The Farber Center: For Radiation Oncology

The Farber Center would like you to know what prostate cancer is. The prostate is a gland about the size of a walnut located in the pelvis and sits under the bladder and in front of the rectum. The prostate is a single gland, but it has a right and left side, or lobes. The prostate tissue is surrounded by a thin capsule. The purpose of the prostate is to aid in making the seminal fluids, which during ejaculation are used to move the sperm out of the body. Two glands, called seminal vesicles, sit behind the prostate gland and secrete about 60% of the substances that makes up semen. The urethra, which is the tube that carries urine and semen out of the body through the length of the penis, runs through the prostate. Running alongside and attached to the sides of the prostate are the nerves that control erectile function.

Most cases of early prostate cancer are found before symptoms present by screening by testing the amount of prostate-specific antigen (PSA) in the blood. Along with PSA testing another way to find prostate cancer is the digital rectal exam (DRE). Symptoms may include:

• Frequent urination, especially at night (nocturia)
• Inability to urinate or difficulty in starting urination
• Weak or interrupted flow of urine
• Trouble emptying the bladder completely
• Painful or burning urination
• Blood in urine or semen
• Continual pain in the lower back or pelvis

Risk Factors

It is not completely understood why many men develop prostate cancer. Certain risk factors have been shown by researchers to lead to a higher incidence. These include:

• Age: The strongest risk factor for prostate cancer. Prostate cancer is very rare before the age of 40, and the chance of developing prostate cancer increases rapidly after age 50. Approximately 2 out of 3 prostate cancers are found in men over the age of 65.
• Race/Ethnicity: There is a higher incidence of prostate cancer among African-American men. African-American men are also more likely to be diagnosed at an advanced stage, and are more than twice as likely to die of prostate cancer than Caucasian men. Prostate cancer occurs less often in Asian-American and Hispanic/Latino men than in non-Hispanic whites.
• Family history: There is a suggestion that in some cases prostate cancer may be inherited or have a genetic factor as it appears to run in some families. Having a father and/or brother diagnosed with prostate cancer, especially at an early age, increases the risk to more than double.
• Genes: Scientists have found several inherited genes that seem to raise prostate cancer risk. Genetic testing is not yet available for most of these genes.

Testing and Screening
Screening refers to medical testing in people who do not have symptoms of that disease. Prostate cancer can often be found early by testing the amount of prostate-specific antigen (PSA) in the blood. Another way to find prostate cancer is the digital rectal exam (DRE). If the results of either one of these tests are abnormal, further testing is needed to see if there is a cancer. If you have routine yearly exams and either one of these test results becomes abnormal, then any cancer you might have has likely been found at an early, more treatable stage.

Digital Rectal Exam (DRE): The simplest screening test for prostate cancer is the digital rectal exam, or DRE. The physician inserts a gloved, lubricated forefinger into the rectum and examines the prostate gland for any irregularities in size, shape, and texture. The DRE is not a definitive cancer test, but regular exams help the physician detect any changes in the prostate over time that might signal non-cancerous conditions such as benign prostatic hypertrophy (BPH) or pre-cancerous conditions.

PSA Test: Prostate-specific antigen (PSA) is a glycoprotein produced by the epithelial cells of the prostate gland. The amount of PSA circulating in the blood is measured by a simple blood test. A normal range is 0-4 ng/mL , however, a PSA above 2.0 ng/mL in men younger than age 60 may be considered abnormal. Other conditions such as infection or other inflammatory processes of the prostate or benign prostatic hyperplasia (enlarged prostate) can also cause a rise in PSA level. Additional testing to determine the reason for the elevation would be recommended. Additionally, low PSA levels don't always mean there's no cancer present. PSA is not specific to cancer, but rather to prostate tissue.

PSA level is used to assess prostate cancer risk:

PSA Level	Probability of Cancer
0-2 ng/mL	1%
2-4 ng/mL	15%
4-10 ng/mL	25%
10 ng/mL	50%

As with all cancers, early detection is the best hope for a cure. Routine prostate screening including a DRE and PSA test is recommended beginning at age 50 for Caucasian men, and age 45 for African-American men or men with a family history (father, brother, son) of prostate cancer.

Tissue sampling and types of biopsies:

If your doctor or health care provider suspects an abnormality in your prostate he/she may order a variety of tests including:

Prostate Biopsy: A biopsy, or sampling of prostate tissue, is a procedure in which a sample of body tissue is removed and then looked at under a microscope. It is currently the only definitive method of diagnosing prostate cancer. A core needle biopsy is the main method used to diagnose prostate cancer. A biopsy is performed on all men with a strong suspicion of cancer based on PSA test results and other factors.

The process takes about 35 minutes and the biopsy itself takes about 15 minutes to perform. It is done as an outpatient procedure. Biopsies are generally well-tolerated with minimal pain and bleeding.

A transrectal ultrasound (TRUS) probe is inserted into the rectum so that the urologist can view the prostate, and allow for guidance of the needles. The doctor inserts a needle through the wall of the rectum into the prostate gland. When the needle is pulled out it removes a small cylinder of tissue, usually about 1/2-inch long and 1/16-inch across. This fine-gauge, spring-loaded biopsy needle is used to remove six to 10 tiny “core” samples of tissue from specific, predetermined areas on the prostate gland. The biopsy specimens take about three to seven days to process.

Gleason Grading System: Almost all pathologists grade prostate cancers according to the Gleason system. This system assigns a Gleason grading scale which runs from 1 to 5 based on how much the cells in the cancerous tissue look like normal prostate tissue. A grade of 1 represents cells that look much like normal prostate tissue, and 5 represents cells that lack normal features of prostate cells. Grades 2 through 4 have features in between these two values.

Prostate cancers often have areas with different grades, a grade is assigned to the 2 areas that make up most of the cancer. The primary grade refers to the most common cell types found and the secondary cell types are the next most common types found in the tissue sample. Together the sum of these 2 grades are yield the Gleason score (also called the Gleason sum) between 2 and 10.

• Cancers with Gleason scores of 2 to 4 are called well-differentiated or low-grade.
• Cancers with Gleason scores of 5 to 7 are called moderately-differentiated or intermediate-grade.
• Cancers with Gleason scores of 8 to 10 are called poorly-differentiated or high-grade.

The Gleason score tends to predict the aggressiveness of the cancer and how it tends to behave. The higher the Gleason score, the less the cells behave like normal cells, and the more aggressive the tumor tends to be.

• Other elements of a biopsy report from the pathologist to give a better idea of the extent of the cancer can include The number of core biopsy samples containing cancer, the percentage of cancer within each core, and whether the cancer is on one side (left or right) of the prostate or both sides (bilateral).

Two systems are in common use for the staging of prostate cancer. The Jewett system (stages A through D) was described in 1975 and has since been modified. In 1997, the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer adopted a revised tumor, nodes, metastasis (TNM) system that employs the same broad T stage categories as the Jewett system but includes subcategories of T stage, such as a stage to describe patients diagnosed through PSA screening. This revised TNM system is clinically useful and more precisely stratifies newly diagnosed patients. In 2002, the AJCC further revised the TNM classification system. Both staging systems are shown below, and both are used in this summary to discuss treatment options. A thorough review of the controversies of staging in prostate cancer has been published.

TNM Definitions

Primary tumor (T)

• TX: Primary tumor cannot be assessed
• T0: No evidence of primary tumor
• T1: Clinically inapparent tumor not palpable nor visible by imaging
• T1a: Tumor incidental histologic finding in 5% or less of tissue resected
• T1b: Tumor incidental histologic finding in more than 5% of tissue resected
• T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)
• T2: Tumor confined within prostate*
• T2a: Tumor involves 50% or less of one lobe
• T2b: Tumor involves more than 50% of one lobe but not both lobes
• T2c: Tumor involves both lobes
• T3: Tumor extends through the prostate capsule**
• T3a: Extracapsular extension (unilateral or bilateral)
• T3b: Tumor invades seminal vesicle(s)
• T4: Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall

* [Note: Tumor that is found in one or both lobes by needle biopsy but is not palpable or reliably visible by imaging is classified as T1c.]

** Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2 not T3.

Regional lymph nodes (N)

• Regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. They include the following groups (laterality does not affect the N classification): pelvic (not otherwise specified [NOS]), hypogastric, obturator, iliac (i.e., internal, external, or NOS), and sacral (lateral, presacral, promontory [e.g., Gerota], or NOS). Distant lymph nodes are outside the confines of the true pelvis. They can be imaged using ultrasound, CT, MRI, or lymphangiography and include: aortic (para-aortic, periaortic, or lumbar), common iliac, inguinal (deep), superficial inguinal (femoral), supraclavicular, cervical, scalene, and retroperitoneal (NOS) nodes. Although enlarged lymph nodes can occasionally be visualized, because of a stage migration associated with PSA screening, very few patients will be found to have nodal disease, so false-positive and false-negative results are common when imaging tests are employed. In lieu of imaging, risk tables are generally used to determine individual patient risk of nodal involvement. Involvement of distant lymph nodes is classified as M1a.
• NX: Regional lymph nodes were not assessed
• N0: No regional lymph node metastasis
• N1: Metastasis in regional lymph node(s)

Distant metastasis (M)*

• MX: Distant metastasis cannot be assessed (not evaluated by any modality)
• M0: No distant metastasis
• M1: Distant metastasis
• M1a: Nonregional lymph node(s)
• M1b: Bone(s)
• M1c: Other site(s) with or without bone disease

* Note: When more than one site of metastasis is present, the most advanced category (pM1c) is used.

Histopathologic grade (G)

• GX: Grade cannot be assessed
• G1: Well differentiated (slight anaplasia) (Gleason score of 2–4)
• G2: Moderately differentiated (moderate anaplasia) (Gleason score of 5–6)
• G3-4: Poorly differentiated or undifferentiated (marked anaplasia) (Gleason score of 7–10)

AJCC Stage Groupings

Stage I
T1a, N0, M0, G1

Stage II
T1a, N0, M0, G2–4
T1b, N0, M0, any G
T1c, N0, M0, any G
T1, N0, M0, any G
T2, N0, M0, any G

Stage III
T3, N0, M0, any G

Stage IV
T4, N0, M0, any G
Any T, N1, M0, any G
Any T, any N, M1, any G

Jewett Staging System

Stage A
Stage A is clinically undetectable tumor confined to the prostate gland and is an incidental finding at prostatic surgery.

• Substage A1: well differentiated with focal involvement and usually left untreated
• Substage A2: moderately or poorly differentiated or involves multiple foci in the gland

Stage B
Stage B is tumor confined to the prostate gland.

• Substage B0: nonpalpable and PSA detected
• Substage B1: single nodule in one lobe of the prostate
• Substage B2: more extensive involvement of one lobe or involvement of both lobes

Stage C
Stage C is tumor clinically localized to the periprostatic area but extending through the prostatic capsule; seminal vesicles may be involved.

• Substage C1: clinical extracapsular extension
• Substage C2: extracapsular tumor producing bladder outlet or ureteral obstruction

Stage D
Stage D is metastatic disease.

• Substage D0: clinically localized disease (prostate only) but persistently elevated enzymatic serum acid phosphatase titers
• Substage D1: regional lymph nodes only
• Substage D2: distant lymph nodes and metastases to bone or visceral organs
• Substage D3: D2 prostate cancer patients who relapsed after adequate endocrine therapy

ACTIVE SURVEILLANCE
The concept of active surveillance, or watchful waiting, has increasingly emerged in the past years because prostate cancer often grows very slowly, and some men (especially those who are older or have other serious health problems) may never need treatment for their prostate cancer. In this case it is common to watch the patient closely with regular PSA tests and digital rectal exams every 3 to 6 months. Transrectal ultrasound-guided prostate biopsies may be done every year as well. Treatment is started if the cancer seems to be growing or getting worse, based on either a rising PSA, a change in the rectal exam, or biopsy results. Active surveillance allows the patient to be observed for a period of time, only treating those men who have a more aggressive form of the cancer. This allows men with a less serious cancer avoid the side effects of treatment that may not have helped them live longer. A possible downside of this approach is that there's a chance it could allow to become more advanced. This could limit treatment options.

This approach may be recommended if the cancer is not causing any symptoms, is expected to grow very slowly, and is small and contained within one area of the prostate. It is not likely to be a good option if you are young, healthy, and/or have a fast-growing cancer (for example, a high Gleason score). Some men are not comfortable with this approach, and are willing to accept the possible side effects of active treatments in order to try to remove or destroy the cancer.

At this time is not clear how often testing should occur for active surveillance. A large study sponsored by the National Cancer Institute and the Veterans Affairs Cooperative Studies Program is looking into how active treatment affects survival and quality of life of prostate cancer patients of different ages. The PIVOT (Prostatic Intervention Versus Observation Trial) is still ongoing.

SURGERY
to remove the prostate gland (prostatectomy) is an option for some individuals with early stage prostate cancer.

A surgical approach toward the treatment of prostate cancer can be used to remove all or part of the prostate. Typically, men with early-stage disease or cancer that is confined to the prostate may undergo surgical removal of the entire prostate gland plus some surrounding tissue (radical prostatectomy).

Radical Retropubic Prostatectomy: the most common type of prostatectomy. It involves making an incision in the abdomen and removal of the prostate from behind the pubic bone. The urethra is stitched directly to the bladder so urine is able to flow.

Radical Perineal Prostatectomy: performed less frequently today. In this approach, the surgeon makes the incision in the perineum and the prostate is removed from behind.

Nerve-sparing prostatectomy: the surgeon cuts very close to the edges of the prostate. Care is taken to spare the nerves responsible for erections that run alongside the prostate. In cases when the nerves cannot be spared it may be possible to perform a surgical grafting procedure.

Laparoscopic Radical Prostatectomy (LRP): minimal invasive surgery. Very small incisions are made in the abdomen, into which the surgeon inserts narrow instruments fitted with cameras (laparoscope) and/or surgical tools, allowing the surgeon to visualize and operate on the internal structures without cutting open the entire abdomen. Using a robotic interface, the surgeon maneuvers the robot’s arms, which in turn control the cameras and instruments inserted in the abdomen. The surgeons can view the treatment area on a monitor, and the entire prostate is removed.

Side effects of prostatectomy
Possible side effects include urinary incontinence (stress and total), erectile dysfunction (ED) and impotence, and post-operative complications.

RADIATION THERAPY

Stereotactic radiosurgery is a medical procedure that utilizes very accurately targeted, large dose(s) of radiation. This procedure has proven to be an effective alternative to surgery, neurosurgery or conventional radiation for treating many types of tumors / cancer, including lung cancer and prostate cancer. Like CyberKnife Elekta is the only other radiation system to use Monte Carlo based dose calculations. Total treatment time for prostate cancer is under 8 minutes for a 5 day course of therapy at The Farber Center for Radiation Oncology..

External beam radiation therapy involves focusing a beam beam of ionizing radiation to the tumor while sparing the surrounding tissue. It is delivered by a series of painless outpatient treatments over five to nine weeks. Treatments are given Monday through Friday and last less than 30 minutes.

3-Dimensional Conformal Radiotherapy (3D-CRT) is a method of treatment delivery that combines multiple radiation treatment fields using 3-Dimensional computer planning to produce a high-dose area of radiation that conforms to the shape of the area to be treated. This technique allows the tailoring of delivery of precise doses of radiation to the targeted area while sparing surrounding normal healthy tissue.

Intensity modulated radiation therapy (IMRT) is an advanced form of 3D-CRT that modifies the intensity or strength of each radiation beam. It utilizes a sophisticated system of treatment delivery that allows a precise adjustment of the radiation beam intensity to the tissue within the target area while minimizing effects on surrounding tissue. This may allow for a higher dose of radiation to be delivered to the tumor from multiple angles. IMRT is the preferred technique for most prostate cancer patients.

IGRT or Image Guided Radiation Therapy is another technology that can also be used to ensure better targeting of daily radiation treatments. 

Stereotactic body radiation therapy (SBRT) is a specialized form of 3D-CRT that delivers high doses of radiation over a period of five to ten days. Instead of giving small doses of radiation each day for several weeks, SBRT involves delivery of very focused beams of high-dose radiation. Several beams are aimed at the tumor from different angles. In order to precisely target the radiation, a specially designed body frame is used for each treatment. This helps to minimize the movement of the lung tumor during breathing. If it is delivered in a single fraction it is known as stereotactic body radiosurgery. Like other forms of external radiation, these treatments are painless. It can be used for some very early stage (small) cancers when surgery isn't an option usually for other medical reasons. There is emerging data demonstrating the role of SBRT in the treatment of prostate cancer.

Brachytherapy refers to the technique of implanting small radioactive sources directly into the prostate gland. This procedure takes place under anesthesia, usually in the operating room. Brachytherapy is generally used only in men with early stage prostate cancer that is relatively slow growing. There are two methods of delivering this type of radiation to prostate cancer:

Permanent (low dose rate, or LDR) brachytherapy: (seed implantation): In this approach seeds of radioactive material such as iodine-125 or palladium-103 are inserted directly into the prostate gland under ultrasound guidance through thin needles through the perineal skin between the scrotum and the rectum. This is typically performed under spinal or general anesthesia. The needles are removed and the seeds are left in the tissue where the radiation decays over time. Typically anywhere from 40 to 120 seeds are placed. Radiation from the seeds travels a very short distance, so the seeds can put out a very large amount of radiation to a very small area. This decreases the amount of damage done to the healthy tissues that are close to the prostate. This procedure is done in an operating room in the hospital.

Temporary (high dose rate, or HDR) brachytherapy: This newer technique involves placing hollow needles through the perineum into the prostate. Soft nylon catheters or tubes are placed through these needles, which are then removed. The catheters stay in place and are then connected to an HDR delivery unit. This computer driven machine sends a single radioactive source (iridium-192) down each catheter for several seconds. The full treatment time is usually 5 to 15 minutes. The patient will receive two15-minute radiation treatments with a four to six hour interval spent in a comfortable room. This process is typically repeated several days later. The patient is only radioactive while connected to the brachytherapy machine. There is no continuing radioactive exposure in the treatment room or at home. This procedure can be done with local anesthesia in the outpatient setting.

In certain situations both external beam radiation therapy and brachytherapy may be recommended. In this case the external beam radiation dose given is lower, with a shorter treatment course (5 weeks) than if used by itself.

HORMONE THERAPY
is also called androgen deprivation therapy (ADT) or androgen suppression therapy. Often hormone therapy will be used in addition to other treatment. It may consist of a combination of injections and oral tablets. Therapy typically begins at least two months prior to radiotherapy and may be recommended for up to three years depending on the clinical situation.

Hormone therapy may be used in several situations:

• unable to have surgery or radiation or because the cancer has already spread beyond the prostate gland
• if the cancer remains or comes back after treatment with surgery or radiation therapy
• along with radiation therapy as initial treatment depending on the risk for cancer recurrence
• before surgery or radiation to try and shrink the cancer to make other treatments more effective

There are several types of hormone therapy used to treat prostate cancer.

Orchiectomy (surgical castration)

Luteinizing hormone-releasing hormone (LHRH) agonists or analogs: LHRH agonists are used to prevent the testicles from producing testosterone. They are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from every month, every 3 or 4 months, up to once a year. The LHRH agonists typical used in the United States are leuprolide (Lupron) and goserelin (Zoladex).

Antiandrogens: Antiandrogens block the action of androgens in the body. Androgens are hormones that promote male sex characteristics. They are taken daily as pills. The most common antiandrogens include flutamide (Eulexin) and bicalutamide (Casodex). Antiandrogens are not often used by themselves. They may be added if treatment with orchiectomy or an LHRH analog is no longer working by itself. An antiandrogen is sometimes given for a few weeks when an LHRH analog is first started to prevent a tumor flare. Antiandrogen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. This is called combined androgen blockade (CAB).