening men who are older than 75 or who are not expected to live at least 10 more years. Screening, once begun, is usually repeated yearly.

To screen for prostate cancer, doctors do a digital rectal examination and a blood test to measure PSA levels. If the prostate gland is hard, irregularly enlarged, or has a lump or if the PSA level is elevated, prostate cancer is more likely. However, PSA levels can be misleading. The PSA level can be normal when prostate cancer is present and can be elevated for reasons other than prostate cancer. PSA levels normally increase with age and with disorders such as BPH and prostatitis. The way doctors tell whether an elevated PSA level or prostate lump represents cancer is to do a transrectal prostate biopsy. Because most men who have elevated PSA levels on screening tests do not have prostate cancer, many biopsies have negative results (but still expose men to discomfort and risk of complications such as infection). Also, even when the biopsy shows prostate cancer, doctors cannot always tell which cancers require treatment. For example, if the biopsy shows a high Gleason score or that cancer has spread far within the prostate, then cancer is likely to cause problems and should be treated. Indeed, such treatment can be life-saving. However, if the biopsy shows a low Gleason score and that cancer involves only a small part of the prostate, then the cancer may not cause problems and may not require treatment.

Thus, screening may find cancers that would probably not hurt or kill a man even if they were never detected. In such cancers, the side effects of treatment (for example, erectile dysfunction or urinary incontinence) can be more damaging than leaving the cancer untreated. Because it is not always clear early on which prostate cancers will be aggressive (for example, for cancers with low Gleason scores and that involve only a small part of the prostate), doctors have typically recommended treatment to all men whose biopsy showed cancer. Thus, many more men are treated for prostate cancer than are cured by such treatment. As a result, many of the men treated derive no benefit from treatment but still risk side effects. Because of this possibility that treatment may not be helpful, doctors may offer certain men with a positive biopsy the option of delaying treatment depending on the results of periodic checkups and tests. Because the best course of action is still not clear, and because men may have different values and preferences, men should discuss the risks and benefits of screening, biopsy, and treatment with their doctor. For example, men who would rather risk a substantial likelihood of side effects resulting from treatment than even a very small risk of death caused by a prostate cancer may choose to be screened. Men who would not want to risk treatment unless it was absolutely necessary may choose not to be screened.

Many decisions that a man makes (for example, whether to be screened, whether to pursue invasive treatment or instead delay treatment depending on the results of periodic checkups and tests) depend largely on his own values and preferences.

Prognosis for most men with prostate cancer is very good. Most elderly men with prostate cancer tend to live as long as other men their age who have similar general health and do not have prostate cancer. For many men, long-term remission or even cure is possible. The prognosis depends upon the cancer's grade and stage. High-grade cancers have a poor prognosis unless treated very early. Cancers that have spread to surrounding tissues also have a poorer prognosis. Metastatic prostate cancer has no cure. Most men with metastatic cancer live about 1 to 3 years after diagnosis, but some live for many years.

Choosing among treatment options can be complicated. Because studies have not directly compared one treatment to another, doctors are uncertain which treatment is most effective. Furthermore, for some men, doctors are not sure whether treatment will prolong life. Such men include those who are not expected to live very long (either because of old age or serious health problems) and those with low PSA levels who have low-grade cancers confined to the prostate. Thus, men often make their decision by balancing their degree of discomfort in living with a cancer that might or might not harm them against the possible side effects of treatment. Surgery, radiation therapy, and hormonal therapy may cause incontinence, erectile dysfunction (impotence), or other problems. For these reasons, men's preferences are a bigger consideration in choosing treatment for prostate cancer than they are for many other disorders.

Treatment for prostate cancer usually involves one of three strategies:
*Active surveillance
*Curative treatment
*Palliative treatment

Active surveillance (formerly called watchful waiting) means doctors give no treatment unless the cancer is progressing or changing. The advantage of this strategy is avoiding or postponing the potential side effects of treatment. Active surveillance should be considered mainly by elderly men whose cancers are unlikely to spread or cause symptoms. For example, most cancers that are confined to a small area within the prostate and have low Gleason scores grow very slowly and usually do not spread for many years. Thus, older men, particularly those who have other serious health problems, are far more likely to die of other causes before such cancers kill them or cause symptoms. In younger men, particularly those who are healthy, even a slow-growing cancer may eventually cause problems. In such men, active surveillance may be less preferred. During active surveillance, doctors periodically question about symptoms, measure the PSA level, and do digital rectal examinations to determine whether the cancer is causing symptoms, growing rapidly, or spreading. Younger men may also have periodic repeat biopsies. If testing shows growth or spread, doctors offer curative or palliative treatment.

Curative treatment aims to remove or kill all of the cancer and includes
*Radiation therapy
*Less often, cryotherapy (freezing)

Curative (also called definitive) treatment is a common strategy for men with cancers confined to the prostate that are likely to cause troublesome symptoms or death. Such cancers include those that are growing rapidly as well as some small, slowly growing cancers in men who are likely to live for some time (perhaps at least 10 or 15 years). Such men are typically those who are healthy, younger (particularly those under 60), or both. Curative treatment is not pursued if cancer has spread widely, but it can benefit some men with cancers that have spread to the area just outside the prostate. Such cancers are likely to cause symptoms within a relatively short period. However, curative treatment is most likely to be successful with cancers that are still confined to the area near the prostate. Curative treatment can prolong life and reduce or eliminate severe symptoms resulting from some cancers. Side effects, although less common with newer treatments, can still develop and diminish quality of life. These can include, for example, erectile dysfunction and, less often, urinary incontinence (most often as a result of surgery) and pain or bleeding during defecation and irritation or bleeding when urinating (as a result of radiation therapy).

Palliative treatment aims to treat the symptoms rather than cure the cancer. Palliative therapies include
*Hormonal therapy
*Radiation therapy.

Palliative treatment is best suited to men with widespread prostate cancer, which is not curable. The growth or spread of such cancers can usually be slowed or temporarily reversed, relieving symptoms. Besides trying to slow the cancer's growth and spread, doctors may try to relieve symptoms resulting from the effects of cancer in other organs and tissues (such as the bones). However, because these treatments cannot cure the cancer, symptoms eventually worsen. Death due to the disease eventually follows.

Surgically removing the prostate (prostatectomy) is useful for cancer that is confined to the prostate. Prostatectomy is not done if staging tests show the cancer has spread. Prostatectomy is very effective in curing low-grade, slowly growing cancers but is less effective in high-grade, fast-growing cancers. Such cancers are more likely to have spread even if spread is not detectable with staging tests at the time of diagnosis.

Prostatectomy requires general or spinal anesthesia, an overnight hospital stay, and a surgical incision. Following surgery, men must have a catheter in their penis for a week or two until the connection between the bladder and urethra heals. Doctors do not routinely give radiation therapy, chemotherapy, or hormone therapy before or after surgery, but studies are being done to determine whether such treatments may benefit certain men.

Prostatectomy may lead to permanent erectile dysfunction and urinary incontinence. Erectile dysfunction may occur because the nerves to the penis that control erection run across the prostate and may be damaged during surgery. Incontinence may occur because part of the sphincter that closes the opening at the bottom of the bladder must be removed during surgery.

Techniques for doing prostatectomy include open radical prostatectomy and laparoscopic or robot-assisted radical prostatectomy.

In open radical prostatectomy, the entire prostate, the seminal vesicles, and part of the vas deferens are removed through an incision in the lower abdomen or, rarely, in the area between the scrotum and anus. Lymph nodes may also be removed to check for cancer. In the laparoscopic and robot-assisted laparoscopic procedures, the same structures are removed, but these procedures are done through smaller incisions and may result in less postoperative pain and blood loss. .

Radical prostatectomy, irrespective of technique, is the surgery done when trying to cure prostate cancer. More than 90% of men with cancer confined to the prostate live at least 10 years after radical prostatectomy. Younger men who can otherwise expect to live at least 10 to 15 more years are most likely to benefit from radical prostatectomy. However, the procedure causes some leakage of urine in up to 10% of men. Temporary incontinence develops in most men and may last for several months. Incontinence is less likely in younger men.

A degree of erectile dysfunction develops in most men after radical prostatectomy, particularly those who had a degree of it before surgery. Usually prostatectomy can be done in such a way that some of the nerves needed to achieve erection are spared—this procedure is called nerve-sparing radical prostatectomy. This procedure cannot be used to treat cancer that has invaded the nerves and blood vessels of the prostate. Nerve-sparing radical prostatectomy is less likely than non–nerve-sparing radical prostatectomy to cause erectile dysfunction. Most men are diagnosed early and, thus, can be treated with nerve-sparing radical prostatectomy.

Blockage of urine flow caused by narrowing of part of the bladder or scarring of the urethra (urethral stricture) develops in 7 to 20% of men. Blockage can usually be easily treated.

Radiation therapy:
Radiation therapy may cure cancers that are confined to the prostate, as well as cancers that have invaded tissues around the prostate. Although radiation therapy cannot cure cancer that has spread to distant organs, it can help relieve the pain resulting from the spread of prostate cancer to bone.

Radiation therapy is sometimes given after surgery to treat the areas around the prostate or if PSA if found in the blood after surgery, suggesting that surgery has not removed all of the cancer.

For many stages of prostate cancer, 10-year survival rates after radiation therapy are nearly as high as those achieved with surgery. More than 90% of men with cancer confined to the prostate live at least 10 years after undergoing radiation therapy. Radiation therapy can be delivered as
*External beam radiation therapy (used to treat cancer within the prostate gland and prostate cancer that has spread to bone)
*Radioactive implants (used to treat cancer within the prostate gland but not prostate cancer that has spread to bone)
*Radium-233, an intravenous drug (used to treat prostate cancer that has spread to bone, but not cancer within the prostate gland)
*External beam radiation therapy uses a machine to send beams of radiation to the prostate and surrounding tissues. CT is often used to help focus the radiation beams more precisely on the cancer by precisely identifying the structures affected. This approach is called three-dimensional conformal radiation therapy. Treatments are usually given 5 days per week for 7 to 8 weeks. Although some degree of erectile dysfunction can occur in up to 40% of men, it is less likely to develop during the period soon after radiation therapy than during the period soon after prostatectomy. However, after months or years, erectile dysfunction seems to be as likely after radiation therapy as after prostatectomy. Incontinence is rare when three-dimensional conformal radiation therapy is used.

Scars that narrow the urethra and impede the flow of urine (urethral strictures) develop in about 7% of men. Other troublesome but usually temporary side effects of external beam radiation therapy include burning during urination, having to urinate frequently, blood in the urine, diarrhea that is sometimes bloody, radiation proctitis (usually causing irritation of the rectum and diarrhea), and sudden urges to defecate.

Other forms of external beam radiation therapy that are newer and may have fewer side effects include proton beam therapy and intensity modulated radiation therapy (IMRT). Both of these techniques allow radiation to be delivered more precisely to cancer cells while avoiding healthy cells. IMRT can deliver radiation of varying strengths (intensities) and so can deliver more intense radiation to the tissues with the most cancer. Proton beam therapy delivers radiation in a form that scatters less. Thus, less radiation may be scattered from the target cancer tissues into nearby normal, healthy tissues.

Radioactive implants can be inserted into the prostate (brachytherapy). The implants are small, seedlike pieces of radioactive material. Doctors inject the implants into the prostate gland through the area between the scrotum and anus using ultrasonography or CT to guide placement. Brachytherapy can be done in less than 2 hours, does not require repeated treatment sessions, and uses only spinal anesthesia. Brachytherapy also can deliver high doses of radiation to the prostate while often sparing healthy surrounding tissues and causing fewer side effects. However, brachytherapy may cause urethral strictures in up to 10% of men. The radioactivity of the seeds decreased with time. Seeds may later be passed in the urine. Men treated with these seeds should avoid close contact with pregnant women and young children for a period of time after the procedure because the radioactivity can be harmful to a fetus or young child. Cure rates 10 to 15 years after brachytherapy are similar to rates obtained with other treatments for some men. Combined treatment with brachytherapy and external beam radiation therapy is sometimes recommended for more aggressive cancers.

Radium-233 is a drug given intravenously that emits a particular type of radiation (alpha radiation). Unlike beam radiation and brachytherapy, it is not directed at a particular target. Radium-233 is used to treat bone metastases from prostate cancer rather than the prostate cancer in the prostate gland. Once in the bloodstream, radium-233 seeks out areas of bone affected by prostate cancer, where it helps destroy cancer cells. Because it targets bone tissue and does not scatter radiation (like radiation beams or seeds), it may spare nearby tissues from radiation damage.

Hormonal therapy:
Because most prostate cancers require testosterone to grow or spread, treatments that block the effects of this hormone (hormonal therapy) can slow progression of the tumors. Hormonal therapy is commonly used to delay the spread of the cancer that has come back after surgery or radiation therapy or to treat widespread (metastatic) prostate cancer. Hormonal therapy is sometimes combined with other treatments. It is not curative. Hormonal therapy can prolong life as well as decrease symptoms. Eventually, however, hormonal therapy is likely to lose effectiveness, and the disease progresses.

Hormonal drugs used to treat prostate cancer in the United States include leuprolide, goserelin, triptorelin, buserelin, histrelin, and degarelix, which prevent the pituitary gland from stimulating the testes to make testosterone. These drugs are administered by injection in a doctor's office every 1, 3, 4, or 12 months, usually for the rest of the man's life. For some men, this treatment may only be given for a year or two and possibly resumed at a later time.

Drugs that block testosterone's effects (such as flutamide, bicalutamide, and nilutamide) may also be used. These drugs are taken daily by mouth. Side effects of hormonal therapy may include hot flashes, osteoporosis, loss of energy, reduction in muscle mass, fluid weight gain, reduction of libido, decrease in body hair, erectile dysfunction, and breast enlargement (gynecomastia).

The oldest form of hormonal therapy involves the removal of both testes (bilateral orchiectomy). The effects of bilateral orchiectomy on testosterone level are equivalent to those produced by leuprolide, goserelin, buserelin, and related drugs. The physical and psychologic effects of bilateral orchiectomy and other hormonal therapies make these therapies difficult for some men to accept.

In men with widespread prostate cancer, hormonal therapy may become ineffective after a few years. When cancer eventually progresses despite hormonal therapy, men may live only a few more years.

Other drugs:
Cancer that does not respond to hormonal therapy that successfully decreases testosterone levels is called castrate-resistant prostate cancer. Docataxel, a chemotherapy drug, can prolong life when cancer does not respond to hormonal therapy.

Recently, many other treatments that prolong life have become available and are being used earlier than previously to treat men with castrate-resistant prostate cancer. These treatments include sipuleucel-T (a vaccine that targets prostate cancer cells), abiraterone and enzalutamide (types of hormonal therapy), and cabazitaxel (a chemotherapy drug). Radium-233 can prolong life by treating or preventing serious complications due to bone spread (such as spinal cord damage).

Drugs used to treat osteoporosis, such as zoledronic acid and denosumab, can be used to strengthen bone that has been weakened by cancer or by hormonal therapy, which tends to weaken bones. These drugs help treat and prevent problems such as pain and the tendency to fracture.

After all forms of treatment, PSA levels are measured at regular intervals (usually every 3 to 4 months for the first year, and then every 6 months for the rest of the man's life). By 1 month after surgery, PSA should not be detected. Following radiation therapy, PSA decreases more slowly and usually does not become undetectable but should remain stable at a low level. Increases in the PSA level may indicate that the cancer has recurred."

Medications Used in Treatment:
1. Androgen Receptor Inhibitors: Casodex®/bicalutamide, Xtandi®, flutamide, Nilandron®
2. CYP17 Inhibitors: Zytiga®
3. Gonadotropin Releasing Hormone Agonists: Lupron® Depot/leuprolide, Zoladex®, Eligard®
4. RANKL Inhibitors: Xgeva®
5. Microtubule inhibitors: Taxotere®/ docetaxel, Docefrez®, Jevtana®
6. Alkylating Drugs: Emcyt®

u>Suggested Links:
*N.H.S. Choices (with Video)

*[Editor] Morgentaler states "The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism.">/strong>,/i>

[Editor] A recent article on the use of testosterone in low, moderate and high risk prostate cancer men has come out being quit e supportive.

*[Editor] An interesting prostate cancer treatment involves the use of mitozantrone and oral ketoconazole. 8% had complete remission and 62% had a partial remission.

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