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A diagnosis like cancer often causes panic, primarily due to the lack of knowledge and fear of the unknown. However, great strides have been made in the treatment of prostate cancer. As never before, you have options, and members of our prostate cancer community who " have been there, done that " will universally recommend that you move beyond the panic stage and start to gain knowledge. Knowledge is power. We recommend that you take your time, do your research and arrive at the best treatment decision for you and your family based on the characteristics of your total health situation ^[1].

Be aware that some medical specialist may steer you in the direction of their specialty and often will understate the risk involved with their treatment of choice. Urologist tends to favor surgical option, radiation therapist favor radiation, and medical oncologist may focus on Androgen Deprivation Therapy (ADT) and/or Chemotherapy.

Sitting in the doctor's consultation room with your spouse or other supportive person(s), a patient will better understand treatment information that your physician is presenting only if the patient and his family have been empowered with knowledge.

Active treatment usually begins a few weeks to months after diagnosis, you should meet with various doctors, identify the stage and extend of the cancer, talk over treatment possibilities from your doctor and learn what survivors in our prostate cancer community have to say about their experiences.

StriveWell's Prostate Cancer Community tries to break down everything you need to know about Prostate Cancer and provide a patients perspective through testimonials.

"We are here to help you make an informed emotional decision"

Contents 1 Understanding Prostate Cancer 1.1 Risk factor 1.2 Prevention 2 Signs and Symptoms 3 Screening 3.1 Blood test for Prostate Specific Antigen (PSA) 3.2 Free PSA 3.3 Digital Rectal Exam (DRE) 3.4 Transrectal Ultrasound 3.5 Color Doppler 3.6 PCA3 3.7 Prostate Biopsy 4 Coping with Prostate Cancer 4.1 Your Feelings 4.2 Family Matters 4.3 Support Groups 4.4 Choosing a doctor 5 Diagnosis and Testing 5.1 Staging 5.2 Gleason Score 5.3 Partin Table 6 Imaging 6.1 Radionuclide Bone Scan 6.2 CT/CAT Scan 6.3 Endorectal MRI with Spectroscopic 6.4 Nuclear Imaging 7 Prognosis 7.1 Prostatic Acid Phosphatase (PAP) 7.2 DNA Ploidy 8 Treatment 8.1 Watchful Waiting 8.2 Surgery 8.3 Radiation Therapy 8.4 High-Intensity Focused Ultrasound 8.5 Hormone Therapy/Androgen Deprivation Therapy (ADT) 8.6 Chemotherapy 9 Potential effects of treatment 9.1 Anemia 9.2 Muscles wasting 9.3 Hot Flashes 9.4 Osteoporosis/Arthritis 9.5 Memory Loss 9.6 Weight Gain 9.7 Rectal Irritation 9.8 Erectile Dysfunction 9.9 Incontinence 10 Drugs 10.1 LHRH agonist 10.2 LHRH Antagonists 10.3 Anti-androgen 10.4 5-alpha reductase (5-AR) inhibitor 10.5 Estrogen 10.6 P450 Enzyme Inhibitor 10.7 Erectile Dysfunction Drugs 10.8 Chemotherapy Drugs 11 Videos 11.1 References

[add] [index] Understanding Prostate Cancer

The prostate is part of a man's reproductive system. It is located in front of the rectum and under the bladder. It surrounds the urethra, the tube through which urine flows. A healthy prostate is about the size of a walnut. The prostate makes part of seminal fluid. During ejaculation, seminal fluid helps carry sperm out of the man's body as part of semen. Male hormones (androgens) make the prostate grow. The testicles are the main source of male hormones, including testosterone. The adrenal gland also makes testosterone, but in small amounts. If the prostate grows too large, it squeezes the urethra. This may slow or stop the flow of urine from the bladder to the penis ^[2].

Cancer begins in cells, the building blocks that make up tissues. Tissues make up the organs of the body. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes, this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. These extra cells can form a mass of tissue called a growth or tumor ^[2].

Tumors can be benign or malignant:

Benign tumors are not cancer:

• Benign tumors are rarely life-threatening.
• Generally, benign tumors can be removed. They usually do not grow back.
• Cells from benign tumors do not invade the tissues around them.
• Cells from benign tumors do not spread to other parts of the body.

Malignant tumors are cancer:

• Malignant tumors are generally more serious than benign tumors. They may be life-threatening.
• Malignant tumors often can be removed. But sometimes they grow back.
• Cells from malignant tumors can invade and damage nearby tissues and organs.
• Cells from malignant tumors can spread (metastasize) to other parts of the body. Cancer cells spread by breaking away from the original (primary) tumor and entering the bloodstream or lymphatic system. The cells invade other organs and form new tumors that damage these organs. The spread of cancer is called metastasis.

When prostate cancer spreads, cancer is often found in nearby lymph nodes. If cancer has reached these nodes, it also may have spread to other lymph nodes, the bones, or other organs. When cancer spreads from its original place to another part of the body, the new tumor has the same kind of abnormal cells and the same name as the primary tumor. For example, if prostate cancer spreads to bones, the cancer cells in the bones are actually prostate cancer cells. The disease is metastatic prostate cancer, not bone cancer. For that reason, it is treated as prostate cancer, not bone cancer. Doctors call the new tumor "distant" or metastatic disease ^[2].

[add] [index] Risk factor

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In general about 17 of every 100 males in the United States will be diagnosed with prostate cancer during their lifetime. This is the absolute risk of prostate cancer for U.S. males ^[3].

What are the risk factors for Prostate Cancer?

• Age : Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40, but the chance of getting it goes up sharply as men get older. The chart below shows the probability of being diagnosed with prostate cancer for different age groups ^[3].

Age Range	Probability of Prostate Cancer Diagnosis
Under age 40	1 in 19,299
Ages 40 through 59	1 in 45
Ages 60-79	1 in 7

• Race : African American men are at highest risk of prostate cancer—it tends to start at younger ages and grows faster than in men of other races. After African American men, it is most common among White men, followed by Hispanic and Native American men. Asian-American men have the lowest rates of prostate cancer ^[3].

• Family history : A man’s risk of prostate cancer is higher than average if his father or brother had the disease. Prostate cancer risk also appears to be slightly higher for men whose mothers or sisters have had breast cancer. Between 5 to 10 percent of prostate cancer cases are believed to be due primarily to high-risk inherited genetic factors or prostate cancer susceptibility genes ^[3].

• Obesity and Weight Gain : A recent prospective study shows clearly that obese men are more likely to develop prostate cancer ^[4] This large study of 287,000 male is the first to show that weight gain after age 18 also increases the risk of dying from prostate cancer. During the first six year of the enrollment into the study, 9986 developed prostate cancer and 173 died of the disease^[5].

BMI category	% increased risk of death compared to a person with BMI < 25
Overweight (BMI 25-29.9)	25% increased risk of death
Mildly obease men (BMI 30-34.9)	46% increased risk of death
Severely obease men (BMI 35)	100% increased risk of death

• Agricultural Pesticide : A long term study by the Agricultural Health Study (AHS) evaluated the role of 45 pesticides if there are possible association with increased prostate cancer risk among pesticide applicators. Methyl Bromide was linked to the risk of prostate cancer in the entire group. Six other pesticides - Chlorpyrifos, Coumaphos, Fonofos, Phorate, Permethrin, and Butylate was found to increase the risk of prostate cancer among men with family history ^{[6] [7]} .

[add] [index] Prevention

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Chemoprevention: Chemoprevention is the use of specific natural or man-made drugs, vitamins, or other agents to reverse, suppress, or prevent cancer growth. Several agents, including difluoromethylornithine (DFMO), isoflavonoids, selenium, vitamins D and E, and lycopene have shown potential benefit in studies. Further studies are needed to confirm this ^[8].

Diet and Lifestyle: The effect of diet on prostate cancer risk is under study. A diet high in fat, especially animal fat, may be associated with an increased risk of prostate cancer. More studies are needed to determine if a low-fat diet with more fruits and vegetables helps prevent prostate cancer .

Studies show that a diet high in dairy products and calcium may be linked to an increased risk of prostate cancer, although the increase may be small ^[8].

Hormonal Prevention: Studies are underway to discover the role of certain drugs, such as finasteride, that reduce the amount of male hormone as preventive agents for prostate cancer ^[8].

[add] [index] Signs and Symptoms

Prostate cancer tends to grow slower than most other cancers, hence symptoms may not show in many cases until the disease has metastasized to other parts of the body. This makes yearly screening for prostate cancer extremely important.

Signs of Prostate cancer:

• A PSA > 2.0 ng/ml.
• A PSA increase of > 0.75 ng/ml in a year.
• A PSA that doubles in less than 10 years.
• An abnormal DRE such as nodule, hardness, irregularities.

What prostate changes should you be aware of?

Growing older raises your risk of prostate problems. The three most common prostate problems are:

• Infection (prostatitis)
• Enlarged prostate ( BPH, or benign prostatic hyperplasia)
• Prostate cancer

These changes, or an infection, can cause problems passing urine. Sometimes men in their 30s and 40s may begin to have these urinary symptoms and need medical attention. For others, symptoms aren't noticed until much later in life.

Be sure to tell your doctor if you have any urinary symptoms like:

• Are passing urine more during the day
• Have an urgent need to pass urine
• Have less urine flow
• Feel burning when you pass urine
• Need to get up many times during the night to pass urine

One change does not lead to another. For example, having prostatitis or an enlarged prostate does not raise your chance of prostate cancer. It is also possible for you to have more than one condition at the same time ^[9].

[add] [index] Screening

Major medical associations and societies have issued conflicting recommendations regarding screening, making it difficult for an individual to decide if screening is right.

American Cancer Society, American Urological Association, and American College of Physicians recommend that men:

• Consider individual prostate cancer risk factors
• Know the potential benefits and harms of screening, diagnosis, and treatment
• Talk to a clinician about concerns or questions.

Us TOO Prostate Cancer Education and Support Group recommends that men have annual prostate examinations, which should include both a PSA blood test AND a digital rectal examination (DRE), starting at the following ages:

• By age 40 if you are an African American man, or have a family history of prostate cancer/breast cancer^{[10] [11]} (either are considered high-risk)
• No later than age 45 for all other men

Moreover,

• It is extremely important to "KNOW YOUR PSA." Keep a record of the exact numbers, not just that it is "in the normal range." Your first PSA blood test establishes your ‘baseline’ PSA score.
• By tracking your PSA from year to year, you will know if it has increased too much since last year. A rise in PSA levels of 0.75 ng/mL or more within one year may require further investigation by your doctor. The rate of change in your PSA level can be a more significant sign of disease than the actual PSA level.

A PSA of 2.0 and over at any age should be investigated to rule out prostate cancer ^[12].

Arguments for screening — Experts in favor of prostate cancer screening cite the following arguments:

• Even though many men with prostate cancer have nonaggressive tumors and do not die of the disease, the cancer is so common that a substantial number of men die from the cancer every year and many more suffer from the complications of advanced disease ^[13].

• For men with an aggressive prostate cancer, the best chance for curing it is probably by finding it at an early stage through screening and then treating it with surgery or radiation. Studies have shown that men who have prostate cancer detected by PSA screening tend to have earlier-stage cancer than men who have a cancer detected by other means^[13].

• The five-year survival for men who have prostate cancer confined to the prostate gland (early stage) is nearly 100 percent; this drops to 30 percent for men whose cancer has spread to other areas of the body. Chemotherapy and radiation therapy are relatively ineffective once prostate cancer has spread outside the prostate gland ^[13].

• The available screening tests are not perfect, but they are easy to perform and are fairly good compared with screening tests for some other cancers ^[13].

• The death rate due to prostate cancer has declined in recent years. This may be due to increased screening or improvements in prostate cancer treatment, particularly for advanced cancers. The death rate may also have declined due to changes in the ways that physicians complete death certificates ^[13].

Arguments against screening:

• The main argument against screening is that it is not clear if screening and treatment help men live longer and/or avoid the complications of advanced prostate cancer. No well-performed studies have determined that prostate cancer screening in the general population saves lives. Studies are currently underway to answer this important question, but the results may not be available for some time ^[13].

• Because of the relatively high number of false-positive DRE and PSA tests, a number of screened men will undergo unnecessary further testing with transrectal ultrasound and prostate biopsy. These secondary tests are relatively safe to perform, but they are not totally without side effects, and they add further costs ^[13].

• The side effects of treatment for early prostate cancers that are detected with screening may be substantial. Surgery and radiation therapy are the most popular therapies, and both can cause side effects. Although there are some tools to predict which cancers are more aggressive than others, these tools are not always accurate^[13].

[add] [index] Blood test for Prostate Specific Antigen (PSA)

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PSA is a protein secreted by the epithelial cells of the prostate gland including cancer cells; an elevated level in the blood indicates an abnormal condition of the prostate gland, either benign or malignant; it is used to detect potential problems in the prostate gland and to follow the progress of PC therapy ^[14]. PSA velocity and PSA doubling time are important markers that can indicate the existence of prostate cancer.

PSA velocity (PSAV) the calculation of the rate of increase in PSA levels in succeeding PSA tests; before diagnosis, a PSAV of 0.75 ng/ml/year (or higher) may be an indication of the presence of PC;

and PSA doubling time (PSADT) the calculation of the time it takes for the PSA value to double based on at least three values separated by at least three months each; before diagnosis, a PSADT of less than 10 years may be an indication of the presence of PC ^[14].

A first step in investigation of a PSA elevated at 2.0 or above should be a free-PSA percentage test. PSA readings that bounce up and down are more indicative of a benign process than a malignant process. A PSA that shows a persistent rise over time, particularly three consecutive rises three months apart, is suspicious for prostate cancer regardless of the PSA level. Any amount of PSA in excess of the measured benign-related PSA should be considered to have been produced by a malignant process until proven otherwise ^[12].

[add] [index] Free PSA

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Free PSA are PSA molecules in the blood stream that are not "bound" to other proteins. Free PSA percentage test reports the percentage of free PSA, which is expressed based on free PSA divided by total PSA x 100. One study showed that men with free PSA % > 25% had low risk of PC while those with < 10% free PSA % were more likely to have PC ^{[15] [16]}.

• Patient's Perspective on Free PSA

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  An elevated PSA and a low free PSA percentage can be caused by Prostatitis, which is a benign rather than a malignant condition. Cancer is more likely when Free PSA percentage is low, more testing should be done ^[17].

• An elevated PSA and a high free PSA percentage (equal to or greater than 25%), an estimate of gland volume by DRE of the prostate may reveal a diagnosis of Benign Prostate Hyperplasia (BPH) ^[12].

[add] [index] Digital Rectal Exam (DRE)

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Digital Rectal Exam is a procedure where the doctor inserts a lubricated, gloved finger into the rectum and feels the prostate through the rectal wall. The prostate is checked for size, hard or lumpy areas and any pain caused by touching or pressing the prostate. The DRE allows the doctor to feel only one side of the prostate. The test lasts about 10-15 seconds.

This exam checks for:

• The size, firmness, and texture of the prostate
• Any hard areas, lumps, or growth spreading beyond the prostate
• Any pain caused by touching or pressing the prostate

The DRE allows the doctor to feel only one side of the prostate. A PSA test is another way to help your doctor check your prostate. ^[2][17].

[add] [index] Transrectal Ultrasound

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Transrectal ultrasound can be done in an office, and no sedation or anesthesia is needed. A small probe, about the size of a finger, is inserted into the rectum, and uses sound waves that bounce off the prostate to create an echo. A computer translates these echoes into an image (called a sonogram) of the prostate. About 80 percent of cancers have an abnormal ultrasound image. Transrectal ultrasound can also help to guide a surgeon to biopsy any area that appears abnormal ^[13].

Transrectal ultrasound (TRUS) may facilitate diagnosis by directing needle biopsy; however, ultrasound is operator dependent and does not assess lymph node size. Moreover, a prospective multi-institutional study of preoperative TRUS in men with clinically localized prostate cancer felt to be eligible for radical prostatectomy showed that TRUS was no better than digital rectal examination in predicting extracapsular tumor extension or seminal vesicle involvement^[18][19].

[add] [index] Color Doppler

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A new development in ultrasound involves the use of color Doppler imaging with microbubble contrast so that physicians are better able to determine the presence and exact location of a mass within the prostate. Doppler imaging can sense differences in velocity (i.e. blood flow versus solid tissue) and transmits these differences through different color pixels to create a picture on a screen. Microbubbles are tiny bubbles of gas that can permeate through small blood vessels without creating any harm. The microbubbles further enhance imaging by increasing the intensity of backscatter signal. Since blood vessels and blood flow are more prevalent in cancerous tissues than regular tissues, microbubbles tend to concentrate in the cancer, which is revealed on the created picture. This allows physicians to more accurately locate where biopsies should be taken ^[20].

Researcher from France recently conducted a clinical study to determine the effectiveness of contrast-enhanced color Doppler ultrasound using microbubbles in determining biopsy sites in men suspected of having prostate cancer. This trial included 85 men who underwent conventional Doppler and microbubble-enhanced color Doppler during the biopsy procedure. The results between the two were directly compared based on biopsy results. Contrast-enhanced color Doppler had a 93% detection rate of prostate cancer, compared with only 54% for un-enhanced color Doppler. Biopsies from areas of the prostate that did not contain cancer occurred in 21% of biopsies under Doppler that was not enhanced, compared with only 11% of biopsies under contrast-enhanced Doppler^[20].

The researchers concluded that microbubble-enhanced color Doppler used for endorectal ultrasound improves the detection of prostate cancer and reduces unnecessary biopsies, compared to color Doppler that is not enhanced. They also state that this procedure is simple and not time consuming^[20][22].

[add] [index] PCA3

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In the early 1990s, at about the same time that PSA testing was starting to gain widespread adoption, a young molecular biologist from Holland began post-doctoral work at The Brady Urological Institute of Johns Hopkins University. There, in the laboratory of William B. Isaacs, Marion Bussemakers performed studies on human prostate tissue using the technique of differential display, a then newly described method to identify gene expression in different tissues. During this series of experiments, an mRNA was discovered that appeared to be highly specific for prostate cancer^[23] .

Recently, an additional new screening tool has become available. Bostwick Laboratories now offers the uPM3 test, the first urine-based genetic test for prostate cancer. uPM3 is based on PCA3, a specific gene that is profusely expressed in prostate cancer tissue. On average, the amount of PCA3 is 34 times greater in malignant prostate tissue than it is in benign prostate tissue. No other human tissues have ever been shown to produce PCA3. The uPM3 test predicts cancer as confirmed by prostate biopsy with 81% accuracy, compared to 47% accuracy for PSA. Therefore, after an elevated PSA, further investigations might reasonably include uPM3 testing to enhance the accuracy of diagnosis. Systematic biopsy of the prostate under ultrasound guidance, however, remains the definitive diagnostic procedure when clinical and/or laboratory findings indicate the possibility of prostate cancer^[23].

[add] [index] Prostate Biopsy

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Prostate Biopsies involve excising cores of tissue from the prostate through the rectum, they should not be performed unless there is a persuasive indication that cancer might be present. Making the decision to biopsy ^[12]:

• An abnormal DRE (a nodule, hardness, or other irregularities) with/without an elevated PSA, may warrant a need for a biopsy.
• An elevated PSA of 4.0 ng/ml or larger after ruling out Prostatitis and Benign Prostate Hyperplasia (BPH), may warrant a biopsy.
• A PSA velocity (PSAV) of 0.75 ng/ml/year or higher has been reported to be an indicator of possible PC. An increase greater than 2 points in a single year has been shown to correlate with a greater probability of aggressive PC, and a biopsy should be considered.
• A PSA doubling time (PSADT) of 10 years or less can relate to a greater probability for prostate cancer, and a biopsy should be considered.

The biopsy is usually performed in a physician's office. Prior to the procedure, most men are given a course of antibiotics to reduce the risk of infection from the procedure. It is not usually necessary to stop eating or drinking before the biopsy. The man is positioned in the fetal position, lying on the side with the knees held against the chest. A urologist (a doctor who specializes in treatment of urinary, bladder, and prostate issues) performs the procedure^[13] .

Before the biopsy, the physician injects the patient with a local anesthetic to numb the skin where the biopsies will be taken (either inside the rectum or at the perineum, the area between the penis and anus). An ultrasound probe (a thin wand) is inserted into the rectum to locate the prostate and guide the biopsies. A spring-loaded device is used to rapidly remove a 1/16 inch (2.5 mm) by 1/2 inch (20 mm) long cylinder of tissue from the prostate; this is usually repeated 12 times to ensure that tissues from the entire prostate are sampled. The entire procedure usually takes about 15 minutes ^[13].

The biopsy samples are then examined with a microscope by a pathologist. The results are usually available within one week. After the procedure, most men feel soreness in the rectum or perineum. Blood may be seen in the urine or semen.

Up to one in five men with a negative result on an initial biopsy will have cancer diagnosed after subsequent biopsies ^[13]. Imaging guided biopsies like the TRUS-guided needle biopsy ^[24] or Endorectal MRI with Spectroscopic guided biopsies can reduce the possibilities of a false negative result.

[add] [index] Coping with Prostate Cancer

[add] [index] Your Feelings

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Learning that you have cancer can come as a shock. How did you react? You may have felt numb, frightened, or angry. You may not have believed what the doctor was saying. You may have felt all alone, even if your friends and family were in the same room with you. These feelings are all normal.

For many people, the first few weeks after diagnosis are very difficult. After you hear the word "cancer," you may have trouble breathing or listening to what is being said. When you are at home, you may have trouble thinking, eating, or sleeping.

People with cancer and those close to them experience a wide range of feelings and emotions. These feelings can change often and without warning. You will have many feelings after you learn that you have cancer. These feelings can change from day to day, hour to hour, or even minute to minute ^[25].

Some of the feelings you may go through include: denial, anger, fear, stress and anxiety, depression and sadness, guilt, loneliness

All these feelings are normal. You may feel like your life is out of control. There are ways you can be in charge:

• Learn as much as you can about your cancer.
• Ask questions. Let your health providers know when you don't understand what they are saying, or when you want more information about something.
• Learn how others deal with cancer. Read our users testimonials in our community.
• Look beyond your cancer. Many people with cancer feel better when they stay busy. You may still go to work, even if you need to adjust your schedule. You can also take part in hobbies such as music, crafts, or reading.

Feeling hopeful is also normal. No one is cheerful all the time, but while you are dealing with cancer, hope can be an important part of your life ^[25].

[add] [index] Family Matters

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Families come in many forms. Some are husband, wife, and children. Others are life partners. Still others are groups of people who love and support each other ^[26].

No matter what form your family takes, your cancer will not only change your life, but also the lives of those around you.

Cancer impacts families in different ways ^[26].

• Roles and duties within the family will change
• Spouse and Partners
• Children
• Adult Children
• Parents
• Close Friends

As you think about how cancer has changed your life and your family's life, think about reaching outside your family to get help ^[26] .

• You may need help with household chores and errands.
• Respite care can give your regular caregivers a much-needed break.
• Counseling and support groups can help your family deal with the issues that cancer raises.

Most families find that being honest and open about the cancer, about the problems that arise, and about their feelings, helps them handle the changes that cancer causes ^[26].

[add] [index] Support Groups

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Cancer support groups are meetings for people with cancer and those touched by cancer. These groups allow you and your loved ones to talk with others facing the same problems. Support groups often have a lecture as well as time to talk. Almost all groups have a leader who runs the meeting. The leader can be someone with cancer or a trained counselor.

You may think that a support group is not right for you. Maybe you think that a group won't help or that you don't want to talk with others about your feelings. Or perhaps you are afraid that the meetings will make you sad or depressed.

It may be good to know that many people find support groups very helpful. People in the groups often:

• talk about what it's like to have cancer
• help each other feel better, more hopeful, and not so alone
• learn about what's new in cancer treatment
• share tips about ways to cope with cancer

Prostate Cancer Support Groups:

• Alabama, Alaska, Arizona
• California, Colorado, Connecticut
• Delaware, Florida, Georgia, Hawaii,
• Idaho, Illinois, Indiana, Iowa,
• Kansas, Kentucky, Louisiana,
• Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri,
• Nebraska, Nevada, New Jersey, New Mexico, New York, North Carolina, North Dakota,
• Ohio, Oklahoma, Oregon,
• Pennsylvania, Rhode Island,
• South Carolina, South Dakota,
• Tennessee, Texas,
• Vermont, Virginia, Virgin Island,
• Washington, Washington DC, West Virginia, Wisconsin

[add] [index] Choosing a doctor

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You will have many factors to consider when choosing a doctor. To make an informed decision, you may wish to speak with several doctors before choosing one. When you meet with each doctor, you might want to consider the following^[27]:

• Does the doctor have the education and training to meet my needs?
• Does the doctor use the hospital that I have chosen?
• Does the doctor listen to me and treat me with respect?
• Does the doctor explain things clearly and encourage me to ask questions?
• What are the doctor’s office hours?
• Who covers for the doctor when he or she is unavailable? Will that person have access to my medical records?
• How long does it take to get an appointment with the doctor?

If you are choosing a surgeon, you may wish to ask additional questions about the surgeon’s background and experience with specific procedures. These questions may include:

• Is the surgeon board-certified?
• Has the surgeon been evaluated by a national professional association of surgeons, such as the American College of Surgeons (ACS)?
• At which treatment facility or facilities does the surgeon practice?
• How often does the surgeon perform the type of surgery I need?
• How many of these procedures has the surgeon performed? What was the success rate?

It is important for you to feel comfortable with the specialist that you choose because you will be working closely with that person to make decisions about your cancer treatment. Trust your own observations and feelings when deciding on a doctor for your medical care ^[27].

Getting a Second Opinion

Once you receive your doctor’s opinion about the diagnosis and treatment plan, you may want to get another doctor’s advice before you begin treatment. This is known as getting a second opinion. You can do this by asking another specialist to review all of the materials related to your case. A second opinion can confirm or suggest modifications to your doctor’s proposed treatment plan, provide reassurance that you have explored all of your options, and answer any questions you may have ^[27].

Getting a second opinion is done frequently, and most physicians welcome another doctor’s views. In fact, your doctor may be able to recommend a specialist for this consultation. However, some people find it uncomfortable to request a second opinion. When discussing this issue with your doctor, it may be helpful to express satisfaction with your doctor’s decision and care, and mention that you want your decision about treatment to be as thoroughly informed as possible. You may also wish to bring a family member along for support when asking for a second opinion. It is best to involve your doctor in the process of getting a second opinion, because your doctor will need to make your medical records (such as your test results and x-rays) available to the specialist ^[27].

Some health care plans require a second opinion, particularly if a doctor recommends surgery. Other health care plans will pay for a second opinion if the patient requests it. If your plan does not cover a second opinion, you can still obtain one if you are willing to cover the cost^[27].

[add] [index] Diagnosis and Testing

[add] [index] Staging

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What does proper staging mean? Staging is determining the extent of disease. In the prostate cancer patient, proper staging means to assess the patient’s risk of having organ-confined disease vs capsular penetration vs seminal vesicle involvement vs lymph node involvement vs bone involvement. It is important to know the stage in order to plan treatment.

The following stages are used for prostate cancer:

As prostate cancer progresses from Stage I to Stage IV, the cancer cells grow within the prostate, through the outer layer of the prostate into nearby tissue, and then to lymph nodes or other parts of the body.

Stage I

In stage I, cancer is found in the prostate only. It cannot be felt during a digital rectal exam and is not visible by imaging. It is usually found accidentally during surgery for other reasons, such as benign prostatic hyperplasia. The Gleason score is low. Stage I prostate cancer may also be called stage A1 prostate cancer.

Stage II

In stage II, cancer is more advanced than in stage I, but has not spread outside the prostate. The Gleason score can range from 2-10. Stage II prostate cancer may also be called stage A2, stage B1, or stage B2 prostate cancer.

Stage III

In stage III, cancer has spread beyond the outer layer of the prostate to nearby tissues. Cancer may be found in the seminal vesicles. The Gleason score can range from 2-10. Stage III prostate cancer may also be called stage C prostate cancer.

Stage IV

In stage IV, cancer has metastasized (spread) to lymph nodes near or far from the prostate or to other parts of the body, such as the bladder, rectum, bones, liver, or lungs. Metastatic prostate cancer often spreads to the bones. The Gleason score can range from 2-10. Stage IV prostate cancer may also be called stage D1 or stage D2 prostate cancer.

[add] [index] Gleason Score

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Gleason score is given to prostate cancer based on it's microscopic appearance. It is the most widespread method of prostate cancer tissue grading used today, is the single most important prognostic factor in PC. The Gleason score is important because higher Gleason scores are associated with cancer which is more aggressive. To assign a Gleason score, a piece of prostatic tissue must be obtained either by sampling the gland with a needle introduced through the rectum (Transrectal biopsy) or by removing the gland (prostatectomy).

The Gleason score ranges from two to ten. A Gleason score of two is associated with the best prognosis and a score of ten with the worst. The final score is a combination of two different scores which each range from one to five. Gleason scores are associated with the following features:

• Grade 1 - The cancerous prostate closely resembles normal prostate tissue. The glands are small, well-formed, and closely packed
• Grade 2 - The tissue still has well-formed glands, but they are larger and have more tissue between them.
• Grade 3 - The tissue still has recognizable glands, but the cells are darker. At high magnification, some of these cells have left the glands and are beginning to invade the surrounding tissue.
• Grade 4 - The tissue has few recognizable glands. Many cells are invading the surrounding tissue
• Grade 5 - The tissue does not have recognizable glands. There are often just sheets of cells throughout the surrounding tissue.

A pathologist examines the biopsy specimen and attempts to give a score to the two patterns. First called the primary grade, represents the majority of tumor (has to be greater than 50% of the total pattern seen). Second - a secondary grade - relates to the minority of the tumor (has to be less than 50%, but at least 5%, of the pattern of the total cancer observed). These scores are then added to obtain the final Gleason score. For example, a prostate biopsy specimen may exhibit two different patterns, one which is assigned a number two and the other a number three. The final Gleason score in this case would be five.

Together with other parameters, the Gleason score is incorporated into a strategy of prostate cancer staging which predicts prognosis and helps guide therapy; prognosis refers to the expected biologic aggressive potential of a patient’s PC to spread to other organs. Hence, once the diagnosis of prostate cancer is made on biopsy, tumor grading, especially the Gleason score, strongly influences decisions regarding options for therapy [13].

[add] [index] Partin Table

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The Partin Tables represent one of the many algorithms that can help to establish probabilities as to the extent of progression of prostate cancer. In 1993, Dr. Alan Partin, et al1 examined medical records of 703 patients with clinically localized disease who underwent a radical prostatectomy between 1982 and 1991. They compared pre-operative findings for:

1. the serum PSA,
2. the Gleason score
3. the estimated clinical stage

with post-surgical findings of organ-confined disease (OCD), extraprostatic extension, seminal vesicle invasion and lymph node invasion. Using this data, they developed a model that could help predict the pathological stage in a newly diagnosed patient with clinically localized PC^[28].

In 2001, the Partin Tables were updated based on a larger series of 5079 men treated with prostatectomy between 1994 and 2000 at Johns Hopkins Hospital. The 2001 Partin Table interactive calculator is available from John Hopkins James Buchanan Brady Urological Institute

The primary value of the updated Partin Tables is for “counseling patients regarding the probability of their tumor being a specific pathologic stage, rather than a strict decision-making tool”. The tables may help a patient determine whether it is advisable to undergo definitive local therapy in the hopes of curing his cancer. Results from the tables may also suggest the patient consider further laboratory, radiological or pathological testing to attempt to determine if the cancer has spread beyond the prostate gland^[28].

[add] [index] Imaging

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[add] [index] Radionuclide Bone Scan

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A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone.

A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in abnormal cells in the bones.

As the patient lies on a table that slides under the scanner, the radioactive material is detected and images are made on a computer screen or film ^[29]

[add] [index] CT/CAT Scan

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A computed tomography scan (CT scan, also called a CAT scan) uses computer-controlled X-rays to create images of the body.

A CT scan is three-dimensional. By imaging and looking at several three-dimensional slices of a body (like slices of bread) a doctor could not only tell if a tumor is present, but roughly how deep it is in the body. A CT scan can be three dimensional because the information about how much of the X-rays are passing through a body is collected not just on a flat piece of film, but on a computer. Conventional CT scans take pictures of slices of the body (like slices of bread).

These slices are a few millimeters apart. The newer spiral (also called helical) CT scan takes continuous pictures of the body in a rapid spiral motion, so that there are no gaps in the pictures collected. ^[31].

A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography ^[29][31].

[add] [index] Endorectal MRI with Spectroscopic

---

Magnetic resonance imaging (MRI) is a technology where a large magnet is used to create images of various tissues in the body that a Radiologist can use to diagnose any abnormalities^[32].

Prostate MRI is most powerful when obtained with an endorectal coil. The technique has demonstrated higher accuracy than other modalities in assessing seminal vesicle invasion and extra-capsular extension (ECE) of prostate cancer (96% and 81% respectively). Endorectal coil MRI is useful for determining the extent of spread and local invasion of cancers of the prostate, rectum, and anus.^[33]

This coil is placed in the rectum at the start of the exam. Similar to ultrasound probe, the coil is placed rectally because it provides the greatest amount of signal when placed near the gland. This increased signal from the endorectal coil helps to provide excellent resolution (image quality)^[32].

The endorectal coil, sometimes called a balloon coil, has a flexible shaft with a small balloon on one end. Once inserted, the balloon is filled with either air or a special liquid until it comes into contact with and conforms to the size and shape of the prostate. It is not painful, however, it may cause some initial discomfort^[32].

The total exam time is about 40 minutes. You may be asked to restrict your diet for a short period prior to the exam^[32].

Magnetic Resonance Spectroscopic Imaging (MRSI)

MRSI is the combination of endorectal MRI with spectroscopy, spectroscopy observes specific resonances (peaks) for citrate, choline and creatine from contiguous small volumes throughout the gland. The amount of choline and citrate is used as a differential test to confirm findings of MRI.

• Prostate cancer tissue: is High in choline and Low in citrate.
• Benign prostate tissue: is Low in choline and High in citrate.

The use of endorectal MRI with spectroscopy has demonstrated high specificity in identifying cancer ^[35].

Video of patient experience courtesy of Us TOO Prostate Cancer Education & Support^[36].

[add] [index] Nuclear Imaging

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[add] [index] Positron Emission Tomography (PET) Scan

---

The positron emission tomography (PET) scan creates computerized images of chemical changes, such as sugar metabolism, that take place in tissue. Typically, the patient is given an injection of a substance that consists of a combination of a sugar and a small amount of radioactively labeled sugar. The radioactive sugar can help in locating a tumor, because cancer cells take up or absorb sugar more avidly than other tissues in the body ^[31].

After receiving the radioactive sugar, the patient lies still for about 60 minutes while the radioactively labeled sugar circulates throughout the body. If a tumor is present, the radioactive sugar will accumulate in the tumor. The patient then lies on a table, which gradually moves through the PET scanner 6 to 7 times during a 45-60-minute period. The PET scanner is used to detect the distribution of the sugar in the tumor and in the body. By the combined matching of a CT scan with PET images, there is an improved capacity to discriminate normal from abnormal tissues. A computer translates this information into the images that are interpreted by a radiologist ^[31].

PET scans may play a role in determining whether a mass is cancerous. However, PET scans are more accurate in detecting larger and more aggressive tumors than they are in locating tumors that are smaller than 8 mm and/or less aggressive. They may also detect cancer when other imaging techniques show normal results. PET scans may be helpful in evaluating and staging recurrent disease (cancer that has come back). PET scans are beginning to be used to check if a treatment is working - if a tumor cells are dying and thus using less sugar ^[31].

Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) does not adequately detect local recurrence after radical prostatectomy, due to the low metabolic activity of prostate cancer and interference with normal urinary activity in the bladder.^[38] PET only has a role in evaluating aggressive advanced prostate cancer. As a result, a more accurate and more sensitive non-invasive test, perhaps used in combination with existing tests, is needed ^[39].

[add] [index] Single Photon Emission Computed Tomography (SPECT) scan

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Similar to PET, single photon emission computed tomography (SPECT) uses radioactive tracers and a scanner to record data that a computer constructs into two- or three-dimensional images. A small amount of a radioactive drug is injected into a vein and a scanner is used to make detailed images of areas inside the body where the radioactive material is taken up by the cells. SPECT can give information about blood flow to tissues and chemical reactions (metabolism) in the body ^[31].

In this procedure, antibodies (proteins that recognize and stick to tumor cells) can be linked to a radioactive substance. If a tumor is present, the antibodies will stick to it. Then a SPECT scan can be done to detect the radioactive substance and reveal where the tumor is located ^[31].

Image of a SPECT scan on the right. It shows high levels of antibody in pelvis and axilla (red) and uptake in skin of the thigh and right shoulder (green) showing areas of cutaneous T-cell lymphoma ^[37]

[add] [index] ProstaScint scan

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ProstaScient is an imaging tool in which a radioactive isotope is attached to an antibody, called monoclonal antibody (mAb). The isotope-monoclonal antibody is injected into the bloodstream and seeks that specific cancer protein called prostate-specific membrane antigen (PSMA)associated with prostate cancer and attaches to it. Four days later, the patient is scanned with a SPECT camera that detects gamma radiation emitted by the isotope-mAb-protein sandwich, which serves to localize the cancer protein.

Why do you need ProstaScint?

• MRI and CT often do not detect soft tissue metastases from prostate cancer ^[39].
• The detection of nodal metastases with MRI and CT is based on size criteria, with a nodal size of 1.0 cm often used as the upper limit of normal. Early metastatic nodal disease from prostate cancer is usually small (<1 cm) and therefore is missed using CT and MRI. ^[40].
• Enlarged nodes with benign processes may be falsely diagnosed as malignant.

Who needs ProstaScint?

1. For the staging of newly diagnosed patients with biopsy-proven prostate cancer who are at a high risk for soft tissue metastases or
2. For the re staging of post-prostatectomy patients with a rising PSA level.
3. For patients planning radiation treatment therapy, looking for more precise interpretation of their CT or MRI with the enhancement role of ProstaScint ^{[41] [42][39]}.

It should be understood, however, that because ProstaScint imaging has been reported in some articles to have a false positive rate as high as 20%, patients with a low risk of nodal metastases are not appropriate candidates for this type of study. On the other hand, men who have an intermediate to high risk of nodal metastases are considered to be more appropriate candidates^[39].

ProstaScint Fusion Imaging with CT or MRI

Fusion imaging combines ProstaScint imaging with CT or MRI imaging and co-registers the images to provide a uniquely detailed fusion image of high diagnostic quality. In order to optimize information obtained from ProstaScint imaging, it is now recommended that all studies be performed with either CT or MRI fusion ^[39].

[add] [index] Prognosis

The prognosis (chance of recovery) and treatment options depend on the following:

• The stage of the cancer (whether it affects part of the prostate, involves the whole prostate, or has spread to other places in the body).
• The patient’s age and health.
• Whether the cancer has just been diagnosed or has recurred (come back).

Prognosis also depends on the Gleason score and the level of PSA.

[add] [index] Prostatic Acid Phosphatase (PAP)

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Prior to the PSA, the major biomarker of prostatic cancer was the prostatic acid phosphatase, or PAP, which is laboratory blood test like the PSA. Many physicians have discarded the PAP while many others still use it as a differential tool in their strategic analysis of the patient. In their experience, the PAP is an important baseline test since it has predictive value regarding the success or failure of RP or RT ^[43].

In a study by Moul et al ^[44], the PAP is useful for predicting the risk of PSA recurrence after a radical prostatactomy :

Baseline PAP (bPAP)/(ng/ml)	PSA Recurrance at 4 years
< 3	21.2%
> 3	61.3%

PAP maybe elevated due to trauma caused by prostate biopsies, DRE or sexual activity involving ejaculation. You should wait at least 5 weeks after a prostate biopsy and 48 hours after a DRE or sexual activity involving ejaculation before taking a PAP test ^[45] .

[add] [index] DNA Ploidy

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An analysis of the tumor cells DNA content, or ploidy, is a valuable prognostic tool. Normal DNA is comprosed of a pair of chromosome, and is thus termed "diploid." Diploid status is more commonly associated with tumors of a low to moderate Gleason score, whereas abnormal ploidy (aneuploid) status is more commonly associated with tumors of a higher Gleason score. However, this is not a hard and fast rule^[46].

The importance of ploidy as an independent prognostic factor is clearly demonstrated by Lerner, et al^[47]. In this paper, Lerner, et al examined the 5-year relapse rates in patients undergoing RP and having "apparent" organ confined disease. When the data were analyzed below with respect to PSA, GS and ploidy status, a significantly higher rate of disease relapse was seen in patients with non-diploid tumors^[46].

% of patients with progression within 5 years ^[46]

PSA	Gleason	Diploid	Anuploid	Tetraploid	Unknown
< 10ng/ml	5	8%	15%	-	10%
	6	15%	30%	-	16%
	7	30%	42%	-	34%
	8-10	42%	61%	-	34%
> 10ng/ml	5	15%	30%	-	16%
	6	30%	61%	42%	34%
	7	42%	61%	-	34%
	8-10	61%	61%	-	59%

[add] [index] Treatment

There are many available treatment options for prostate cancer. The type of treatment that you or your loved one receives will be based on the stage of prostate cancer. You should work together with your doctor to weigh the risks, advantages, and disadvantages of each option and its side effects and determine what treatment is right for you or your loved one^[48].

If you have been diagnosed with:

• Early stage prostate cancer with a low risk of progression, or you are not expected to tolerate other therapies, your doctor may recommend watchful waiting, or short-term monitoring of the cancer with routine digital rectal exams (DREs) and prostate specific antigen (PSA) tests^[48].

• Early stage prostate cancer, when cells have not spread outside of the prostate, your doctor may recommend surgery to remove the prostate and the seminal vesicles, cyrosurgery or radiation therapy to remove or destroy prostate gland and the cancer contained in it^[48].

• Advanced prostate cancer, when cancer cells have spread to other parts of the body (called metastasis), your doctor may recommend hormone therapy to slow cancer cell growth and/or palliative radiation (to destroy as much of the prostate cancer as can be easily done)^[48].

• Metastatic prostate cancer that is not responsive to hormone therapy (hormone resistant prostate cancer or androgen independent prostate cancer), your doctor may recommend radiation or chemotherapy that would be injected and treat the entire body^[48].

[add] [index] Watchful Waiting

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Watchful waiting is often called "active surveillance" or "observation" and means that you decide to have no active treatment now. Your doctor will want to follow you closely to look for any signs that the disease may be changing. You will have tests like the ones you've already had such as digital rectal exams, PSA tests, and repeat biopsies. You can change your mind and decide to have treatment at any time. Watchful waiting is based on the fact that many early-stage prostate cancers grow so slowly that they may never cause problems or become life threatening. In some cases, it may be a way to avoid the harms of treatment without shortening life expectancy. Or it can be a decision based on your age and other serious health problems - older men in their 70s and 80s may not have the same views about undergoing surgery or radiation therapy as younger men ^[49].

[add] [index] Surgery

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Surgery is often a treatment choice for men who have early-stage prostate cancer and are in good health. Surgery to remove the prostate is called prostatectomy (PRAHS-ta- TEK-toe-mee). There are two approaches that are typically used by surgeons: Open(Retropubic) prostatectomy or Laproscopic Prostatectomy. The newest type of surgery to remove the prostate is called Robotic-Assisted Laparoscopic surgery (da Vinci)^{[49] [48]}.

Advantages of Prostatectomy

• One-time procedure
• May prevent spread of cancer to other tissues
• May cure early-stage prostate cancer (if cancer cells are only located in the prostate)
• Removes the prostate gland and the problem of future overgrowth of the prostate (called BPH—benign prostate hyperplasia—the non-malignant enlargement of the prostate)
• May help extend life
• When this operation is performed by an expert, the advantages are much more likely to occur, and the disadvantages are less likely to occur

Disadvantages of Prostatectomy

• Requires hospitalization
• May cause impotence (also known as erectile dysfunction, ED, the inability to get an erection of sufficient quality to penetrate or to fulfill the sexual act)
• May cause incontinence (loss of urinary control)
• May cause narrowing of the urethra, making urination difficult
• When this operation is performed by a non-expert/caregiver, the disadvantages are more likely to occur

[add] [index] Radical Retropubic Prostatectomy

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Your surgeon can remove the prostate through an incision just above the pubic bone in your lower abdomen^[49].

• The surgical removal of the prostate and nearby tissues and lymph nodes where cancer may have spread^[48]

• Most often used during early stages (Stages Tl and T2), when cancer cells are located only within the prostate^[48]

• Some surgeons are skilled in nerve-sparing techniques to maximize the preservation of nerves, muscles, organs, and other structures surrounding the prostate. If the nerves are not damaged during surgery, men have a better chance of having erections again between two and 18 months after the operation. Potency rates following nerve-sparing radical prostatectomy vary widely among surgeons and academic centers. In the hands of a highly skilled surgeon performing the technique in a center with extensive experience in the procedure, potency rates are much higher than the rates seen in community practice^[48].

[add] [index] Radical Perineal Prostatectomy

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This type of surgery, which is not used as often, reaches the prostate through an incision between your scrotum and anus.With this method, your surgeon is not able to check the lymph nodes for cancer. It is also more difficult to spare the nerves that control erections. This approach is used when the cancer is confined to the prostate ^[49].

[add] [index] Laprascopic Prostatectomy

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Laparoscopic surgery is a new type of surgery to remove the prostate. It is done with smaller incisions using a slender tube with a camera on the end (laparoscope) that provides 3D images of the interior of the body. The scope is inserted through the navel, and the surgeon can see a highly enlarged image of the prostate. Other long instruments are used to assist with the removal of the prostate through 4-5 small slit (1 inch) incisions. Compared with other types of prostatectomy, this technique may lead to shorter hospital stays, faster recovery, and less blood loss and pain ^[49][48].

[add] [index] Robotic-Assisted Laprascopic Prostatectomy

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Recent developments in the field of surgical robotics have ushered in a new era of minimally invasive surgery that now challenges conventional open surgery.

• This new technique is similar to laproscopic prostatectomy, but is robot-assisted using the da Vinci system. This robotic technique allows complex surgical tasks to be performed with dexterity and minimal fatigue due to their ergonomic design, expanded degree of movements, tremor filtering, and 3-D stereoscopic visualization^[48]

• Two highly trained and skilled surgeons perform this surgery, one is beside the patient and the other controls the robotic system consisting of a laproscope and two multi-jointed arms^[48]

• In addition to the advantages of laproscopic prostatectomy, benefits of robotic technology include the use of even more delicate instruments for more precise movement and maximum preservation of nerves, muscles, organs, and other structures surrounding the prostate. Outcomes may vary depending on the skill level and experience of the surgeon. Surgery time is about the same or slightly longer than open or laproscopic surgery (often being performed in one and a half to two hours)^[48]

The robotic surgical team includes both console-side and patient-side surgeons. The operating surgeon sits at the console, and is not scrubbed. After the patient-side team is scrubbed, they place the ports, present the operative field to the operating surgeon, and use suction to keep the field clean^[50].

[add] [index] Cryosurgery (Cryo)

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Cryosurgery freezes and thaws tissue to kill prostate cancer with the surgeon being guided by ultrasound. Also called cryotherapy, it is often used when the prostate has more advanced, yet still confined disease, and when surgery is not an option. The prostate is not removed with this approach^[49].

Cryosurgery can result in injury to the rectum, incontinence, swelling of the scrotum, pain or numbness in the penis, or blocked urine flow. In 1 in 200 cases, a hole (called a fistula) appears between the rectum and prostate. Results depend highly on the doctor's skill and experience. Success rates may not be as high as with prostatectomy or with any form of external beam radiation therapy. Long-term results for this type of treatment are not yet known ^[49].

• Relatively new technique that is still emerging
• Used to treat localized prostate cancer (Stages T1 and T2)
• Freezes and immediately kills prostate cancer cells
• Performed under anesthesia, uses ultrasound-guided placement of cooling probes into the prostate
• Can be combined with hormone therapy to reduce the size of the tumor prior to freezing
• Long-term effectiveness is not well known^[48].

Advantages of Cryosurgery

• Avoids major surgery
• Less likely to cause urinary tract damage, obstructions, or bowel difficulties than radiation
• Procedure takes an hour and a half or less and patients often fully recover within days
• Protects healthy tissue from damage
• This procedure is becoming more reliable and with less complication in the hands of an expert

Disadvantages of Cryosurgery

• Impotence due to nerve damage is a common occurrence
• Urinary incontinence can occur but is rare
• Approximately 2% of men develop an abnormal tissue mass (fistula) that connects the rectum and the bladder that may require surgery to repair
• When this procedure is not performed by an expert, or without the most current equipment or techniques, the disadvantages are more likely to occur

[add] [index] Radiation Therapy

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This type of treatment uses high-energy rays (eg, x-rays) or particles (eg, electrons or protons) to kill prostate cancer cells or prevent cancer cells from growing and spreading. Radiation therapy is an option when cancer is in your prostate but has not spread to other organs (Stage T1 and T2). It is also used when you cannot have surgery because of your age, health, or personal choice.

Radiation therapy is often used in combination with hormone therapy if cancer cells have spread beyond the prostate (Stage T3). Radiation therapy may be used for pain relief in prostate cancer that is no longer responding to hormone therapy and has spread to other tissues in the body, primarily bones (Stage M+)^[48][49].

Radiation therapy techniques:^[48]

External Beam Radiation Therapy (EBRT): radiation is generated and administered by a machine outside the body, usually in brief daily sessions for several weeks.

• The newest advance in radiation therapy is IMRT, intensity modulated radiation therapy, which minimizes radiation damage to normal tissues.

• Proton Beam Therapy (PBT): this radiation therapy uses proton beams instead of x-rays to kill cancer. It is the most precise form of radiation, traveling through noncancerous areas to rest directly on the targeted area. The precision of this method allows for stronger doses of beam radiation with minimal damage to surrounding tissue.

• 3-D Conformal Radiation Therapy (3DCRT): this improvement in radiation treatment allows closer targeting of the prostate gland. The most cutting edge technique combines 3DCRT and IMRT, which more selectively focuses the dose of radiation on prostate cancer cells.

Internal Radiation Therapy:also called brachytherapy uses radiation that is placed very close to or inside the tumor. The radiation source is usually sealed in a small holder called an implant. Implants may be in the form of thin wires, plastic tubes called catheters, ribbons, capsules, or seeds. The implant is put directly into the body. Internal radiation therapy may require a hospital stay.

• Seeds brachytherapy: radiation comes from small radioactive seeds (about the size of a grain of rice) inserted directly into the prostate that administer a constant dose of radiation for a few weeks to a year. Seeds are inserted while under anesthesia, and are too small to cause discomfort.

• High-Dose Rate (HDR) Brachytherapy: short-term internal beam therapy that uses higher dosage, non-permanent seeds. Because the seeds are implanted for a much shorter amount of time (approximately 1 hour), there is less likelihood of them migrating in the body.

• Systemic Radiation Therapy: radiation is delivered by injection of a radioactive compound to control pain caused by metastasized (Stage M+) prostate cancer that no longer responds to hormone therapy.

Advantages of Radiation Therapy

• Avoids major surgery
• May cure prostate cancer in its early stages and may help extend life or eliminate symptoms in later stages
• Most side effects are minor and disappear after therapy stops, especially when the latest IMRT and seeds techniques and equipment are used
• This treatment can be very effective when performed by a radiation expert

Disadvantages of Radiation Therapy

• May cause damage to healthy cells, leading to side effects
  • Tiredness
  • Skin reactions
  • Frequent and painful urination
  • Upset stomach
  • Diarrhea
  • Rectal irritation or bleeding

• Cancer of other tissues near the prostate could occur later due to the radiation.
• The vascular tissues surrounding the prostate are damaged by the radiation. This damage will progress and continue for many years, possibly causing impotence
• All radiation therapy is associated with decreased red blood cells, white blood cell, and platelet counts
• The amount of radiation a human body can accept is limited, making future use of radiation therapy in most situations dangerous

[add] [index] 3-D Conformal Radiation Therapy

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Traditionally, the planning of radiation treatments has been done in two dimensions (width and height)^[52]. Radiation doses delivered to the prostate gland have been limited by the toxicity to the rectum and bladder in the conventional external beam radiation therapy (EBRT)^[53].

Three-dimensional (3D) conformal radiation therapy uses computer technology to allow doctors to more precisely target a tumor with radiation beams (using width, height, and depth). Many radiation oncologists use this technique. A 3D image of a tumor can be obtained using computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or single photon emission computed tomography (SPECT). Using information from the image, special computer programs design radiation beams that “conform” to the shape of the tumor. Because the healthy tissue surrounding the tumor is largely spared by this technique, higher doses of radiation can be used to treat the cancer^[52].

A clinical study shows that 90% patients that were receiving higher doses of radiation achieved an optimal response, compared to 58-76% in patients that received a lower dose. The results of this clinical study suggest treatment with high-dose 3D-CRT for localized prostate cancer is safe and feasible, and may result in improved local control of disease^[53].

[add] [index] Intensity Modulated Radiation Therapy (IMRT)

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IMRT has revolutionized the delivery of radiation therapy. IMRT is a new type of 3D conformal radiation therapy that uses radiation beams of varying intensities to deliver different doses of radiation to small areas of tissue at the same time. The technology allows for the delivery of higher doses of radiation within the tumor and lower doses to nearby healthy tissue. Some techniques deliver a higher dose of radiation to the patient each day, potentially shortening the overall treatment time and improving the success of the treatment. IMRT may also lead to fewer side effects during treatment^[52].

IMRT is a combination of

1. digitally reconstructed radiographs (DRRs) of the 3-dimensional reconstruction of organs and
2. computer- derived dose volume histograms (DVHs) allow the physician to know the exact volume of tissue receiving a specific dose of radiation.

There are literally thousands of beamlets or “pencil beams” coming from every conceivable direction to create radiation dose shapes never before possible. The process involves the physician outlining all the structures in the anatomical area on each 1 mm slice of the CT scan or MRI scan of the patient’s prostate. More recently, fusion of the two scans occurs with sophisticated software to create the most accurate representation of the patient’s anatomy (Figures 1-2). ^[54].

The radiation is delivered by a linear accelerator that is equipped with a multileaf collimator (a collimator helps to shape or sculpt the beams of radiation). The equipment can be rotated around the patient so that radiation beams can be sent from the best angles. The beams conform as closely as possible to the shape of the tumor. Because IMRT equipment is highly specialized, not every radiation oncology center uses IMRT^[52].

Comparing IMRT to 3-D Conformal radiation

3-D Conformal	IMRT
uses forward planning treatment which sets the fields of radiation and then adjusts the dose weighting and delivery, by trial and error, to refine the radiation plan. This method is thought to be accurate within 7 to 10 milimeters[54].	uses inverse planning treatment which sets a dose for the tumor/target volume and restricts the dose amount to adjacent structures. It is considered to be accurate within 1-3 millimeters[54].
In a report by Zelefsky et al, patients were treated to doses of 8100cGy: Grade 2 rectal toxicity of 13% and Grade 3 rectal toxicity of 2% [55]	In a report by Zelefsky et al, patients were treated to doses of 8100cGy: Grade 2 rectal toxicity of 0.5% and Grade 3 rectal toxicity of 0.5% [55].

Reported rates of long-term side effects from 3D-Conformal radiation are 2-3 times those reported with IMRT. IMRT represents the most refined and precise form of 3D-Conformal treatment. The long experience with 3D-Conformal provides an important foundation for implementing IMRT ^[54].

[add] [index] Proton Beam Therapy (PBT)

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Proton therapy is the most precise and advanced form of radiation treatment today. It primarily radiates the tumor site, leaving surrounding healthy tissue and organs intact. Conventional x-ray radiation often radiates healthy tissue in its path and surrounding the tumor site. Chemotherapy moves throughout the entire body, unlike radiation and surgery which are considered "site specific" treatments^[56].

Proton Therapy was first proposed in 1954, but primarily had been available for very limited use. There was no hospital-based treatment centers in the world until the Proton Treatment Center opened in 1990 at Loma Linda University Medical Center. Most radiation oncologists know about proton therapy, but have not had experience working with the proton technology, making it difficult for them to advise patients on this form of treatment. But the benefits of proton treatment are expanding to other regions of the USA, including the southwest, midwest, southeast, and mid-atlantic^[56].

A recent study at Loma Linda University concludes that when higher doses of conformal proton therapy are delivered at the target site, the results show a "low incidence of side effects" compared to conventional radiation^[56].

Proton therapy has minimal to no side effects, compared to conventional forms of radiation. Hence it is much more easily tolerated than standard radiation therapy. Tumors like Prostate cancer that are localized and have not spread to distant areas of the body are the best candidate for Proton therapy^[56].

Proton therapy can take anywhere from one day to seven weeks depending on the tumor site. The length of treatment time will also decrease over time as heavier doses begin to increase^[56].

Nearly all insurance providers nationwide cover proton therapy as does the U.S. medicare program. Proton therapy costs more than conventional radiation, but generally less than surgery^[56].

Nearly all insurance providers nationwide cover proton therapy as does the U.S. medicare program. Proton therapy costs more than conventional radiation, but generally less than surgery^[56].

"Unlike conventional radiation," says Dr. Jerry Slater, Clinical Director of Loma Linda's Proton Therapy Center, " proton radiation has a well-defined high-dose area which can be manipulated to precisely surround an irregularly shaped target such as the prostate gland. This inherent characteristic of protons allows very little scatter to the bladder and rectal areas, higher doses to the prostate, and significantly less side effects^[56]."

Video on new prostate cancer treatment Proton Therapy courtesy of The National Association for Proton Therapy ^[56]

[add] [index] High Dose Radiation (HDR) Brachytherapy

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HDR brachytherapy is a short-term internal beam therapy that uses higher dosage, non-permanent seeds. Because the seeds are implanted for a much shorter amount of time (approximately 1 hour), there is less likelihood of them migrating in the body^[48].

There are four basic steps to HDR brachytherapy. They are

1. image-guided applicator insertion (Figure 1),
2. image acquisition of the completed implant (simulation),
3. dose distribution calculations (computerized dosimetry), and
4. treatment delivery7,8.

Advantages of HDR Brachytherapy:^[57]

• Short course compared to other types of radiation treatment (1 week)
• Preservation of organ structure and function
• Few side effects
• Excellent coverage of microscopic extension of cancer
• Knowledge of radiation dose distribution before treatment is given
• Accuracy and precision of tumor-specific radiation dose delivery
• Optimal radiation dose uniformity (avoids hot and cold spots)
• Organ motion (target movement) is not a problem for HDR as with external beam radiation
• Effective treatment for cancer recurrence (termed "salvage" therapy)
• No radiation source (seed) migration into other organs
• No radiation exposure to other people.

HDR is reliable in treating both early stage prostate cancer as well as early intermediate stage that extends beyond the prostate. HDR brachytherapy has a “scaffolding matrix” feature that provides both general stability and the ability to place catheters at or beyond the prostate capsule and into the seminal vesicles without the concern for source loss or migration to other organs^[57].

Figure 3 shows the 100% therapeutic isodose line extending beyond the prostate capsule. High local tumor control rates in all risk groups confirm the efficacy of HDR to control disease both in and around the prostate^[58][59].

As shown in Table 7, the results of HDR monotherapy for low-risk and early intermediate-risk groups in the literature are excellent^[60][61][62]. A study of 294 patients from CET and William Beaumont Hospital showed the 5-year control rates to be 94%, the cause-specific survival to be 100%, and the fact that no patients had distant metastasis. The rectal complication rates were < 1% and there were < 5 % grade 3 urinary complications^[57].

[add] [index] Brachytherapy (Seeds)

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Seed implantation is a type of internal radiation therapy. Radiation is delivered inside your body by implanting tiny seeds in your prostate. Usually 40 to 130 seeds are inserted into the prostate, depending on the size of your prostate. Each seed has a small amount of radioactive material that emits radiation within an inch of its surroundings. Low-dose seeds are left in the prostate permanently, although their radiation lasts for only 3 to 6 months. This procedure is usually done on an outpatient basis, without a hospital stay^[49].

In recent years, seed implantation has become more popular as a treatment option. It has been estimated that up to 50% of patients with early stage prostate cancer are now receiving ultrasound-guided seed implantation^[63][64].

This rise in popularity is most likely due to

1. the fact that five- and ten-year disease control rates of brachytherapy equal those of the top surgical and radiation series,
2. the toxicity and side-effects are perceived to be lower, and
3. the brachytherapy involves just a single outpatient treatment

Low energy of I-125 (Iodine 125) and Pd 103 (Palladium 103) isotopes dose falls off quickly with distance and, therefore, the seeds deliver low doses to the adjacent rectum and bladder^[64].

The ultrasound-guided transperineal approach resulted in relatively even distribution of seeds throughout the prostate; this marked a major advance in prostate brachytherapy in that it minimized the need for external beam radiation and allowed more precise planning of the implant prior to the procedure. These advances also significantly increased the accuracy of seed placement and insured that the prostate would receive the proper number, strength, and positioning of radioactive sources. Derivatives of this technique are in wide use today.(see Figure 1)

Steps for Seed Implantation process:

1. Patient selection

• Stages and Extend of Cancer : Seed Implantation as a the only therapy is suitable for early stages where there is a very low risk of disease in the seminal vesicles or lymph nodes, and a modest risk of disease that extends through the outer wall. For intermediate risk patients, the choices of treatment is between implant alone or EBRT and seeds^[64].

• Prostate Size : Prostate size greater than 60cc can become technically challenging since the greater number of needles required causes more swelling during the procedure, and there is a higher probability that a portion of the gland will be positioned behind the pubic bone obstructing the placement of needles^[64].

• Prior Prostate Surgery : A prior TURP (Trans-Urethral Resection of the Prostate) can prevent the a quality implant. TURPs can leave a large hole in the center of the gland allowing little room for seed placements. TURP patients also experience higher rates of incontinence with seed implantation^{[65][66][67][68][69][64]}.

• Urinary Function : The need for a temporary catheter after implantation increases as the AUA score increases .(AUA score is a measure of the blockage present before implantation)A AUA score of above 15 is at higher risk of needing a catheter after implantation. Some may require treatment like alpha-blockers, surgical intervention like TUIP (transurethral incision of the prostate) or TURP (Trans-Urethral Resection of the Prostate) to relief the obstruction problem^[64].

2. Treatment planning

• Volume Study : The first step is a volume study with a series of cross-sectional ultrasound of the prostate. A plan which is a map of the prostate and precise position of each needle position is developed^[64].

• Isotope selection : I-125 and Pd 103 are the primary isotopes used in permanent seed implantation. The primary difference between the two isotopes is the rate at which they decay, I125 has a half life of 60 days vs. 17 days for Pd 103. The American Brachytherapy Society does not recommend one isotope over the other ^[70][64]

• Prescription Dose : The doses prescribed today are the result of initial calculations and the subsequent experience from treating thousands of men^[64].

3. Seed implantation

• Seed Placement (Preloaded Needles or MICK Applicator) : The procedure is a 45-90 minute outpatient procedure performed under spinal or general anesthesia^[64].

• Urology / Radiation Oncology Physician participation : The radiation oncologist's job is to insure the precise placement of the seeds and, if necessary, to recommend additional seeds. The urologist’s job is to place the needles and to perform necessary urologic evaluations and procedures^[64].

• Radiation Safety Consideration : The energy of I-125 and 103-Pd is so low that there is minimal risk of radiation exposure to friends and relatives of the patient^[64].

4. Post-Operative evaluation

• In OR: Ultrasound/Fluoroscopy : The assessment of implant quality can take place, to a certain degree, during the procedure through the use of ultrasound, and possibly fluoroscopy, to visualize the needles and seeds as they are being placed^[64].

• CT Based Dosimetry : Definitive evaluation, however, takes place post-operatively using CT scans that identify the position of each seed and allow the brachytherapy team to calculate the dose delivered by the seeds to the gland. CT dosimetry shows the radioactive seeds in cross-sectional images as they lie within the prostate (Figure 4) ^[64].

• Dose and Biochemical Control : With the aid of treatment planning software, the dose is calculated and compared to the pre-plan dosimetry (Figure 5)^[64].

• Quality Control : Quality assurance is an important part of seed implantation. The learning curve that practitioners typically experience before they can perform high quality implants on a consistent basis can be formidable. Fortunately, careful evaluation and post-implant CT dosimetry can identify any under-dosed areas, or cold spots, that may exist, allowing corrective treatment to take place in a timely manner^[64].

[add] [index] High-Intensity Focused Ultrasound

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HIFU: is a medical device piloted by a computer designed to treat localized prostate cancer using high intensity focused ultrasound (HIFU)^[48].

What is HIFU?

• HIFU is a procedure where the temperature inside the prostate is raised to 85° Celsius using a focused ultrasound beam
• A probe is placed into the rectum after spinal or epidural anesthesia has been administered
• This probe emits a beam of high intensity focused ultrasound
• At the point where the ultrasound is focused (focal point) the sudden and intense absorption of the ultrasound beam quickly raises the temperature which destroys targeted cells
• The area destroyed by each beam is very small and precise
• By repeating the process and moving the focal point it is possible to destroy the prostate tissue
• The treatment takes from 1 to 3 hours depending upon the size of the prostate and is usually performed on an outpatient basis^[48].

What Do the Clinical Studies Show?

• HIFU has been extensively used in Europe
• One report of 137 patients showed that 93% of the patients had negative prostate biopsies and 87% had PSA levels of less than 1.0 five years after the treatment
• Over 90% of patients undergoing HIFU therapy will not require further treatment for their prostate cancer
• HIFU treatment does not preclude other treatments. In those developing a recurrence, they remain candidates for surgery, radiation or hormone therapy
• HIFU treatment has a similar success rate to radical prostatectomy but has the major advantage of using non-invasive technology with many fewer side effects
• HIFU has proven to be an effective treatment for localized recurrent prostate cancer
• Published results indicate that 100 consecutive unsuccessful external beam radiation patients shows 62% of patients had negative biopsies, stable psa results and zero rectal fistulae^[48].

Is HIFU a Proven Therapy?

• In 1989, three European research groups united in their efforts and initiated a project to develop an efficient and non-surgical treatment for localized prostate cancer
• After ten years of development, HIFU was approved for treatment in Europe. At present, HIFU is being used throughout Europe, Russia, Japan and other Asian countries. In 2003, it received Canadian government approval and patients are being treated in Toronto, Canada
• To date, thousands of patients have been treated successfully in many European centers and throughout the world^[48].

Advantages of HIFU

• Destruction of the cancerous tissue with no risk of injury to the surrounding organs
• No chance of rectal injury
• Patient does not undergo any radiation exposure
• Usually no hospital stay is required
• Treatment is performed under spinal or epidural anesthesia
• Treatment can be repeated if necessary
• Other therapeutic alternatives can be considered in case of incomplete results
• Nerve sparing procedure can be performed
• HIFU can be used for the treatment of local recurrences (i.e. after external beam radiotherapy)^[48].

Disadvantages of HIFU

• No pathology (no tissue) to be examined following the procedure
• A TUR-P may be required prior to treatment
• Not yet available in the United States
• Patients must travel to Canada for treatment
• Not covered by many insurance plans, as treatment not available in the U.S.^[48].

[add] [index] Hormone Therapy/Androgen Deprivation Therapy (ADT)

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Prostate Cancer is an Endocrine-Related Malignancy. Hormone Therapy or Androgen Deprevation Therapy (ADT) is essentially depriving the tumor cell of a necessary growth substance - androgen (Testosterone, 5α-dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione). Most patients with PC will show some response to ADT. The degree of response is related to the tumor cell population being either androgen-dependent PC (ADPC) or androgen-independent PC (AIPC) and whether or not the testosterone level has been reduced to castration levels of below 20 ng/dl or below 0.69nM/L ^[71].

ADT is often recommended for patients who are planning treatment with EBRT, brachtherapy or cryosurgery. This is most common in settings where the prostate gland volume is too large to be effectively treated without the risk of excessive radiation scatter to the bladder and rectum. ADT can reduce gland volume, making local therapies more effective and reduce side effects^[72].

EBRT of any kind, brachytherapy and cryosurgery are all cancer volume dependent therapies. If the volume of the cancer and/or gland is too large, these treatments will be less effective and in some cases completely ineffective. ADT, therefore is often used prior to and during these treatments^[72].

Some patients initiate ADT to buy time to research their options for standard primary therapies of Radical Prostatectomy, Radiation therapy or cryosurgery^[72].

Hormonal Pathways of Prostate Cancer

An understanding of the hormonal pathways involved in prostate cancer (PC) is important in the management of this disease. Knowledge of the biochemical steps that lead to testosterone and dihydrotestosterone (DHT) synthesis may allow for therapeutic maneuvers that can result in more complete androgen blockade^[73].

• The primary pathway is via production of luteinizing hormone (LH) from the pituitary. LH stimulates the testicles to manufacture testosterone (T). T is carried into the prostate cell and interacts with the androgen receptor (AR) within the nucleus of the cell. T is also converted to dihydrotestosterone (DHT), a metabolite that is five times as potent as T in its effects on prostate cell growth^[72](Figure 7).

• The additional pathway to the prostate cell is via the adrenal androgen precursors DHEA-S and androstenedione. These are also converted within the prostate cell to T and then to DHT. This is part of the intracrinology of the prostate cell^[72](Figure 7).

• The prostate cells contain 5-alpha reductase (5-AR) that converts testosterone (T) to the five times more potent DHT (dihydrotestosterone)^[72](Figure 7).

What are the different types of Hormone Therapy ?

Single Hormone Blockade - Hormone Therapy typically employs a drug called LHRH agonist or LHRH-A (luteinizing hormone-releasing hormone agonist) which ultimately involves turning off a pituitary hormone called luteinizing hormone (LH) that normally stimulates the testicles to make testosterone. LHRH agonist currently being used are Leuprolide acetate (Lupron®), Goserelin acetate (Zoladex®) or Triptorelin pamoate (Trelstar® LA)^[71].

• Advantages of LHRH Agonists
  • Easy administration of injections monthly or every 1, 3, 4, or 12 months
  • Treatment with LHRH agonists is as effective as orchiectomy in reducing testosterone levels
  • Side effects can be reversible upon termination of the treatment so as to allow IAD therapy
  • Causes immediate suppression of testosterone levels without the initial “flare” except for tumors that are large and next to the spine
  • No need for antiandrogen therapy unless the tumor is large and next to spine
  • Less clinical data available for LHRH antagonists compared with LHRH agonists
• Disadvantages of LHRH Agonists
  • Side effects of hormone therapy may be difficult to treat and hard for some people to accept
  • In a few patients, LHRH agonist therapy may cause a brief initial rise in symptoms “testosterone flare” before the testosterone level begins to fall
  • Requires monthly injections or every 1, 3, 4, or 12 months^[48]

LHRH antagonist drug can be used in place of LHRH agonists to reduce the testosterone level in the body. LHRH antagonists work by directly inhibiting LHRH so that there is no more production of testosterone. In contrast, the LHRH analogs stimulate the LHRH receptor and cause initial production of testosterone for one to two weeks which is then exhausted^[48]. LHRH antagonists currently being used are Abarelix.

Double Hormone Blockade - typically uses LHRH agonist + an Anti-androgen drug. Anti-androgen drugs block androgen receptors and prevents T and DHT from stimulating Prostate Cancer growth. Anti-androgen drugs currently being used are Bicalutamide (Casodex®), Flutamide (Eulexin®), Nilutamide (Nilandron®, and Cyproterone acetate (Androcur®)^[71].

• Advantages of Antiandrogen Therapy
  • May provide a small survival advantage over either orchiectomy or LHRH analog therapy alone
• Disadvantages of Antiandrogen Therapy
  • In addition to common side effects of hormone therapy, you also may develop
    • Breast pain or enlargement
    • Diarrhea
    • Gastrointestinal pain
    • Anemia
    • Adverse effects on liver function (possible elevation of liver enzymes that must be monitored)^[48].

Triple Hormone Blockade - uses three agents, LHRH agonist + Anti-androgen + 5-alpha reductase (5-AR) inhibitor. 5-AR inhibitor blocks conversion of testosterone to DHT (dihydrotestosterone) which is a more potent prostate cancer growth stimulator than testosterone. 5-alpha reductase (5-AR) inhibitor drugs currently being used are Finasteride (Proscar®) and Dutasteride (Avodart®)^[71].

• Advantages of 5-alpha Reductase (5-AR) Inhibitor
  • Reduces the prostate cell growth and prostate size.
  • Highly effective in reducing PSA levels when used in combination with antiestrogens.
  • May reduce the risk of recurrence following surgery
• Disadvantage of 5-alpha Reductase (5-AR) Inhibitor
  • Causes only modest reductions in PSA levels (15-20%) when used alone.
  • May not be effective in the treatment of advanced cancer^[48].

Patients who exhibit progressive disease and who were initially treated with monotherapy using an LHRH agonist or orchiectomy, should consider the use of combination finasteride (Proscar) + flutamide (Eulexin).The pros and cons of for specific drugs to be used individually or in combination need to be throughly discussed with your doctor^[71].

Orchiectomy is an operation that removed the testicles, which produces 95% of the body's testosterone^[48].

• Advantages of Orchiectomy :
  • One time procedure
  • Effective, Permanant reduction in testosterone
  • Same day surgery
  • Cost relatively inexpensive.
• Disadvantages of Orchiectomy :
  • Side effects, such as reduced or absent sexual desire, impotence, and hot flashes and emotional impact make this procedure difficult for some patients to accept
  • Irreversible surgical procedure
  • In some cases, may require hospitalization
  • Will not allow for intermittent androgen deprivation (IAD) therapy^[48].

Estrogen Therapy Administration of estrogen hormones lowers testosterone production and has some direct apoptotic effects on both androgen-dependent and androgen-independent prostate cancer cells. Estrogen drugs currently being used are diethylstilbestrol (DES), Stilphosterol® (stilbestrol diphosphate), Honvan® (fosfestrol tetrasodium), Estradurin® (polyestradiolphosphate), Estraderm® patch (estradiol)-only a small scale trial has investigated the benefit of delivering estrogen through the skin to block testosterone production in men with prostate cancer. In that study, the patch was successful in reducing testosterone levels, with fewer cardiovascular or other side effects (gynomastia). Phase III trials are currently comparing the effects of patch and injected forms of estrogen in men with prostate cancer^[48].

• Advantages of Estrogen Therapy
  • Does not cause bone loss
  • Dose not induce androgen-independent cancer growth
  • Can dramatically slow the growth of some prostate cancer cell types
  • Inexpensive
• Disadvantages of Estrogen Therapy
  • Will cause gynecomastia, unless prevented by breast irradiation
  • Depending on the rate of administration, it may promote hypercoagulation of blood, causing blood clots in the legs, lungs, heart, and brain. Blood thinners may need to be taken to prevent these complications.
  • Causes decreased libido and impotence^[48].

P450 Enzyme Inhibitors The P450 enzymes are involved in the synthesis of several hormones, including testosterone, that stimulate prostate cancer cell growth. Inhibitors of these enzymes can decrease the levels of testosterone and adrenal androgens, and have direct cytotoxic effects on prostate cancer cells. P450 Enzyme inhibitors currently being used are Ketoconazole (Nizorol®)^[48].

• Advantages of P450 Enzyme Inhibitors
  • May still be useful in men for whom CAB has failed (who are androgen resistant)
  • Reduces both testicular testosterone and adrenal androgen production
  • Additional cytotoxic effect on prostate cancer cells
• Disadvantages of P450 Enzyme Inhibitors
  • Requires continued use of LHRH agonists or estrogen therapy to block pituitary stimulation of testicular hormone production (unless the patient had an orchiectomy)
  • Non-selective effects on other cells may cause discomfort (nausea, gastric irritation)
  • May have significant adverse effects on liver function (must measure liver enzymes)^[48].

Common side effects of hormone therapy: (listed in order of most to least common)

• Osteoporosis (bone weakening)
• Loss of muscle mass and increase of body fat
• Hot flashes
• Anemia (decreased level of red blood cells)
• Depression
• Gynecomastia (breast enlargement)
• Reduced libido
• Impotence^[48].

Videos

Click Image to play video	Topic	Presenter(s)
	Management of Side Effects Related to ADT Video	Richard Lam, MD
	Hormonal Therapy of Prostate Cancer At All Stages Video	Steven Tucker, MD

[add] [index] Chemotherapy

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Prostate cancer that is no longer responsive to hormone therapy is referred to as hormone-resistant prostate cancer or androgen-independent prostate cancer. There is currently no cure for hormone refractory prostate cancer. However, several therapies can extend life and reduce pain and discomfort. Treatment of hormone-resistant prostate cancer that has metastasized (Stage N+ and M+) may require systemic radiation therapy or chemotherapy^[48].

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated ^[29].

Chemotherapy is the administration of powerful toxic drugs that circulate throughout the body and eliminate rapidly growing cancer cells. Chemotherapy also affect rapidly growing healthy cells, which can lead to side effects hence it is reserved for patients with advanced stage cancer (Stage M+) that does not respond to hormone therapy.

Advantages of Chemotherapy:

• May prolong survival
• Provides cancer symptom improvement

Disadvantages of Chemotherapy:

• Side effects : Hair loss, Nausea, Vomiting, Diarrhea, Anemia, Reduced blood clotting, Increased risk of infection, Lowered white cell count (ie, leukine)

Currently available chemotherapy drugs:

• Novantrone® (mitoxantrone; specifically approved for hormone resistant prostate cancer)
• Taxotere® (docetaxel)
• Taxol© (paclitaxel)
• Emcyt® (estramustine)
• Adriamycin® (doxorubicin)
• Cytoxan® or Neosar® (cyclophosphamide)
• Paraplatin® (carboplatin)
• Thalomid® (thalidomide)

Videos

Click Image to play video	Topic	Presenter(s)
	Treating Androgen Independent PC Without Chemotherapy Video	Mark Scholz, M.D.
	Chemotherapy for Prostate Cancer Video	Jacek Pinski, MD, PhD
	Novel Therapies for Prostate Cancer The Future is Now Video	Mitchell Gross, MD, PhD

[add] [index] Potential effects of treatment

[add] [index] Anemia

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Anemia of androgen deprivation may occur especially in men > 73. Anemia if severe or symptomatic can be treated with Epogen or Procrit^[73].

[add] [index] Muscles wasting

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Muscle wasting with prolonged use > 1 year of hormone therapy can be diminished or prevented by exercise and weight lifting^[73].

[add] [index] Hot Flashes

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Hot flashes can be treated with homeopathic agents like Lachesis or Chinese herbs like TCB 3 and TCB 7. If patients are severely affected the use of depo-provera injection can be considered after discussion with the patient about potential concerns of the use of a progestin. This concern may not be justified but should be explored. The injection of depo-provera, 200-400 mg im can eliminate hot flashes. The issue is whether the effect of this drug is due to its metabolism to androstenedione or to an effect on a receptor that involves the mechanism for hot flashes i.e. the LHRH receptor. Perhaps depo-provera may stabilize the LHRH receptor^[73].

[add] [index] Osteoporosis/Arthritis

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Hormone therapy may cause arthritic symptoms possibly due to acute osteoporosis. Osteoporosis/Arthritis may be prevented and treated with

• bisphosphonate compounds such as Fosamax or Aredia.
• These should be used in conjunction with calcium citrate supplements (1000 mg per day) and vitamin D.
• Vitamin D can be given as vitamin D-3 at 400 units per day or more aggressively as 1,25 dihydroxycholecalciferol (Rocaltrol),a much more potent synthetic vitamin D, as 0.5 micrograms per day with this dose increased to 1 microgram assuming calcium levels remain normal. This latter agent requires a prescription.
• Slow-release sodium fluoride will help with bone formation. This is usually given as 25 mg twice a day. Currently this drug has not been approved by the FDA^[73].

[add] [index] Memory Loss

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Memory loss could possibly be helped by the use of Gingko at 60 mg three times a day. Agents such as Hydergine could be used as well as Nicotine gum to increase cerebral blood flow. Other smart drugs such as Deprenyl, Piracetam or Vinpocetin could be tried. Clinical studies are needed^[73].

[add] [index] Weight Gain

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Cholesterol/triglyceride increases could be managed by exercise and a low fat diet^[73].

[add] [index] Rectal Irritation

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[add] [index] Erectile Dysfunction

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Erectile dysfunction (ED) has been a major problem because a high percentage of men treated with radical prostatectomies, radiation therapy, and cryosurgery have traditionally become impotent as a result^[74] .

Erectile dysfunction can be treated with:

• PDE-5 inhibitors drugs - Viagra®, Levitra®, and Cialis®. These medication cannot be taken with any nitrate like Nitroglycerin to treat chess pain^[75]. Alpha-blockers for BPH must be used cautiously with Viagra®, Levitra®, and Cialis®.

• Vacuum Erection Devices - a cylinder is placed over the penis, using a lubricant to create a seal. Vacuum pressure provided by a pump draws blood into the penis. A rubber band traps the blood in the penis. These devices can be helpful also, in maintaining penile length after prostate cancer surgery. Many men have found these devices to be successful, while others find them cumbersome to use.

• MUSE (Medical Urethral System for Erection) - This is Prostaglandin-E medicine that is applied into the urethra. The man then rubs the penis causing the medicine to dissolve and be absorbed into the glans and erectile bodies of the penis. The erection occurs usually within 10-15 minutes if this medicine is going to work for the patient. MUSE has had less success than the oral medications for most men^[76][74].

• Inflatable Penile Prosthesis - A penile implant is a great option for a couple facing ED. However, most men will never consider this treatment option unless all other treatment options fail. The thought of a penile implant seems unnatural to most men, and they just cannot picture themselves getting this type of a surgery. In fact, the manufacturer reports that approximately 90% of men and their partners proceeding with this treatment are extremely satisfied.
  • Most men prefer the inflatable penile implant as it gives the most natural erection. The erection is immediate and simulates a natural erection. (See Figure 2.) The procedure, which is covered by most insurance companies and Medicare, is performed as an outpatient and is about as invasive as a hernia operation. Thus, most men can return to work within four to seven days of surgery and are able to have sexual relations within six to eight weeks.15 Over the past 30 years, more than 300,000 men have had penile protheses implanted. And the present inflatable implants have much greater success than earlier models, with fewer leaks and mechanical malfunctions. Today, in fact, the implant manufacturers give a lifetime warranty^[74].

• Penile Injection Therapy- The thought of a penile injection has to be the most foreign thought for any man, but it is probably one of the most effective treatments available. There is a small plastic device that automatically performs the injection on the side of the penis. It feels like a pinch on the shaft of the penis. There are a number of medications that can be directly applied into the erectile chambers.
  • The advantage of this treatment is that it gives a very natural and firm erection. In fact, I have a number of patients who prefer this treatment over the oral medications because of its dependability and quick onset of action. Most of my patients report that the erection occurs within 3-5 minutes after an automatic injector device is used^[76]. The medicine can be titrated to give an erection that will last about 45 minutes. However, a side effect can be a prolonged erection that will last four hours or more^[74].

[add] [index] Incontinence

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Loss of bladder control (urinary incontinence) after prostate surgery is a devastating complication, which has a significant negative impact on quality of life. Normally, as the bladder fills to capacity, there is very little change in bladder pressure and the sphincter remains closed allowing the man to stay dry. When incontinence occurs following prostatectomy, this normal balance of bladder and sphincter function is disturbed^[77].

Three main causes of post-prostatectomy incontinence (ppi) based on urodynamic findings in men with ppi:

1. High pressure (with ‘spasms’ of the bladder) developing in the bladder as the bladder fills (50% of men with ppi). These bladder spasms may cause urge incontinence, frequent urination, and sometimes loss of urine at night.
2. Damage to the sphincter muscle (35% of men with ppi). This damage results in stress incontinence with loss of urine during coughing, straining, or vigorous physical activity.
3. A combination of bladder malfunction and sphincter damage (10% of men with ppi). Men with this combined problem usually experience “mixed incontinence” symptoms with a combination of both urge and stress incontinence.

Treatment for post-prostatectomy incontinance related to high bladder pressure:

• Medications to relax the bladder are usually effective to treat high bladder pressure problems. These medicines (generally known as anti-cholinergics) include Ditropan XL, Detrol LA, the Oxytrol patch, and imipramine. Both Ditropan and Detrol are oral medications that are taken once daily. These medications use a ‘time release’ mechanism to maintain adequate blood levels of the drug to relax the bladder and eliminate ‘bladder spasms’ over 24 hours.
  • Side effects of these medications include dry mouth, constipation, and sometimes blurry vision.
  • These drugs should not be used in patients with narrow angle glaucoma or in men who do not empty their bladder well.
  • The Oxytrol patch sends the medication to relax the bladder through the skin. This patch is changed twice per week and may have fewer side effects than the oral medications.

• Interstim® “Bladder Pacemaker” When the usual medical treatments to lower high bladder pressures are not successful, the Interstim “bladder pacemaker” may be an excellent alternative. This treatment involves a two-stage approach with both stages performed under local anesthesia as an outpatient procedure. The first stage involves placing a special stimulation electrode next to the main nerve that controls the bladder. The patient then wears an external stimulation box for 7-10 days as a “test stimulation” to evaluate the response of the bladder to the electrical stimulation to “relax” the bladder. When a good response is obtained, we proceed with the second stage of the procedure, which involves implantation of an internal ‘pacemaker’ that is attached to the stimulation electrode and programmed through the skin. Overall approximately 50% of patients respond to the first stage trial of test stimulation. When we proceed with the second stage implant, about 85% of patients have an excellent response. Thus, use of the Interstim “bladder pacemaker” is an effective treatment option for those patients who have high-pressure bladder dysfunction who do not respond to the usual forms of medical treatment.

Treatment for post-prostatectomy incontinance related to sphincter damage:

Options for treatment of sphincter damage include biofeedback, injection therapy (which is generally not successful), the artificial urinary sphincter, and more recently the male sling procedure.

• The Artificial Urinary Sphincter (AUS) Perfected over the last 20 years, the artificial urinary sphincter is a device implanted into the body to correct stress incontinence in men with significant sphincter damage. The AUS has three components: a cuff that helps close the urethra, a pump placed inside the scrotum, and a pressure regulating balloon which is placed in the lower abdomen. When the man wants to urinate, he squeezes the pump in the scrotum, which opens the cuff around the urethra. Automatically, after 3-5 minutes, the fluid returns into the cuff allowing the cuff to close. After the device is tested during surgery, the cuff is “locked” open, and is only activated when swelling around the pump is gone (usually about 4-6 weeks after surgery).
  • With the current model of the AUS, long-term patient satisfaction has been excellent with less that a 15% mechanical malfunction rate at 7.5 years after implantation of the device^[78].
  • Despite these excellent long-term results, however, some men are hesitant to have this prosthetic device placed. For these men, as well as for those with more minor degrees of ppi or for men who do not have the manual dexterity to squeeze the pump in the scrotum, the male sling is a promising alternative.

• Male Sling Procedure Over the last two years, the male sling procedure has become a viable treatment alternative for men with ppi due to sphincter damage causing stress incontinence. The surgical procedure to implant the sling takes about one hour and can be done either on an outpatient basis or with an overnight hospital stay. The purpose of the “sling” is to compress the urethra and help eliminate loss of urine with coughing, sneezing, or vigorous activity.
  • The sling is placed via an incision between the scrotum and rectum. After exposing the pelvic bone on each side, six titanium bone screws are placed into the pubic bone (three screws on each side). A permanent suture is attached to each bone screw (see Figure 2). These sutures are then passed through the material used to create the sling, which will compress the urethra. The material used for the sling may be cadaveric (from a dead body) tissue, processed non-human tissues, or synthetic materials. The author prefers to use commercially available non-frozen cadaveric fascia lata (connective tissue from thigh).
  • Three sutures on one side are passed through one edge of the sling and tightly tied. The three sutures on the other side of the pubic bone are then passed through the sling and tied to create closure of the urethra at a pressure of 60cm water pressure. This pressure is confirmed by running sterile fluid backward into the urethra at 60cm water pressure and confirming that this fluid perfusion stops when the sling is tightened down (see Figure 3). The incision is then closed. A catheter is usually left in place for 24 hours with most men being able to urinate with good control immediately after the catheter is removed.
  • Thus far, the results with the male sling have been encouraging. In one series of men undergoing the male sling, 40% of men are completely dry, 40% are significantly improved, and 20% are considered failures. Of those men who did not respond to the male sling, an artificial urinary sphincter could be considered as a second alternative.

[add] [index] Drugs

[add] [index] LHRH agonist

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LHRH (Luteinizing hormone-releasing hormone) agonist can prevent the testicles from producing testosterone.

[add] [index] Leuprolide Acetate (Lupron®, Viadur®)

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The acetate salt of a synthetic nonapeptide analogue of gonadotropin-releasing hormone. Leuprolide binds to and activates gonadotropin-releasing hormone (GnRH) receptors. Continuous, prolonged administration of leuprolide in males results in pituitary GnRH receptor desensitization and inhibition of pituitary secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH), leading to a significant decline in testosterone production; in females, prolonged administration results in a decrease in estradiol production. This agent reduces testosterone production to castration levels and may inhibit androgen receptor-positive tumor progression ^[79].

Synonyms	Leuprorelin, Leuprorelin Acetate
US brand names	Lupron,Lupron Depot, Lupron Depot-3 Month, Lupron Depot-4 Month, Lupron Depot-Ped, Viadur®, Eligard®
Foreign brand names	Carcinil, Enanton, Enantone, Enantone-Gyn, Ginecrin, Leuplin, Lucrin, Lucrin Depot, Procren, Procrin, Prostap, Trenantone, Uno-Enantone

[add] [index] Goserelin acetate (Zoladex®)

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A synthetic decapeptide analog of luteinizing hormone-releasing hormone (LHRH) with antineoplastic activity. Goserelin binds to and activates pituitary gonadotropin releasing hormone (GnRH) receptors. Prolonged administration of goserelin inhibits the secretion of pituitary gonadotropin, thereby decreasing levels of testosterone (in males) and estradiol (in females). Administration of this agent in a depot formulation may result in the regression of sex hormone-sensitive tumors and a reduction in sex organ size and function ^[79].

US brand names

Zoledex

[add] [index] Triptorelin pamoate (Trelstar® LA)

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The pamoate salt of triptorelin, a synthetic decapeptide agonist analog of luteinizing hormone releasing hormone (LHRH). Possessing greater potency than endogenous LHRH, triptorelin reversibly represses gonadotropin secretion after prolonged administration. After chronic, continuous administration, a sustained decrease in LH, FSH and testicular and ovarian steroidogenesis is observed. The serum testosterone concentration may fall to levels typically seen in surgically castrated men ^[79].

Synonyms	Pamorelin
US brand names	Trelstar Depot, Trelstar LA

[add] [index] LHRH Antagonists

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LHRH antagonists work by directly inhibiting LHRH so that there is no more production of testosterone. In contrast, the LHRH analogs stimulate the LHRH receptor and cause initial production of testosterone for one to two weeks which is then exhausted^[48]. LHRH antagonists currently being used are Abarelix.

[add] [index] Abarelix (Plenaxis)

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A synthetic decapeptide and antagonist of naturally occurring gonadotropin-releasing hormone (GnRH). Abarelix directly and competitively binds to and blocks the gonadotropin releasing hormone receptor in the anterior pituitary gland, thereby inhibiting the secretion and release of luteinizing hormone (LH) and follicle stimulating hormone (FSH). In males, the inhibition of LH secretion prevents the release of testosterone. As a result, this may relieve symptoms associated with prostate hypertrophy or prostate cancer, since testosterone is required to sustain prostate growth ^[79].

US brand names

Plenaxis

[add] [index] Anti-androgen

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Antiandrogens can block the action of androgens (hormones that promote male sex characteristics).

[add] [index] Bicalutamide (Casodex®)

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A synthetic, nonsteroidal antiandrogen. Bicalutamide competitively binds to cytosolic androgen receptors in target tissues, thereby inhibiting the receptor binding of androgens. This agent does not bind to most mutated forms of androgen receptors ^[79].

Us brand names	Casodex
Foreign brand names	Cosudex

[add] [index] Flutamide (Eulexin®)

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A toluidine derivative and nonsteroidal antiandrogen that is structurally related to bicalutamide and nilutamide. Flutamide and its more potent active metabolite 2-hydroxyflutamide competitively block dihydrotestosterone binding at androgen receptors, forming inactive complexes which cannot translocate into the cell nucleus. Formation of inactive receptors inhibits androgen-dependent DNA and protein synthesis, resulting in tumor cell growth arrest or transient tumor regression ^[79].

Synonyms	Flucinom, Flugerel, Niftolid
US brand names	Eulexin
Foreign brand names	Apimid, Chimax, Drogenil, Euflex, Eulexine, Flucinome, Fluken, Flulem, Flutabene, Flutacan, Fluta-Gry, Flutamex, Flutamin, Flutan, Flutaplex, Fugerel, Grisetin, Oncosal, Profamid, Prostacur, Prostadirex, Prostica, Prostogenat, Tafenil, Tecnoflut, Testotard

[add] [index] Nilutamide (Nilandron®)

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A synthetic, nonsteroidal agent with antiandrogenic properties. Nilutamide preferentially binds to androgen receptors and blocks androgen receptor activation by testosterone and other androgens; this agent may inhibit androgen-dependent growth of normal and neoplastic prostate cells ^[79].

[add] [index] Cyproterone acetate (Androcur®)

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The acetate salt of a synthetic steroidal antiandrogen with weak progestational and antineoplastic activities. Cyproterone binds the androgen receptor (AR), thereby preventing androgen-induced receptor activation in target tissues and inhibiting the growth of testosterone-sensitive tumor cells. This agent also exerts progestational agonist properties at the level of the pituitary that reduce luteinizing hormone (LH), resulting in reductions in testicular androgen secretion and serum testosterone levels. Treatment with cyproterone alone results in incomplete suppression of serum testosterone levels ^[79].

Synonyms	cyproterone
Foreign brand names	Androcur, Cyprone, Cyprostat, Dianette

[add] [index] 5-alpha reductase (5-AR) inhibitor

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Limits the formation of testosteron into dihydrotestosterone (DHT) which is 4x more potent form of testosteron. Prostate cancer cells depends on both testosterone and DHT to survive, so blocking the formation of DHT is a anti-cancer precaution ^[79].

[add] [index] Finasteride (Proscar®)

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A synthetic 4-azasteroid compound. Finasteride competitively binds to and inhibits steroid type II 5-alpha-reductase in the prostate gland, liver, and skin, thereby interfering with the enzymatic conversion of testosterone to 5-dihydrotestosterone (DHT) and reducing serum DHT levels. The reduction in serum DHT levels results in diminished stimulation of androgen receptors in the nuclei of prostate cells and, so, diminished prostate cell proliferation ^[79].

US brand names	Proscar
Foreign brand names	Finastid, Pro-Cure, Prostide, Uprosan

[add] [index] Dutasteride (Avodart®)

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A synthetic 4-azasteroid compound. Dutasteride competitively and specifically binds to isoenzymes 1 and 2 of 5-alpha-reductase, forming stable enzyme complexes and inhibiting the conversion of testosterone to 5α-dihydrotestosterone (DHT); the reduction in DHT activity may mitigate or prevent enlargement of the prostate gland. The type 2 5-alpha-reductase isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also active in skin and the liver ^[79].

US brand names

Avodart

[add] [index] Estrogen

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[add] [index] Diethylstilbestrol (DES)

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DES; the acronym for diethylstilbestrol, a synthetic, nonsteroidal form of estrogen. A well-known teratogen and carcinogen, DES inhibits the hypothalamic-pituitary-gonadal axis, thereby blocking the testicular synthesis of testosterone, lowering plasma testosterone, and inducing a chemical castration^[79].

Synonyms	Diethylstilbenediol, Diethylstilbestrol Dipropionate, Diethylstilbestrolum, Diethylstilboestrol, Sinestrol, Stilboestrol Dipropionate
US brand names	Acnestrol, Cyren A, Deladumone, Diastyl, Domestrol, Estrobene, Estrobene, Estrosyn, Fonatol, Makarol, Milestrol, Neo-Oestronol I, Oestrogenine, Oestromenin, Oestromon, Palestrol, stilbestrol, Stilbetin, Stilboestroform, Stilboestrol, Synestrin, Synthoestrin, Vagestrol
Foreign brand names	Antigestil, Apstil, Boestrol, Bufon, Distilbene, Estrogenine, Estromenin, Grafestrol, Microest, Oestromensyl, Serral, Sexocretin, Sibol, Stilboefral, Stilkap

[add] [index] P450 Enzyme Inhibitor

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[add] [index] Ketoconazole (Nizorol®)

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A synthetic derivative of phenylpiperazine with broad antifungal properties and potential antineoplastic activity. Ketoconazole inhibits sterol 14-a-dimethylase, a microsomal cytochrome P450-dependent enzyme, thereby disrupting synthesis of ergosterol, an important component of the fungal cell wall^[79].

Us brand names	Nizoral
Foreign brand names	Fungarest, Fungoral, Ketoderm, Ketoisdin, Orifungal M, Panfungol

[add] [index] Erectile Dysfunction Drugs

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PDE-5 inhibitors drugs used to treat erectile dysfunction are Viagra®, Levitra® and Cialis®. All three of these medications work in a similar fashion by blocking the breakdown of the enzyme, cyclic GMP, which is responsible for the smooth muscle relaxation and trapping blood in the penile tissue when a man is sexually stimulated^[80][81][82].

Basic common similarities include:

• They require sexual stimulation.
• They should be tried multiple times before calling them a failure (I tell my patients to try each medication 5-10 times before giving up on it).
• PDE-5 medicines cannot be taken with any nitrate^[75]. Nitroglycerin is used to treat chest pain and must not be taken in combination with Viagra®, Levitra®, or Cialis®. There is no negotiation about the use of PDE-5 and nitrates. In a rare patient, they can cause a significant drop in blood pressure, up to 30 mmHg or more. If someone has chest pain after taking one of these PDE-5 inhibitors, the treating physician should be told so that he knows to give you an alternative medicine to nitroglycerin.
• Alpha-Blockers used for the treatment of Benign Prostatic Hypertrophy (BPH) must be used cautiously in combination with Viagra, Levitra®, or Cialis®^[75].The combined use of these medications is generally safe, but can cause a drop in blood pressure resulting in light headedness or dizziness in a rare patient. Unfortunately, we do not know which patient will have the drop in blood pressure. The vast majority of men tolerate alpha blockers and PDE-5 medications without any side effects. Therefore, the following precautions should be taken:
  • Viagra®: The alpha-blocker can be taken simultaneously with a 25 mg dose. When taking the 50 mg or 100 mg dose, there should be a four hour separation between Viagra® and the alpha-blocker^[75]
  • Levitra® and Cialis®: The alphablocker or Levitra® should be started at the lowest prescribing dose for both drugs and raised to the most efficacious dose slowly to ensure tolerability^[75].

[add] [index] Sildenafil Citrate (Viagra®)

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The citrate salt of a pyrazolopyrimidinone derivative structurally related to zaprinast. Sildenafil selectively inhibits cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase, resulting in vasodilation in the corpus cavernosum of the penis and penile erection^[79].

Us brand names

Viagra®

Approximately a 4-5 hour half-life allowing for sexual activity for up to six hours or longer. Viagra® should be taken about one hour before use if on an empty stomach (up to two hours after a fatty meal or with alcohol)^[75][74].

[add] [index] Vardenfil HCL (Levitra®)

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LEVITRA® is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) ^[79].

Us brand names

Levitra®

Approximately a 4-5 hour half-life allowing for sexual activity up to six hours or longer. It may be taken with a low fat meal and alcohol one hour before expected relations. With a high fat meal, a man should take it two hours before sexual relations^[75][74].

[add] [index] Tadalafil (Cialis®)

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A carboline-based compound with vasodilatory properties. Tadalfil selectively inhibits the cyclic guanosine monophosphate (cGMP)-specific type 5 phosphodiesterase- (PDE-5)-mediated degradation of cGMP, which is found in the smooth muscle of the corpus cavernosa and corpus spongiosum of the penis. Inhibition of cGMP degradation by tadalfil results in prolonged muscle relaxation, vasodilation, and blood engorgement of the corpus cavernosa, and, so, prolonged penile erection^[79].

Us brand names

Cialis®

It has a 17.5 hour half-life with double blind studies showing activity up to 36 hours. A man can take Cialis® earlier in the day or on a Friday evening and choose to have sexual relations at the most natural or convenient time. This time freedom is attractive to both men and women because sex appears to be more natural and not dictated by the clock^[75][74].

[add] [index] Chemotherapy Drugs

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[add] [index] Mitoxantrone Hydrochloride (Novantrone®)

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The hydrochloride salt of an anthracenedione antibiotic with antineoplastic activity. Mitoxantrone intercalates into and crosslinks DNA, thereby disrupting DNA and RNA replication. This agent also binds to topoisomerase II, resulting in DNA strand breaks and inhibition of DNA repair. Mitoxantrone is less cardiotoxic compared to doxorubicin.

Synonyms	dihydroxyanthracenedione, Dihydroxyanthracenedione Dihydrochloride, mitoxantrone dihydrochloride, mitoxantrone HCl, Mitoxantroni Hydrochloridum, Mitozantrone
US brand names	Novantrone
Foreign brand names	Mitroxone, Neotalem, Onkotrone, Pralifan

[add] [index] Docetaxel (Taxotere®)

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A semi-synthetic, second-generation taxane derived from a compound found in the European yew tree, Taxus baccata. Docetaxel displays potent and broad antineoplastic properties; it binds to and stabilizes tubulin, thereby inhibiting microtubule disassembly which results in cell- cycle arrest at the G2/M phase and cell death. This agent also inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and displays immunomodulatory and pro-inflammatory properties by inducing various mediators of the inflammatory response. Docetaxel has been studied for use as a radiation-sensitizing agent.

US brand names

Taxotere®

Docetaxel is approved by the Food and Drug Administration (FDA) to be used alone or with other drugs to treat certain types of breast and non-small cell lung cancer (NSCLC). It is also approved to be used with other drugs to treat squamous cell carcinoma of the head and neck (SCCHN) and certain types of gastric and prostate cancer.

[add] [index] Paclitaxel (Taxol©)

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A compound extracted from the Pacific yew tree Taxus brevifolia with antineoplastic activity. Paclitaxel binds to tubulin and inhibits the disassembly of microtubules, thereby resulting in the inhibition of cell division. This agent also induces apoptosis by binding to and blocking the function of the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2).

US brand names	Taxol
Foreign brand names	Anzatax, Asotax, Bristaxol, Praxel, Taxol Konzentrat

[add] [index] Estramustine (Emcyt®)

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The orally available disodium salt, monohydrate, of estramustine phosphate, a synthetic molecule that combines estradiol and nornitrogen mustard through a carbamate link. Estramustine and its major metabolite estramustine bind to microtubule-associated proteins (MAPs) and tubulin, thereby inhibiting microtubule dynamics and leading to anaphase arrest in a dose-dependent fashion. This agent also exhibits anti-androgenic effects.

Synonym	Estramustine Phosphate
US brand names	Emcyt
Foreign brand names	Estracyt

[add] [index] Doxorubicin (Adriamycin®)

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The hydrochloride salt of doxorubicin, an anthracycline antibiotic with antineoplastic activity. Doxorubicin, isolated from Streptomyces peucetius var. caesius, is the hydroxylated congener of daunorubicin. Doxorubicin intercalates between base pairs in the DNA helix, thereby preventing DNA replication and ultimately inhibiting protein synthesis. Additionally, doxorubicin inhibits topoisomerase II which results in an increased and stabilized cleavable enzyme-DNA linked complex during DNA replication and subsequently prevents the ligation of the nucleotide strand after double-strand breakage. Doxorubicin also forms oxygen free radicals resulting in cytotoxicity secondary to lipid peroxidation of cell membrane lipids; the formation of oxygen free radicals also contributes to the toxicity of the anthracycline antibiotics, namely the cardiac and cutaneous vascular effects.

Synonym	ADM, ADR, Adria
US brand names	Adriamycin
Foreign brand names	Adriacin, Adriblastina, Rubex

[add] [index] Cyclophosphamide (Cytoxan® Neosar®)

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A synthetic alkylating agent chemically related to the nitrogen mustards with antineoplastic and immunosuppressive activities. In the liver, cyclophosphamide is converted to the active metabolites aldophosphamide and phosphoramide mustard, which bind to DNA, thereby inhibiting DNA replication and initiating cell death.

Synonym	Ciclofosfamida, Ciclofosfamide, Claphene, CP monohydrate, CPM, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphanum, Cytophosphane, Mitoxan, Syklofosfamid, Zytoxan
US brand names	Clafen, Cytoxan, Neosar
Foreign brand names	Carloxan, Cicloxal, Cycloblastin, Cycloblastine, CYCLO-cell, Cyclostin, Cyclostine, Cytophosphan, Endoxan, Endoxana, Enduxan, Fosfaseron, Genoxal, Ledoxina, Procytox, Sendoxan

[add] [index] Carboplatin (Paraplatin®)

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A second-generation platinum compound with a broad spectrum of antineoplastic properties. Carboplatin contains a platinum atom complexed with two ammonia groups and a cyclobutane-dicarboxyl residue. This agent is activated intracellularly to form reactive platinum complexes that bind to nucleophilic groups such as GC-rich sites in DNA, thereby inducing intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links. These carboplatin-induced DNA and protein effects result in apoptosis and cell growth inhibition. This agent possesses tumoricidal activity similar to that of its parent compound, cisplatin, but is more stable and less toxic.

Synonym	Carboplatin Hexal, Carboplatino
US brand names	Paraplat, Paraplatin
Foreign brand names	Blastocarb, Carboplat, Carbosin, Carbosol, Carbotec, Displata, Ercar, Nealorin, Novoplatinum, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo

[add] [index] Thalidomide (Thalomid®)

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A synthetic derivative of glutamic acid (alpha-phthalimido-glutarimide) with teratogenic, immunomodulatory, anti-inflammatory and anti-angiogenic properties. Thalidomide acts primarily by inhibiting both the production of tumor necrosis factor alpha (TNF-alpha) in stimulated peripheral monocytes and the activities of interleukins and interferons. This agent also inhibits polymorphonuclear chemotaxis and monocyte phagocytosis. In addition, thalidomide inhibits pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thereby inhibiting angiogenesis.

Synonym	Alpha-Phthalimidoglutarimide, N-Phthaloylglutamimide, N-Phthalylglutamic Acid Imide
US brand names	Synovir, Thalomid
Foreign brand names	Contergan, Distaval, Kevadon, Neurosedyn, Pantosediv, Sedoval K-17, Softenon, Talimol

[add] [index] Videos

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Click Image to play video	Topic	Presenter(s)
	Management of Side Effects Related to ADT Video by Dr. Lam	Richard Lam, MD
	Hormonal Therapy of Prostate Cancer At All Stages Video by Dr Tucker	Steven Tucker, MD

View More Videos

[add] [index] References

1. ↑ The Prostate, National Cancer Institute,
2. ↑ ^{2.0 2.1 2.2 2.3} What you need to know about Prostate Cancer, National Cancer Institute
3. ↑ ^{3.0 3.1 3.2 3.3} Cancer Risk: Understanding the puzzle, National Cancer Institute
4. ↑ Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality, Wright ME, Chang SC, Schatzkin A, Albanes D, Kipnis V, Mouw T, Hurwitz P, Hollenbeck A, Leitzmann MF, PubMed
5. ↑ Obesity and Weight Gain Linked to Prostate Cancer Mortality, National Cancer Institute
6. ↑ Agricultural Health Study: Q&A, National Cancer Institute
7. ↑ Agricultural Health Study, National Institutes of Health, National Cancer Institute, National Institute of Enviromental Health Sciences, Environmental Protection Agency
8. ↑ ^{8.0 8.1 8.2} Prostate Cancer Prevention(PDQ),National Cancer Institute
9. ↑ Understanding Prostate Changes:A health guide for men, National Cancer Institute
10. ↑ Bennett KE, Howell A, Evans DG, et al: A follow-up study of breast and other cancers in families of an unselected series of breast cancer patients. Br J Cancer 86:718-22, 2002
11. ↑ Goldgar DE, Easton DF, Cannon-Albright LA, et al: Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86:1600-8, 1994
12. ↑ ^{12.0 12.1 12.2 12.3} What Every Doctor Who Treats Male Patients Should Know, PCRI Insights May, 2005 vol. 8, no.2. Stephen B. Strum, MD, FACP, Medical Oncologist Specializing in Prostate Cancer and Donna Pogliano
13. ↑ ^{13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11} Patient information: Prostate cancer screening, Richard M Hoffman, MD, MPH
14. ↑ ^{14.0 14.1} Prostate Specific Antigen, Glossary of Prostate Cancer Related Terms, Prostate Cancer Research Institute, PCRI
15. ↑ Ito K, Yamamoto T, Ohi M, et al: Free/total PSA ratio is a powerful predictor of future prostate cancer morbidity in men with initial PSA levels of 4.1 to 10.0 ng/mL. Urology 61:760-4, 2003
16. ↑ Prostate Specific Antigen, Wikipedia
17. ↑ ^{17.0 17.1} Understanding Prostate Changes: Types of Tests, National Cancer Institute
18. ↑ Smith JA Jr, Scardino PT, Resnick MI, et al.: Transrectal ultrasound versus digital rectal examination for the staging of carcinoma of the prostate: results of a prospective, multi-institutional trial. J Urol 157 (3): 902-6, 1997.PUBMED Abstract
19. ↑ Stage InformationProstate Cancer Treatment, National Cancer Institute
20. ↑ ^{20.0 20.1 20.2} Enhanced Ultrasound Improves Detection of Prostate Cancer,Us TOO Prostate Cancer Education & Support
21. ↑ Color Doppler and Tissue Harmonic Ultrasound in the Early Detection and Staging of Prostate Cancer,Duke K. Bahn, M.D., Prostate Institute of America Prostate Cancer Research Institute
22. ↑ Roy C, Buy X, Lang H, et al. Contrast enhances color Doppler endorectal sonography of the prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure. The Journal of Urology. 2003;170:69-72
23. ↑ ^{23.0 23.1} PCA3: A Genetic Marker of Prostate Cancer,PCRI Insight August, 2003 vol. 6, no. 3 By Alejandra B.Torres and Leonard S.Marks, MD Urological Sciences Research Foundation (USRF) also: David Geffen School of Medicine at UCLA, Department of Urology
24. ↑ Renfer LG, Schow D, Thompson IM, et al.: Is ultrasound guidance necessary for transrectal prostate biopsy? J Urol 154 (4): 1390-1, 1995.PUBMED Abstract
25. ↑ ^{25.0 25.1} Your Feelings: Learning You Have Cancer, National Cancer Institute
26. ↑ ^{26.0 26.1 26.2 26.3} Family Matters, National Cancer Institute
27. ↑ ^{27.0 27.1 27.2 27.3 27.4} How To Find a Doctor or Treatment Facility If You Have Cancer, National Cancer Institute
28. ↑ ^{28.0 28.1} Risk Assessment and Algorith, Partin Tables, Prostate Cancer Research Institute
29. ↑ ^{29.0 29.1 29.2} Stages of Prostate Cancer, National Cancer Institute
30. ↑ Images courtesy of Dr. Peter Choyke, Department of Radiology, Clinical Center, National Institutes of Health.
31. ↑ ^{31.0 31.1 31.2 31.3 31.4 31.5 31.6} Cancer Imaging Program,National Cancer Institute
32. ↑ ^{32.0 32.1 32.2 32.3} Prostate MRUs TOO Prostate Cancer Education and Support
33. ↑ Casciani E, Polettini E, Bertini L, Emiliozzi P, Amini M, Pansadoro V, Gualdi GF (2004). "Prostate cancer: evaluation with endorectal MR imaging and three-dimensional proton MR spectroscopic imaging". Radiol Med (Torino) 108 (5-6): 530-541.PMID 15722999
34. ↑ The Role of Combined MRI & MRSI in Treating Prostate Cancer,Prostate Cancer Research Institute
35. ↑ Kurhanewicz J, Vigneron DB, Hricak H, et al: Prostate cancer: metabolic response to cryosurgery as detected with 3D H-1 MR spectroscopic imaging. Radiology 200:489-96, 1996
36. ↑ Us TOO Prostate Cancer Education and Support
37. ↑ ^{37.0 37.1} Image coutesy of Dr. Jorge Carrasquillo, Nuclear Medicine Department, Clinical Center, National Institutes of Health.
38. ↑ Hofer C, Kubler H, Hartung R, et al. Diagnosis and monitoring of urological tumors using positron emission tomography. Eur Urol 2001; 40(5): 481-487.
39. ↑ ^{39.0 39.1 39.2 39.3 39.4} Update on ProstaScint®: CT and MRI Fusion as Diagnostic Tools,Samuel Kipper, M.D., Pacific Coast Imaging, Irvine, CA,PCRI Insights August 2003 vol. 6, no. 3
40. ↑ Tiguert R, Gheiler EL, Tefilli MV, et al. Lymph node size does not correlate with the presence of prostate cancer metastasis. Urology 1999; 53:367-371.
41. ↑ Ellis RJ, Sodee DB, Spirnak JP, et al. Feasibility and acute toxicity of radioimmunoguided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47: 683-7.
42. ↑ Hamilton RJ, Blend MJ, Pelizzari CA, et al. Using vascular structure for CT_SPECT registration in the pelvis. J Nucl Med 1999; 40: 347-51.
43. ↑ A Strategy Of Success in the Treatment of Prostate Cancer,PCRI Insights July, 2002 vol. 5, no. 1 By Stephen B. Strum, MD, FACP, Prostate Cancer Research Institute
44. ↑ Moul JW, Connelly RR, Perahia B, et al: The contemporary value of pre-treatment prostatic acid phosphatase to predict pathological stage and recurrence in radical prostatectomy cases. J Urol 159:935-40, 1998.
45. ↑ Textbook "A primer on Prostate Cancer",by Stephen B. Strum, M.D. Medical Oncologist for Prostate Cancer and Donna Pogliano
46. ↑ ^{46.0 46.1 46.2} Ploidy Analysis, Prostate Cancer Research Institute
47. ↑ Lerner SE, Blute ML, Bergstrahl EJ, et al: Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. J Urol 156:137-43, 1996.
48. ↑ ^{48.00 48.01 48.02 48.03 48.04 48.05 48.06 48.07 48.08 48.09 48.10 48.11 48.12 48.13 48.14 48.15 48.16 48.17 48.18 48.19 48.20 48.21 48.22 48.23 48.24 48.25 48.26 48.27 48.28 48.29 48.30 48.31 48.32 48.33 48.34 48.35} Treatment OptionsUsTOO Prostate Cancer Education and Support
49. ↑ ^{49.0 49.1 49.2 49.3 49.4 49.5 49.6 49.7 49.8} Treatment Choices for Men with Early-Stage Prostate Cancer, National Cancer Institute
50. ↑ ^{50.0 50.1 50.2} Nerve Sparing Robotic Prostatectomy: A Novel and Minimally Invasive Treatment of Prostate Cancerby Ashutosh Tewari, MD, Director Robotic Oncology and Prostate Cancer Outcomes at Weill Cornell Medical School, New York Presbyterian Hospital, and Mani Menon, MD, Director of Vattikuti Institute of Urology, Henry Ford Hospital, Detroit, MI
51. ↑ The Prostate Cancer Centre
52. ↑ ^{52.0 52.1 52.2 52.3} Radiation Therapy for Cancer: Questions and Answers,National Cancer Institute
53. ↑ ^{53.0 53.1} Three-dimensional conformal radiation therapy delivers a greater radiation dose and may improve management of prostate cancer.,International Journal of Radiation Oncology, Biology, Physics, Vol 41, No 3, pp 491-500, 1998
54. ↑ ^{54.0 54.1 54.2 54.3 54.4 54.5} Targeting For Cure: Intensity Modulated Radiation Therapy, by Lisa M Chaiken, MD and Michael L Steinberg, MD, FACR
55. ↑ ^{55.0 55.1} Zelefsky, M. et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urology166: 876-881, 2001.
56. ↑ ^{56.00 56.01 56.02 56.03 56.04 56.05 56.06 56.07 56.08 56.09 56.10} The National Association for Proton Therapy
57. ↑ ^{57.0 57.1 57.2} High Dose Rate (HDR) Brachytherapy:Very Well Suited for Prostate Cancer, By D. Jeffrey Demanes M.D., FACRO, FACR California Endocurietherapy (CET) Cancer Center Oakland, California
58. ↑ Demanes D, Rodriguez R, Schour L et al High-dose-rate intensity-modulated brachytherapy with external beam radiotherapy for prostate cancer: California Endocurietherapy’s 10-year results. Int. J. Radiat Oncol Biol Phys. 2005; 61: 1306-1316
59. ↑ Demanes D, Altieri G, Brandt D et al. Long term results of high dose rate brachytherapy and external beam with and without androgen suppression for prostate cancer. (Abstr) Int. J. Radiat Oncol Biol Phys. 2005; 63: S38
60. ↑ Yoshioka Y, Nose T, Yoshida K et al High-dose-rate brachytherapy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity. Int. J. Radiat Oncol Biol Phys. 2003; 56: 213-220
61. ↑ Mark R, Paul J, Anderson P et al Interstitial high-dose rate (HDR) brachytherapy for early stage prostate cancer; A report of 193 cases Brachytherapy, Volume 6, Issue 2, April-June 2007, Pages 85-86
62. ↑ Demanes J et al accepted for ASTRO Annual Meeting 2007
63. ↑ Prostate Canvcer Brachytherapy: Clinical and Financial Imperatives for Permanent Implantation, in Oncology Roundtable Annual Meeting. Washington, D.C., The Advisory Board Co., 2000, p 15
64. ↑ ^{64.00 64.01 64.02 64.03 64.04 64.05 64.06 64.07 64.08 64.09 64.10 64.11 64.12 64.13 64.14 64.15 64.16 64.17} Prostate Seed Implantation for Prostate Cancer, By Peter Grimm, D.O., Charles Heaney, Ph.D., John Sylvester, M.D., and John Blasko, M.D. Seattle Prostate Institute
65. ↑ Blasko JC, Ragde H, Luse RW, Sylvester JE, Cavanagh W, Grimm PD: Should brachytherapy be considered a therapeutic option in localized prostate cancer? Urol Clin North Am 1996; 23:633-649
66. ↑ Blasko JC, Ragde H, Grimm PD: Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. Scand J Urol Nephrol Suppl 1991; 137:113-118
67. ↑ Talcott JA, Clark JA, Stark PC, Mitchell SP: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001; 166:494-9.
68. ↑ Wallner K, Lee H, Wasserman S, Dattoli M: Low risk of urinary incontinence following prostate brachytherapy in patients with a prior transurethral prostate resection. Int J Radiat Oncol Biol Phys 1997; 37:565-9
69. ↑ Stone NN, Ratnow ER, Stock RG: Prior transurethral resection does not increase morbidity following real-time ultrasound-guided prostate seed implantation. Techniques in Urology 2000; 6:123-7
70. ↑ Nag S, Beyer D, Friedland J, Grimm P, Nath R: American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789-99
71. ↑ ^{71.0 71.1 71.2 71.3 71.4} A primer on Prostate Cancer. The empowered Patient's Guide. Stephen B. Strum, M.D and Donna Pogliano
72. ↑ ^{72.0 72.1 72.2 72.3 72.4 72.5 72.6} Intermittent Androgen Deprivation, By Stephen B. Strum, M.D
73. ↑ ^{73.0 73.1 73.2 73.3 73.4 73.5 73.6} Hormone Therapy in Prostate Cancer, Stephen B. Strum M.D., Mark C. Scholz M.D., Glenn Tisman M.D.
74. ↑ ^{74.0 74.1 74.2 74.3 74.4 74.5 74.6} The Treatment of Erectile Dysfunction,By Stephen M.Auerbach, MD California Professional Research, Newport Beach, CA
75. ↑ ^{75.0 75.1 75.2 75.3 75.4 75.5 75.6 75.7} United States Package Insert (UPSI) for Sildenafil, Vardenafil, Tadalafil, Food and Drug Administration, 2005
76. ↑ ^{76.0 76.1} Clinical experience of Stephen M. Auerbach, MD
77. ↑ Incontinence Treatment Options for Post-Prostatectomy, by Gary E. Leach, MD, Director, Tower Urology Institute for Continence, Los Angeles
78. ↑ Haab F, Trockman B, Zimmern P, and Leach G: Quality of life and continence assessment of the artificial urinary sphincter in men with minimum 3.5 years of follow up. J. Urology 158:435-439, 1997.
79. ↑ ^{79.00 79.01 79.02 79.03 79.04 79.05 79.06 79.07 79.08 79.09 79.10 79.11 79.12 79.13 79.14 79.15} NCI Drug dictionary webpage
80. ↑ Goldstein, I., Lue, T.F., Padma-Nathan, H., Rosen, R.C., Steers, W.D., and Wicker, P.A.: Oral Sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group, N. England Journal of Medicine, 338: 1397, 1998.
81. ↑ Brock, G, McMahon, C.G., Chen, K.K., Costigan, T., Shen, W., Watkins, V. et al: Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses, J Urology, 168: 1332, 2002.
82. ↑ Stark, S., Sachse, R., Liedl, T., Hensen, J., Rhode, G., Wensing G., et al: Vardenafil increases penile rigidity and tumescence in men with erectile dysfunction after a single oral dose. Eur Urol, 40: 181, 2001