Prostate Cancer

Anatomy of the male pelvis, genitals, and urinary tract

The prostate:

The prostate is a glandular organ, which a part of the male reproductive system. It is often described as the same size of a walnut, normally about 3 cm long (slightly more than 1 inch); it weighs about 30 g (1 ounce) and is located at the neck of the bladder and in front of the rectum.

The prostate surrounds the urethra, which is a tubular structure that carries the urine (produced by the kidney and stored in the bladder) out of the penis during voiding, and the sperm (produced in the testicle) during ejaculation.

In addition, during ejaculation a thin, milky fluid produced by the prostate is added to the mix. This ejaculate that also includes fluid from the seminal vesicles, constitutes the male semen.

Physiopathology:

In prostate cancer, normal cells undergo a transformation in which they not only grow and multiply without normal controls, but they also change in their microscopic appearance and can invade adjacent tissues. Prostate cancer cells form into malignant tumors or masses, which then overwhelm surrounding tissues by invading their space and taking vital oxygen and nutrients.

Cancer cells from these tumors can eventually invade remote organs via the bloodstream and the lymphatic system.This process of invading and spreading to other organs is called metastasis. Common metastatic locations where prostate cancer cells may eventually be found include pelvic lymph nodes, and bones. The lungs and the liver may also show deposits of, or metastases from, prostate cancer, but that is less common.

Almost all prostate cancers arise from the glandular cells in the prostate. Cancer arising from a glandular cell in any organ in the body is known as adenocarcinoma. Therefore, the most common type of prostate cancer is an adenocarcinoma. The most common non-adenocarcinoma is transitional cell carcinoma. Other rare types include small cell carcinoma and sarcoma of the prostate.

Older men commonly have an enlarged prostate, caused by a benign (noncancerous) condition called benign prostatic hyperplasia (BPH). Prostate gland cells simply keep growing in number in the prostate gland in BPH. BPH can cause urinary symptoms but is not a form of prostate cancer (see BPH).

Epidemiology:

In the U.S., prostate cancer is the most common cancer in men and is the second leading cause of cancer death in men (the first being lung cancer). One man in 7 will be diagnosed with prostate cancer in their lifetime. In many cases it can be a slow moving disease and does not result in death before other natural causes. Only one man in 39 will die of prostate cancer. Some 180,000 new cases of prostate cancer are projected this year and there will be 26,000 deaths due to prostate cancer this year.

This low death rate also suggests that increased public awareness with earlier detection and treatment has begun to affect mortality from this prevalent cancer.

Prostate cancer has seemed to increase in frequency, due in part to the widespread availability of serum prostate specific antigen (PSA) testing. However, the death rate from this disease has shown a steady decline, and currently more than 2 million men in the U.S. are still alive after being diagnosed with prostate cancer at some point in their lives.

The estimated lifetime risk of being diagnosed with the disease is 17.6% for Caucasians and 20.6% for African Americans. The lifetime risk of death from prostate cancer similarly is 2.8% and 4.7%, respectively. Because of these numbers, prostate cancer is likely to impact the lives of a significant proportion of men that are alive today.

Most men with prostate cancer have no symptoms.

• This is particularly true of early prostate cancer. Symptoms usually appear when the tumor causes some degree of urinary blockage at the bladder neck or the urethra.
• The usual symptoms include difficulty in starting and stopping the urinary stream, increase in frequency of urination, and pain while urinating. These symptoms are commonly referred to as “irritative” or “storage” urinary symptoms.
• The urinary stream may be diminished (urinary retention), or it may simply dribble out and a feeling of bladder fullness after urination can appear as well. These symptoms are commonly referred to as “voiding” or “obstructive” urinary symptoms.
• It is noteworthy that these symptoms, by themselves, do not confirm or necessarily reflect the presence of prostate cancer in any single individual. Indeed, most, if not all of these can occur in men with noncancerous (benign) enlargement of the prostate (BPH), which is the more common form of prostate enlargement. However, the occurrence of these symptoms should prompt an evaluation by a physician to rule out cancer and provide appropriate treatment.
• If the cancer causes a chronic (long-term) or more advanced obstruction, the bladder may be affected and be more prone to recurring urinary tract infections(UTI).
• Rare symptoms that may manifest occasionally when the cancer is advanced may include blood in the urine (hematuria), painful ejaculation, and impotence (inability to have an erection).
• If the cancer has spread to remote organs (metastasis) symptoms may include fatigue, malaise, and weight loss. Metastasis to the bones can cause deep bone pain, particularly in the hips and back or even bone fractures from weakening of the bone.

The specific cause of prostate cancer remains unknown. Hormonal, genetic, environmental, and dietary factors are thought to play roles. Yet, the only well-established risk factors for prostate cancer are age, ethnicity, and heredity.

• Age: There is a strong correlation between increasing age and developing prostate cancer. The incidence of prostate cancer increases steadily as men grow older. The median age at diagnosis of prostate cancer is 70.5 years of age. Most prostate cancers are diagnosed in men older than 65 years of age. Autopsy records indicate that a majority of men older than 90 years of age have at least one region of cancer in their prostate.
• Ethnic origin: In the U.S., African American men are more likely than Caucasian men to develop prostate cancer. They are also more likely to die from this disease as compared to Caucasian men of a similar age. Asian Americans, on the other hand, have a much lower chance of getting prostate cancer as compared to Caucasians or African Americans. Internationally, Caucasian men from Scandinavian countries experience the highest rates whereas men from Asia the lowest. Although, these ethnic criteria have been used to study and describe the disease in the past, there is no defined biologic basis for this classification. In other words, these differences in diagnosis and death rates are more likely to reflect a difference in factors like environmental exposure, diet, lifestyle, and health-seeking behavior rather than racial susceptibility to prostate cancer. Recent evidence, however, suggests that this disparity is progressively decreasing with high chances of complete cure in men undergoing treatment for organ-confined prostate cancer (cancer that is limited to within the prostate without spread outside the confines of the prostate gland) irrespective of race.
• Family history: Men who have a history of prostate cancer in their family, especially if it is a first-degree relative such as a father or brother, are at an increased risk of developing prostate cancer. If one first-degree relative has prostate cancer, the risk is at least doubled. If two or more first-degree relatives are affected, the risk increases by 5- to 11-fold.
• Diet: Dietary factors may influence the risk of developing prostate cancer. Specifically, total energy intake (as reflected by body mass index) and dietary fat have been incriminated. In addition, there is some evidence that suggests that obesity leads to an increased risk of having a more aggressive, larger prostate cancer, which results in a poorer outcome after treatment. Nevertheless, the question remains whether there is enough evidence to recommend lifestyle changes specifically to prevent prostate cancer independently of the known health and cardiovascular benefits.
• Infection: Recent evidence has suggested the role of sexually transmitted infections as one of the causative factors for prostate cancer. People who have had sexually transmitted infections are reported as having 1.4 times greater chance of developing the disease compared to the general population.
• Cadmium: Exposure to chemicals such as cadmium may be implicated in the development of prostate cancer.
• Selenium and vitamin E: While initial reports of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements, recent conclusions confirmed that vitamin E not only fails to prevent prostate cancer but actually increases prostate cancer risk. In this study, men who took vitamin E supplement 400 IU per day had a 17% increase in their risk of the disease. Therefore, patients should be advised not to take vitamin E supplement.
• Vitamin C: Vitamin C 500 mg PO every other day did not reduce the incidence of prostate cancer in the Physicians' Health Study-II (PHS II) after a median follows up of 8 years. Therefore vitamin C should not be recommended to prevent prostate cancer.

Factors not associated with prostate cancer:

• Benign prostatic hyperplasia (BPH): Prostate cancer does not appear to be related to benign prostatic hypertrophy (BPH); however, BPH increases the risk of a high PSA, which may lead incidentally to a diagnosis of disease.
• Vasectomy: Vasectomy is not a risk factor for prostate cancer.
• Sexual activity: There is no proven link between frequency of sexual activity and prostate cancer risk.

One should consult a health care professional if any of the following symptoms are present:

• Difficulty initiating and/or stopping a urine stream
• Frequent urination
• Pain on urination
• Pain on ejaculation
• Decreasing speed of urine flow or a urine stream that stops and starts
• A sensation of incomplete emptying of the bladder even after passing urine
• Erectile dysfunction
• Bone pain and/or fractures

One should go to the nearest hospital emergency department without delay if any of the following symptoms occur:

• Urinary tract infection (UTI): Burning pain on urination, urgency, or frequent urination, especially with fever.
• Bladder obstruction: Not urinating or urinating very little despite drinking enough fluid; producing little urine despite straining; pain due to a full bladder.
• Acute kidney failure: Not urinating or urinating little, with little discomfort, despite drinking enough fluid.
• Deep bone pain, especially in the back, hips, or thighs, or bone fracture: Possible sign of advanced prostate cancer that has spread to the bone.
• Spinal cord compression: This occurs when the cancer has spread to vertebrae of the spine and tailbone region. The weakened vertebrae can collapse on the spinal cord. Typical symptoms that might signal acute spinal cord compression include weakness in the legs and difficulty walking, increased difficulty urinating, difficulty controlling the bladder or bowels, and decreased sensation, numbness, or tingling in the groin or legs. These are often preceded by a persistent new central pain in the back lasting a few days or weeks. This condition is a true emergency and requires immediate evaluation in the nearest hospital emergency department. Failure to be treated immediately can result in permanent spinal cord damage with paralysis.

Although currently controversial, most urologists would recommend regular screening for prostate cancer using PSA and DRE in men who are likely to live more than 10 years (for example, life expectancy >10 years).

• Elevated prostate serum antigen (PSA): Although the PSA test is not useful to actually diagnose prostate cancer, it predicts the risk of prostate cancer being present. Currently, most prostate cancers are discovered when a prostate biopsy is performed after a raised serum prostate specific antigen (PSA) blood test is detected. A PSA test is usually performed as a part of a health screening program. However, its use as a screening method is controversial as there is no universally accepted threshold above which the PSA is considered abnormal. Raising the threshold value reduces the number of unnecessary biopsies, but increases the number of cancers that are missed. Lowering the threshold value reduces the number of cancers that are missed, but may lead to the detection of more cancers that will never become clinically significant.
• Abnormal digital rectal exam (DRE): Prostate cancers may be suspected with an abnormal prostate exam detected by digital rectal exam (DRE). A digital rectal exam is part of a thorough regular health examination. During DRE, the examiner inserts a gloved and lubricated finger (“digital” refers to finger) in the rectum to feel the back of the prostate for abnormalities. The exam may reveal asymmetry, swelling, tenderness, nodules, or irregular areas in the prostate. In contrast, symmetric enlargement and firmness of the prostate are more frequently seen in men with benign prostatic hyperplasia (BPH). A suspicious prostate exam prompts the physician to request a prostate biopsy to confirm or rule out the presence of prostate cancer (details regarding PSA and prostate biopsy are available in subsequent sections). This finger exam cannot detect all tumors of the prostate gland. About 25% to 30% of prostate tumors are located in areas of the gland that cannot be felt during digital rectal examination. Prostate cancer is found in approximately 30% of men with suspicious prostate examination.
• Elevated prostate cancer antigen 3 (PCA3): PCA3 is new test that may help to discriminate between cancer-related versus nonspecific PSA elevations. There is not enough data to determine if PCA3 is useful for prostate cancer screening, but it may help to determine the need for biopsy. Measuring PCA3 is done using a urine sample after a prostate massage.

Screening recommendation:

• Screening is used for the detection of prostate cancer in men from the general population with no related symptoms. The purpose of screening is to detect and treat the disease earlier in order to reduce prostate cancer mortality.
• The decision to screen is a shared decision between the patient and the physician.
• The physician should discuss the benefits, risks, and limitations of prostate cancer screening with patients and then offer testing.
• The American Urological Association (AUA) issued their latest guidelines for prostate cancer in 2013. According to these guidelines, men at the age of 55-69 should be offered a baseline serum PSA test and a prostate exam (DRE) to ascertain the risk of prostate cancer. Subsequent screening and tests may be performed according to the findings on this initial evaluation and an individual's risk of getting the disease on the basis of other factors such as race, ethnicity, and family history of prostate cancer. Most urologists currently would advise some form of screening in men with life expectancy greater than 10 years. Most frequently, it would be performed on an annual basis.
• There is no universally accepted age limit after which screening should be stopped. AUA guidelines recommend that the decision on whether to screen in men age >75 years should be made on an individual basis.

Medical interview and physical examination:

A proper medical interview eliciting a thorough medical history and a physical examination are essential in the diagnostic workup of any man in whom prostate cancer is suspected. He may be referred to a physician who specializes in urinary tract diseases (a urologist) or in urinary tract cancers (a urologic oncologist). A man will be asked questions about his medical and surgical history, lifestyle and habits, and any medications he takes. Risk factors including family history of prostate cancer will be assessed (see prostate cancer risk factors).

Digital rectal examination (DRE) is part of the physical examination: All men with firm swelling, asymmetry, or palpable, discrete, firm areas or nodules in the prostate gland require further diagnostic studies to rule out prostate cancer, particularly if they are over the age of 45 or have other risk factors for the disease (see risk factors of prostate cancer).

Because urological symptoms (see prostate cancer symptoms) can indicate a variety of conditions, a man may undergo further testing to pinpoint their cause. Initial screening tests include blood testing for PSA and urine testing for blood or signs of infection.

Prostate specific antigen (PSA):

PSA is an enzyme produced by both normal and abnormal prostate tissues. It may be elevated in noncancerous conditions, such as prostatitis (inflammation of the prostate) and benign prostatic hypertrophy (noncancerous enlargement of the prostate), as well as in cancer of the prostate. Therefore, confirmation of an elevated serum PSA is advisable prior to proceed to prostate biopsy.

PSA values over time may also be more helpful for monitoring recurrence of cancer and the response to treatment than in diagnosing a previously unknown cancer.

The following standards have been set for PSA levels:

• Less than 4 ng/mL: Normal value. The management of men with lower PSA elevations (<4 ng/mL) is less clear since most will have negative biopsies. However, a substantial number of men with prostate cancer do have a serum PSA concentration of less than 4 ng/mL.
• 4 to 10 ng/mL: Prostate biopsy is usually recommended for men with a total serum PSA between 4 to 10 ng/mL, regardless of the digital rectal examination findings, in order to increase the chances of diagnosing disease while it is organ-confined. In men with PSA in this range, approximately one in five biopsies will reveal cancer.
• Greater than 10 ng/mL: Prostate biopsy is strongly recommended. Although the chance of finding prostate cancer is over 50 percent, the benign prostatic disease does produce a marked increase in serum PSA in some men.
• Less than 0.2 ng/mL: After the prostate is surgically removed.

Traditionally, a PSA of 4 ng/mL has been used as a cutoff value for deciding for or against doing a prostate biopsy. However, some experts now recommend lowering that to 2.5 ng/mL and performing the biopsy in men who have levels in excess of this threshold. The American Urological Association guidelines (2009) do not define a definite cutoff point but advise that all the other risk factors for prostate cancer be taken into account while making a decision on whether to proceed for a biopsy. One of the important factors that need to be considered is the rate at which the PSA value has increased over time on repeated measurements (referred to as the PSA velocity).

Based on the symptoms, physical examination, DRE and PSA level, further blood tests may include:

• Complete blood cell count (CBC): The relative amounts of different blood cells are checked. Anemia is a common sequel to cancers, as are certain other blood irregularities.
• Alkaline phosphatase: This enzyme is found in the liver and in bone. It is a sensitive indicator of both liver and bone abnormalities including cancer spread to these areas.
• BUN and creatinine: These measures are used to assess how well the kidneys are working. Levels can be elevated in a number of conditions (such as kidney failure) and may suggest an obstruction or blockage in the urinary system.

When the findings of the physical exam, DRE, and PSA level, suggest that a cancer might be present in the prostate, the diagnosis must be confirmed by biopsy (taking a sample of the tumor). The sample of tumor tissue is then examined by a pathologist, (doctor who specializes in diagnosing diseases by microscopic evaluation) to confirm the presence of cancer.

Main indication for prostate biopsy:

• Suspicious prostate exam with DRE
• Abnormal PSA level
• Abnormal change in PSA or PSA velocity

According to AUA guidelines there is no single threshold value of PSA that should prompt biopsy. Although the decision to take a biopsy is to be based primarily on PSA and DRE, it should take into consideration other factors such as PSA velocity, family history, ethnicity, prior biopsy results, and underlying medical conditions.

Biopsy procedure:

• Prostate biopsy is usually performed in an office as an outpatient procedure. The biopsies are obtained using a needle inserted through the rectum using transrectal ultrasound (TRUS) guidance while the patient is under local anesthesia.
• Local anesthetic is injected around the periphery of the prostate to reduce discomfort associated with prostate biopsy.
• TRUS imaging guides collection of the tissue sample.
• Tissues samples are systematically collected by inserting a needle into the tumor and withdrawing tissue. Typically 10 to 12 pieces of tissue are extracted from different parts of the prostate gland to look for the presence of cancer in the entire prostate.
• Most commonly, in preparation for the procedure, patients are administered a fluoroquinolone antibiotic and given a cleansing enema.
• Major complications, such as bleeding and/or infection requiring hospitalization are rare; however, hematuria (blood in the urine) and hematospermia (blood in the semen) are common sequelae of the procedure.

Pathology biopsy results:

• A pathologist examines biopsy pieces under the microscope to assess the type of cancer present in the prostate and the extent of involvement of the prostate with the tumor. One can also get an idea about the areas of the prostate that are invaded with the tumor by assessing which of the pieces contain the cancer and which of them do not.
• Another very important assessment that the pathologist makes from the specimen is the grade (Gleason score) of the tumor. This indicates how different the cancer cells are from normal prostate tissue.
• Grade gives an indication of how fast a cancer is likely to grow and has very important implications on the treatment plan and the chances of cure after treatment. A Gleason score of 6 generally indicates low grade (less aggressive) disease while that of 8 to 10 suggests high grade (more aggressive) cancer. A grade of 7 is regarded as somewhere in between these two.

If cancer is present on biopsy, workup for metastasis may be indicated. Imaging studies may reveal the size and location of the tumor in the prostate as well as the extent of spread of the disease.

• Chest X-ray film: To detect whether or not cancer has spread to the lungs.
• Technetium Tc 99m bone scan: This test provides an image of the entire skeleton after a mildly radioactive substance is administered into a vein. The radioactive substance highlights areas where the cancer has affected the bones. This test is usually reserved for men with prostate cancer who have deep bone pain or a fracture or who have biopsy findings and high PSA values (>10 to 20 ng/mL) suggestive of advanced (metastatic) or aggressive disease.
• CT scan or MRI of abdomen and pelvis: This is the best way to detect the extent of the primary cancer as well as distant metastases. Pelvic CT or MRI may be considered to assess lymph node metastasis or when PSA >20 ng/mL, Clinical stage T3 to T4, or Gleason score ≥8.
• Endorectal coil MRI: The use of an endorectal probe with MRI can improve spatial resolution and thus better assess the likelihood of seminal vesicle involvement or extension beyond the prostate in men who are thought to have localized prostate cancer.
• Transrectal ultrasonography (TRUS): TRUS can be used to assess the local extension of prostate cancer. Three-dimensional TRUS provides more information about the location and extent of prostate cancer with the prostate gland compared to two-dimensional imaging. However TRUS is not an accurate method for localizing early prostate cancer and is not recommended for use in prostate cancer screening. The primary role of TRUS in prostate cancer detection and diagnosis is to ensure accurate sampling of prostate tissue by prostate biopsies.
• Ultrasound of kidneys, bladder, and prostate: Ultrasonography can be used to look for the effects of a urinary blockage on the kidneys. This is indicated by signs of swelling within the kidney (hydronephrosis) or swelling of the ureters (hydrometers). This study can also be used to assess the bladder for any sign of urinary obstruction due to prostate enlargement by looking at the thickness of the bladder wall and the amount of urine left inside the bladder after passing urine.
• Cystoscopy: This is a test that uses a thin, flexible, lighted tube with a tiny camera on the end that is inserted through the urethra to the bladder. The camera transmits images to a video monitor. This may show whether or not the cancer has spread to the urethra or bladder. This exam doesn't always require general anesthesia.

The primary staging assessment of prostate cancer is usually made by digital rectal examination (DRE), prostate specific antigen (PSA) measurement, and bone scan, supplemented with computed tomography (CT) or magnetic resonance imaging (MRI) and chest X-ray in specific situations.

Staging is a system of classifying tumors by size, location, and extent of spread, local and remote.

Staging is an important part of treatment planning because tumors respond best to different treatments at different stages.

Stage is also a good indicator of prognosis, or the chances of success after treatment.

Clinical staging provides the initial information about the extent of disease that is used to plan therapy. However, clinical staging can underestimate the extent of the tumor, when compared with results based upon pathologic examination of a resection specimen (pathological staging).

Conventional stages of prostate cancer are as follows:

• Stage I (or A): The cancer cannot be felt on digital rectal exam, and there is no evidence that it has spread outside the prostate. These are often found incidentally during surgery for an enlarged prostate.
• Stage II (or B): The tumor is larger than a stage I and can be felt on digital rectal exam. There is no evidence that the cancer has spread outside the prostate. These are usually found on biopsy when a man has an elevated PSA level.
• Stage III (or C): The cancer has invaded other tissues neighboring the prostate.
• Stage IV (or D): The cancer has spread to lymph nodes or to other organs.

Tumor, node, and metastases (TNM) staging:

Most urologists currently use the 2010 TNM (Tumor, Node, Metastases) staging system for prostate cancer. This is based on a combination of three criteria: the extent of the primary tumor (T stage), involvement of lymph nodes by the cancer (N stage), and the presence or absence of spread to distant areas of the body in the form of metastasis (M stage). The TNM 2010 staging system is as follows:

T-staging refers to the size of the tumor and whether it has invaded nearby tissue.

• The first level is the assessment of local tumor stage, where the distinction between intracapsular (T1 to T2) and extraprostatic (T3 to T4) disease has the most profound impact on treatment decisions.
• DRE often underestimates the tumor extension. Two-dimensional or three-dimensional ultrasound can be used to assess T-staging.
• Seminal vesicle biopsies may be used to increase the accuracy of preoperative staging in specific cases.

N-staging refers to the presence of lymph node metastases.

• Assessment should be performed only when the findings will directly influence a treatment decision.
• Current research results indicate that CT and MRI perform similarly in the detection of pelvic lymph node metastases.
• The gold standard for N-staging is operative lymphadenectomy, either by open or laparoscopic technique.
• This is usually achieved through pelvic lymph node dissection (PLND) which is a surgical procedure performed during radical prostatectomy (see section on surgical treatment). The procedure can sometimes be done through laparoscopy as a separate procedure.
• Lymphatic mapping with sentinel lymph node (SLN) biopsy is being studied as an alternative to pelvic LND in men with newly diagnosed prostate cancer. SLN evaluation has the potential to accurately identify patients with node-positive disease, while reducing the extent of surgery.

M-staging refers to the assessment of distant metastases.

• As discussed earlier, prostate cancer usually metastasizes to bone. Consequently, radionuclide bone scan, axial skeleton MRI, and PET have all been used to detect evidence of bone metastases.
• Radionuclide bone scan is the standard test for evaluation of bone metastases; however, it is not offered systematically to all patients. For example, some centers do not offer it to patients with a clinical T2 or lower, a combined Gleason score <6 and a serum PSA <10 ng/mL.
• Axial skeleton MRI is usually used to confirm the possibility of distant disease after a positive or equivocal bone scan. It has not yet replaced the scan as a primary test.
• Positron emission tomography (PET) has limited utility in clinically localized prostate cancer. Cellular uptake of the most commonly used radiotracer (18-F-fluorodeoxyglucose, FDG) is highly variable.

Evaluation of the (primary) tumor ("T"):

• TX: Cannot evaluate the primary tumor.
• T0: No evidence of tumor.
• T1: Tumor present but not detectable clinically or with imaging.
  • T1a: The tumor was incidentally found in less than 5% of prostate tissue resected (for other reasons).
  • T1b: The tumor was incidentally found in greater than 5% of prostate tissue resected.
  • T1c: The tumor was found in a needle biopsy performed due to an elevated serum PSA.
• T2: The tumor can be felt (palpated) on examination but has not spread outside the prostate.
  • T2a: The tumor is in half or less than half of one of the prostate gland's two lobes.
  • T2b: The tumor is in more than half of one lobe but not both.
  • T2c: The tumor is in both lobes.
• T3: The tumor has spread through the prostatic capsule (if it is only part-way through, it is still T2).
  • T3a: The tumor has spread through the capsule on one or both sides.
  • T3b: The tumor has invaded one or both seminal vesicles.
  • T4: The tumor has invaded other nearby structures.

It should be stressed that the designation "T2c" implies a tumor which is palpable in both lobes of the prostate. Tumors which are found to be bilateral on biopsy only but are not palpable bilaterally should not be staged as T2c.

Evaluation of the regional lymph nodes ("N"):

• NX: The regional lymph nodes cannot be evaluated.
• N0: There has been no spread to the regional lymph nodes.
• N1: There has been spread to the regional lymph nodes.

Evaluation of distant metastasis ("M"):

• MX: A distant metastasis cannot be evaluated.
• M0: There is no distant metastasis.
• M1: There is the distant metastasis.
  • M1a: The cancer has spread to lymph nodes beyond the regional ones.
  • M1b: The cancer has spread to bone.
  • M1c: The cancer has spread to other sites (regardless of bone involvement).

Overview

• Treatments for prostate cancer are generally effective in most men. Different treatment options are indicated depending on the severity of the disease.
• Treatment for localized prostate cancer include:
  • Active surveillance
  • Radical prostatectomy
  • Radiation therapy
  • Cryotherapy and HIFU
• Treatment for advanced disease includes:
  • Hormonal therapy
  • Chemotherapy
• A combination of factors defines the severity of the disease or the prognosis (including the chances of dying of the disease).
• Specifically these factors include:
  • Tumor stage, defined by the extent of the disease (localized vs advanced) given by TNM staging.
  • Tumor grade, defined by the pathologists report on the biopsies or surgical specimen given by the Gleason score.
  • PSA value (Prostate Specific Antigen blood test).
• In addition, the therapeutic plan takes into consideration potential benefits vs. side effects of the treatment but also individual factors including the patient's biological -- as opposed to their chronological -- age as well as the presence or absence of comorbidities (other diseases).
• A man's treatment plan should be tailored to his individual case and it may be adjusted according to his expectations, specific needs, and feelings about the different options available.
• It is important that a man understands and discusses his treatment plan with his medical team and specifically with his urologist and/or oncologist (cancer specialist).

Active surveillance is an appropriate management for selected patients with localized disease. This involves monitoring one's cancer to see if it gets worse and how quickly, while not doing anything else to treat it at the present time.

• Often, many PSA-detected prostate cancers are small, well differentiated, and thought to have a relatively low risk of progression. For this reason, many men will receive no active treatment or they will postpone it for some time without significantly decreasing the chance of cure.
• The goal of active surveillance is to avoid treatment-related complications for men whose cancers are not likely to progress while maintaining an opportunity for cure in those who show evidence of progression.
• Active surveillance is a conservative regimen that includes regular visits to the urologist for digital rectal exams, PSA measurements, and, if necessary, imaging tests and/or repeated prostate biopsies to assess if the cancer is becoming more aggressive over time.
• One benefit of active surveillance is that one does not experience the side effects of treatment. On the other hand, symptoms (if any) will continue. In some cases, symptoms can be at least partly relieved with medication.
• Active surveillance is most often used for men who have very early-stage cancers and for men who are not candidates for surgery and other aggressive therapies.
• If the cancer starts to grow, the urologist may recommend treatment.
• Active surveillance should be distinguished from "watchful waiting," which is based upon the premise that some men will not benefit from definitive treatment of localized prostate cancer.
• For patients managed with watchful waiting, the decision is made at the outset to forego definitive treatment and to provide palliative treatment (typically androgen-deprivation therapy) for symptomatic local or metastatic progression.
• Watchful waiting may be an acceptable alternative for elderly men or those with substantial comorbidities.

Radical prostatectomy is the surgical removal of the entire prostate. This operation is indicated for cancer that is limited to the prostate and has not invaded the capsule of the prostate, any other nearby structures or lymph nodes, or distant organs.

• The entire prostate, seminal vesicles, and ampulla of the vas deferens are removed, and the bladder is connected to the membranous urethra to allow free urination.
• Radical prostatectomy is used to treat men with clinically-localized prostate cancer who have a life expectancy of at least 5 years. Although there are not specific or universally accepted age limits for radical prostatectomy, the life expectancy of men above 70 to 75 years of age is low enough that few men in this age range undergo radical prostatectomy.
• Anesthesia for radical prostate surgery has been provided using general, spinal, and epidural approaches; however, most surgeons today prefer regional anesthesia, which has been reported to be associated with less blood loss and a lower risk for pulmonary emboli.
• Complications of this procedure include urinary incontinence and impotence. Newer techniques spare the nerves that controls urination and erection. Of men who undergo these newer techniques, most are continent, and a majority are able to have an erection.
• Radical prostatectomy can be combined with radiation therapy in men with cancer for whom the surgery showed positive margins and which is likely still isolates in the prostate surgical bed. There is an excellent survival rate if cancer has not spread further than this.
• A man should be certain to understand the risks and benefits of this procedure before deciding to go ahead.
• Surgical techniques include open retropubic radical prostatectomy, open perineal radical prostatectomy, and minimally invasive radical prostatectomy (laparoscopic radical prostatectomy and robotic-assisted radical prostatectomy [RARP]).
• Both retropubic and perineal radical prostatectomy techniques are widely used “open” surgical approaches. They both include skin incisions.
• Minimally-invasive techniques have become popular over the past decade and are largely replacing open prostatectomy in most large U.S. centers.
  • Laparoscopic radical prostatectomy: This type of surgery follows the same oncological principles as "open" radical prostatectomy. Rather than a large incision, laparoscopic methods make use of abdominal distention with air that allows a working space using surgical instruments that are introduced through small abdominal incisions.
  • Robot-assisted radical prostatectomy (RARP): This technique gives the surgeon better operative site visualization and more natural hand motions to control the surgical instruments. Currently, many radical prostatectomy surgeries in the U.S. are performed with the help of the da Vinci robotic system. For robot-assisted surgery, five small incisions are made in the abdomen through which the surgeon inserts tube-like instruments, including a small camera. This creates a magnified three-dimensional view of the surgical area. The instruments are attached to a mechanical device, and the surgeon sits at a console and guides the instruments through a viewing device to perform the surgery. The instrument tips can be moved in a variety of ways under the control of the surgeon to achieve greater precision in surgery. So far, studies show that traditional open prostatectomy and robotic prostatectomy have had similar outcomes related to cancer-free survival rates, urinary continence, and sexual function. However, in terms of blood loss during surgery and pain and recovery after the procedure, robotic surgery has been shown to have a significant advantage. Robotic procedures, however, are usually more expensive and the extra cost may not be covered by insurance.
• Quality of life after radical prostatectomy:
  • The complications of most concern to men who undergo these procedures are urinary incontinence and impotence, which are due to operative damage to the urinary sphincter and penile nerves. The frequency of incontinence and erectile dysfunction depends in part upon the experience and expertise of the surgeon.

Transurethral resection of the prostate (TURP) is an alternative to radical prostatectomy.

• Only part of the prostate is removed by an instrument inserted through the urethra.
• An electric current passes through a small wire loop at the end of the instrument. The electrical current cuts away a piece of the prostate.
• This procedure is used to remove tissue that is blocking urine flow in patients with extensive disease or those that are not fit enough to undergo radical prostatectomy. It is not considered a procedure for cure.

The goal of radiotherapy for men with localized prostate cancer is to deliver enough radiation to the tumor while minimizing radiation to adjacent normal tissues.

Two types of radiation therapy are used in prostate cancer -- external beam radiation therapy and brachytherapy. Both are used to treat prostate cancer that has not spread outside the prostate. In terms of survival, radiotherapy appears to achieve similar results as those obtained with radical prostatectomy.

• External-beam radiation therapy (EBRT) involves targeting a beam of high-energy radiation directly at the localized cancer. The radiation beam may include photons or protons today in most cases, depending on the equipment utilized.
• Radiation therapy has also been used to treat cancer in which there has been localized spread of the cancer outside of the prostate in combination with other types of treatment (surgery).
• Side effects of external beam radiation are usually temporary and may include:
  • Skin burning or irritation
  • Hair loss at the area where the radiation beam goes through the skin
  • Severe fatigue
  • Diarrhea
  • Erectile dysfunction
  • Urinary frequency, discomfort at urination, and/or urgency
  • Some studies have shown an increased risk of bladder and rectal cancer with radiotherapy. However, the magnitude of this risk remains small and the risk of dying from a secondary malignancy at 10 to 15 years after treatment is no higher than the perioperative mortality associated with radical prostatectomy.
• Brachytherapy (internal or implanted radiation) is a variation of radiation therapy in which a small radioactive pellet is implanted into the prostate. An imaging technique, such as transurethral ultrasound (TRUS), CT, or MRI, is used to accurately place the radioactive pellets. This provides radiation to a smaller area than external-beam radiation and minimizes exposure of surrounding normal tissue. The pellets provide radioactivity for weeks to months and can simply be left in place once exhausted. In comparison to external beam radiotherapy, this treatment requires only a one-time treatment, rather than the daily therapy required in EBRT.
• The main complications of brachytherapy are:
  • Urinary symptoms including transient urinary frequency, urgency, and discomfort at urination
  • Erectile dysfunction
  • Gastrointestinal symptoms

Chemotherapy is also used against prostate cancer.

• The utility of chemotherapy in the management of metastatic prostate cancer continues as an area of ongoing research.
• This therapeutic option has been explored most in patients with the hormone-resistant disease.

Newer chemotherapy medicines, such as docetaxel (Taxotere), have shown some promise in prolonging the survival of some patients with extensive prostate cancer. They may also decrease the pain related to widespread cancer. However, this comes at the cost of significant side effects that may impact the quality of life.

Symptom palliation: The primary approach to the management of symptoms in patients with advanced prostate cancer is systemic therapy with both older and newer forms of hormonal treatments, then chemotherapy. Today immunotherapy and radioactive isotope treatments may be used. Radiation to painful bone lesions may be used. Throughout all of this, optimal pain medication use and other therapies for cancer-related symptoms should be administered. For patients with castrate-resistant prostate cancer, palliative therapy may be indicated to treat symptomatic bone metastases or symptoms arising from progressive disease.

Besides radical prostatectomy, external beam radiation and/or brachytherapy, cryosurgical ablation of the prostate and high-intensity focused ultrasound (HIFU) have emerged as alternative therapeutic options in patients with clinically localized prostate cancer.

Cryotherapy and high-intensity focused ultrasound (HIFU) has been used to destroy tissue, either by freezing or by generating local thermal energy. These techniques can be applied focally, sub-totally, or to the entire prostate gland. However, the role of these techniques remains uncertain. Potential advantages in men with the localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure. As such, these procedures are associated with minimal blood loss and pain. There is also faster post-treatment convalescence.

Cryotherapy

This technique involves inserting a probe through a small skin incision and freezing areas of cancer in the prostate.

• This therapy is reserved for cancer localized within the prostate as well as for men who are unable to withstand the conventional therapies such as surgery or radiation.
• The probe is guided to areas of cancer by using TRUS. Cancerous tissue appears on the ultrasound and allows the surgeon to monitor therapy and limit damage to normal prostate tissue.
• There are several advantages to using this procedure over surgery and radiation therapy. There is less blood loss, a shorter hospital stay and recovery time, and less pain than with conventional surgery.
• The long-term effectiveness of this procedure is unknown because it is a newer treatment.
• The role of cryotherapy in the management of localized disease remains uncertain. Even among men with low-risk disease, it is not yet clear that results with cryotherapy are equal to those with radical prostatectomy or radiotherapy.

HIFU

• HIFU (high-intensity focused ultrasound) was first developed as a treatment for benign prostatic hyperplasia (BPH) and is now also being used as a procedure for the killing of prostate cancer cells. This procedure utilizes transrectal ultrasound that is highly focused into a small area, creating intense heat of 80° C to 100° C, which is lethal to prostate cancer tissue.
• The published clinical experience with HIFU for this application is limited and the procedure is not yet approved by the FDA for use in the U.S.

Prostate cells are physiologically dependent on male hormones called androgens. Androgens cause hormonal stimulation of the prostate cancer cells causing them to grow, function, and proliferate. Testosterone, although not directly carcinogenic, is essential for the growth and perpetuation of tumor cells. The tests are the source of most androgens. The goal of hormonal therapy is to lower levels of testosterone or to stop testosterone from working. This can be achieved with surgery or with drug treatment. Often, the initial response is good, but cancer may progress over time.

Androgen deprivation therapy: This therapy is likely to be used in cases in which the cancer has spread to distant regions. Therefore, it is not currently used among the standard options for men with localized prostate disease. It may be added to surgery and radiation in cases at high risk for relapse due to high Gleason score and/or positive surgical margins.

• The testes produce much of the testosterone that stimulates cancer growth. Surgical removal of both testicles (castration, or orchiectomy) is the best way to stop hormonal stimulation of the tumor.
• Men usually prefer medical castration to surgical castration as it is temporary and reversible, albeit much more expensive. A variety of agents have been used to suppress androgen levels acting at different levels of hormonal production and release.
  • Nowadays, GnRH agonists are the most widely used. They induce a medical castration by suppressing luteinizing hormone production and, therefore, the synthesis of testicular androgens. A number of GnRH agonists are available (leuprolide, goserelin, buserelin, and triptorelin).
  • GnRH antagonists (degarelix) may be beneficial in cases when immediate decrease in testosterone levels is required.
  • Estrogen, in the form of diethylstilbestrol, can also be used to suppress testosterone. Because of its extensive side effects, estrogen is not used very often.
• Antiandrogen monotherapy: Antiandrogens bind to androgen receptors and competitively inhibit their interaction with male hormones (testosterone and dihydrotestosterone).
  • Unlike medical castration, antiandrogen therapy does not decrease luteinizing hormone (LH) levels and androgen production. Rather, testosterone levels are normal or increased. Thus, men treated with antiandrogen monotherapy do not have the full spectrum of side effects attributable to low levels of testosterone, and many maintain some degree of potency.
  • These agents are usually used in combination with a GnRH agonist either continuously or for 2 to 4 weeks during the initiation of treatment with a GnRH agonist. This is also known as "complete androgen blockade."
  • The most common agents are flutamide (Eulexin), bicalutamide (Casodex) and nilutamide.
• Drugs that stop the adrenal glands from making androgens are sometimes used.
• Side effects of these medications vary. Orchiectomy and LHRH agonists may cause impotence, hot flashes, and loss of sexual desire, osteoporosis, and bone fractures. Antiandrogens may cause nausea, vomiting, diarrhea, and breast enlargement or tenderness. Any of these therapies can weaken bones.

Follow-up care is especially important for patients who opted for a more conservative approach (such as watchful waiting) to treat prostate cancer. It is imperative that a man see his urologist for digital rectal exams, PSA level tests, and other tests as recommended to follow the progression of cancer growth.

For men who have undergone radical prostatectomy, radiation therapy, or both, follow-up care is important to prevent cancer recurrence.

• PSA has been shown to be useful in detecting recurrences. PSA levels should be less than 0.2 ng/mL after radical prostatectomy.
• PSA levels should be checked every 3 months for 1 year, every 6 months for the second year, and annually after that.
• A man should have a physical examination, including digital rectal exam, every 3 months for 1 year, then every 6 months for a year, then yearly after that.
• In certain cases after radical prostatectomy, additional treatment may be required based on the final pathology report of the removed prostate or if the PSA starts increasing after surgery.
• This may be in the form of additional radiation treatment to the area where the prostate once was and/or hormonal treatment with LHRH agonists or antiandrogens as mentioned earlier.

The high lifetime risks of prostate cancer development, the morbidities associated with treatment of established prostate cancer, and the inability to eradicate life-threatening metastatic prostate cancer offer compelling reasons for prostate cancer prevention.

However, because the cause of prostate cancer is uncertain, preventing prostate cancer may not be possible. Certain risk factors, such as age, race, sex, and family history, cannot be changed. Nevertheless, because diet and other lifestyle factors have been implicated as a potential cause, living a healthy lifestyle may afford some protection.

• Proper nutrition, such as limiting intake of foods high in animal fats and increasing the amount of fruits, vegetables, and grains, may help reduce the risk of prostate cancer.
• The following supplements should NOT be used to prevent prostate cancer:
  • Vitamin E
  • Selenium
  • Vitamin C

5-alpha reductase Inhibitors (5-ARI):

• Using 5-ARIs for prostate cancer is controversial.
• Initial studies have shown that finasteride decreased the risk of developing prostate cancer by 25% (Prostate Cancer Prevention Trial). However, initial reports indicated that, while fewer cases of low and intermediate grade prostate cancer did develop resulting in about a 25% lower risk of developing prostate cancer overall, high-grade prostate cancer was more likely to occur in men treated with finasteride. Even though this increased risk with finasteride may be due to a selection bias, there is no proof that finasteride would not increase the true incidence of high-grade cancer.
• In the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, dutasteride decreased the risk of developing Gleason score 5 to 6 cancer but not Gleason 7 to 10 cancer.
• In both trials 5-ARIs increased the risk of erectile dysfunction and loss of libido.
• Although it is possible that 5-ARIs reduced the risk of being diagnosed with prostate cancer, it is unknown if this will translate into reduced mortality.
• 5-ARIs are not FDA approved for the prevention of prostate cancer.

The prognosis in prostate cancer depends on the stage of the cancer and the degree of differentiation.

• Differentiation refers to how closely the cancer resembles normal tissue. This is assessed by calculating the Gleason score as mentioned earlier. The less differentiated the cancer, the poorer the prognosis.
• The stage refers to the extent of the cancer -- whether it is localized or has spread beyond the prostate. The greater the degree of cancer spread, the poorer the outlook.

5-year survival rates are very good for men with prostate cancer.

• According to the American Cancer Society, most men with these cancers survive at least 5 years.
• Most prostate cancers are slow growing, as shown by the fact that a majority of men with prostate cancer survive at least 10 years.
• Sometimes, however, prostate cancers grow and spread rapidly. Therefore, early diagnosis is essential for a cure.

If a man is elderly and has other medical conditions, watchful waiting may be the most prudent course.

• Therapy may be more harmful than the cancer.
• This is especially true if a man's life expectancy is less than 10 years.
• Many times, elderly men with prostate cancer actually die of something else, such as heart disease, not the slow-growing prostate cancer.

A man and his family members should discuss this with his urologist.

Living with cancer presents many new challenges for a man and for his family and friends.

• A man will probably have many worries about how the cancer will affect him and his ability to live a normal life, that is, to care for his family and home, to hold his job, and to continue the friendships and activities he enjoys.
• Many people feel anxious and depressed. Some people feel angry and resentful; others feel helpless and defeated.

For most people with cancer, talking about their feelings and concerns helps.

• Friends and family members can be very supportive. They may be hesitant to offer support until they see how the man with cancer is coping. Don't wait for them to bring it up. If one wants to talk about their concerns, let them know.
• Some people don't want to burden their loved ones or prefer talking about their concerns with a more neutral professional. A social worker, counselor, or member of the clergy can be helpful if a man wants to discuss his feelings and concerns about having cancer. A urologist or oncologist should be able to recommend someone.
• Many people with cancer are profoundly helped by talking to other people who have cancer. Sharing one's concerns with others who have been through the same thing can be remarkably reassuring. Support groups of people with cancer may be available through the medical center where one receives treatment. The American Cancer Society also has information about support groups all over the U.S.