Advanced Prostate Cancer and suggested Treatments

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Patient information: Advanced prostate cancer

Author
Nancy A Dawson, MD
Section Editors
Nicholas Vogelzang, MD
W Robert Lee, MD, MS, MEd
Jerome P Richie, MD, FACS
Deputy Editors
Leah K Moynihan, RNC, MSN
Michael E Ross, MD

Last literature review version 16.3: October 2008 | This topic last updated: January 23, 2008 (More)
INTRODUCTION — Over the last 20 years, more cases of prostate cancer have been detected in the early stages, when it is confined to the prostate gland. Prostate cancer that is confined within the prostate gland can be effectively treated and is often cured (show figure 1).

However, approximately 15 to 20 percent of newly diagnosed prostate cancers are advanced by the time they are detected, meaning that the cancer has spread outside the prostate gland (called locally advanced prostate cancer) and/or involved the lymph nodes or other organs (called metastatic prostate cancer).

Cases of advanced prostate cancer can also occur in men who are initially treated for localized disease and whose prostate cancer then recurs (commonly referred to as a relapse). Following treatment of early stage prostate cancer, men are routinely monitored with blood PSA levels. A rising PSA level suggests that prostate cancer has returned (termed a recurrence). Often, there is no evidence of metastatic cancer in the bones or other tissues at the time the PSA is rising, and the rising PSA is the only sign that the prostate cancer has recurred.

These men represent a unique category of advanced prostate cancer for two reasons:

The average time it takes for signs of more advanced disease to appear (eg, bone metastases) may be as long as eight years. In some men, there will never be symptoms of advanced disease. Despite this fact, many men are uncomfortable with an untreated rising blood PSA, and treatment is often considered, even if symptoms or signs of advanced disease are absent.
Some men with a rising PSA as the only sign of disease recurrence may be curable with further local therapy (ie, radiation, surgery, or cryotherapy [freezing of the prostate gland]). Men who have the best chance of long-term control of the prostate cancer with local-only therapy are those who have less aggressive cancers (ie, lower Gleason grade and lower blood PSA level), and a slowly rising PSA level. (See "Salvage local therapy for a rising PSA after surgery or radiation" below).
This topic review will discuss the treatment of men with advanced prostate cancer. A separate topic review is available about the treatment of early stage prostate cancer. (See "Patient information: Early prostate cancer treatment").

STAGING OF PROSTATE CANCER — Treatment for prostate cancer depends upon its "stage", which indicates how far the cancer has spread within the body. Prostate cancer is usually staged according to the system known as TNM (tumor, node, metastasis), in which the cancer is characterized by its extent within the prostate gland itself (tumor or T stage), whether the lymph nodes in the region are involved with cancer (node or N stage), and whether the cancer has metastasized to other parts of the body (metastasis or M stage, show table 1). A full discussion of the diagnosis and staging of prostate cancer is available separately. (See "Patient information: Prostate cancer diagnosis and staging").

Various combinations of T, N, and M stage are grouped together to form stage groupings, from I to IV, which designate whether the cancer is considered localized (stage I and II), locally advanced (stage III), or metastatic (stage IV) (show table 2).

T3 and T4 tumors that lack involvement of lymph nodes or distant organs are considered locally advanced, meaning that although the cancer is outside of the prostate gland, it has not extended beyond the tissues adjacent to the original tumor. On the other hand, metastatic (stage IV) prostate cancer has spread beyond the prostate to either the lymph nodes or to other organs or the bones.

TREATMENT OF METASTATIC (STAGE IV) PROSTATE CANCER — When cancer has spread beyond the prostate gland, androgen deprivation therapy (ADT) is usually recommended as the initial treatment. Metastatic prostate cancer is not considered a curable condition. However, treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life.

Initial androgen deprivation therapy — The rationale for using ADT for advanced prostate cancer is that male hormones (androgens such as testosterone) promote or stimulate tumor growth. When deprived of male hormones, the cancerous cells of the prostate gland (as well as normal cells) die and the prostate gland shrinks in size. ADT is effective against cancer cells within the prostate gland and for any cancer cells that may have spread outside of the prostate.

There are several ways in which ADT can be accomplished:

Orchiectomy — ADT can be accomplished by removing the testicles, where most of the body's androgens are produced (this operation is called an orchiectomy). The penis and scrotum (skin pouch in which the testicles are located) remain intact.

GnRH agonists — An alternate way to accomplish ADT is to take a medication that disrupts androgen production in the body. These drugs work by interfering with gonadotropin releasing hormone (GnRH), which is the chemical that regulates the amount of androgen that a man's testicles make under normal conditions. Drugs in this class include leuprolide (Lupron®) and goserelin (Zoladex®). These are given by injection.

Guidelines for treatment of men with advanced prostate cancer from the American Society of Clinical Oncology (ASCO) recommend either orchiectomy or a GnRH agonist as the initial form of hormone therapy [1]. GnRH agonists and orchiectomy are similarly effective in men with advanced prostate cancer, and they share a similar side effect profile (see "Side effects of ADT" below). However, there are some differences which may influence an individual man's choice of one or the other.

GnRH agonist therapy requires repeated physician visits for an injection every 3 to 6 months. For men without health insurance prescription drug coverage, GnRH agonist therapy can be expensive.
Orchiectomy is a one-time surgical procedure.
Combined androgen blockade (CAB) — Sometimes, a GnRH agonist or orchiectomy may be combined with drug of a different class called an antiandrogen. Examples include flutamide (Eulexin®) and bicalutamide (Casodex®). Antiandrogens take over the cell receptors that usually respond to androgens and prevent the body from using its own androgens. Antiandrogens alone are not considered a form of ADT because they do not lower the body's production of androgens.

While they are rarely used alone (see "Antiandrogen monotherapy" below), antiandrogens are often combined with a GnRH agonist or orchiectomy. Combined therapy is referred to as "combined androgen blockade", or CAB. Whether CAB provides better control of prostate cancer growth than either a GnRH alone or orchiectomy is controversial. Although CAB may slightly increase the likelihood that man with metastatic prostate cancer will still be alive in five years (by approximately 1 to 5 percent), there are also more treatment-related side effects, and the cost is much higher compared to single agent therapy. ASCO guidelines do not specifically recommend CAB over orchiectomy or a GnRH analog, but they suggest that this approach be considered [1]. (See "Side effects of ADT" below).

Timing of ADT — A major controversy for men with metastatic prostate cancer (particularly those with only a rising PSA and no other evidence of advanced disease) is the optimal timing of ADT. ADT can be started immediately (early ADT) or delayed until symptoms develop or there are obvious signs of tumor involvement in distant organs (metastases, most commonly involving the bones).

Many doctors recommend starting treatment at the time of diagnosis in the hope of delaying disease progression and possibly prolonging survival. Others have argued that early ADT is not curative and is associated with bothersome side effects, and that treatment is best delayed until symptoms develop.

Some research results suggest that earlier ADT decreases the likelihood of dying from prostate cancer and delays the onset of symptoms [2,3]. Neither of these studies was performed in men with a rising blood PSA as the only evidence of disease recurrence:

In one trial, a higher proportion of men found to have lymph node involvement at the time of prostatectomy who received early ADT remained progression-free (77 versus 18 percent) and fewer died of prostate cancer (4 versus 31 percent) compared to those who were treated at a later time [2].
In the second study, which included men with locally advanced prostate cancer and those with metastatic disease (although without any symptoms from tumor involvement at any site), those undergoing early ADT had fewer complications related to prostate cancer (eg, painful bone metastases) [3]. However, the likelihood of surviving the prostate cancer was significantly better only for the group of men with nonmetastatic (ie, locally advanced) disease, and not for those with metastatic disease.
The only available data in men with a rising PSA as the only sign of advanced disease come from a review of 804 men with a rising PSA after radical prostatectomy [4]. Men who received early ADT survived just as long as those treated at the time when metastases became evident, although the time to develop metastases was longer for the men who received early ADT

Although controversial, many doctors suggest early treatment for the following reasons:

It is associated with less disease progression and fewer complications of untreated disease (eg, urinary obstruction, painful bone metastases)
There is a possible survival benefit, particularly in men with minimal disease.
Many men are uncomfortable with delaying treatment, particularly if the PSA continues to rise.
Men should discuss the relative benefits and risks of early versus delayed ADT with their physician.

Duration of benefit of ADT — Most men with advanced prostate cancer initially respond well to ADT, but most have prostate cancer recurrence within two years. At this point, the cancer is termed androgen-resistant, meaning that ADT alone is no longer effective. Once this occurs, secondary hormone therapy is usually considered. Even when prostate cancer becomes resistant, some form of ADT is usually continued because at least a portion of the cancer cells may still be responsive to removing the influence of androgens (see "Secondary hormone therapy" below).

Side effects of ADT — Side effects from ADT are related to the lower levels of androgens in a man's body, and include decreased libido (interest in sex), impotence (ability to have an erection sufficient for sexual intercourse), hot flashes, and temporary enlargement of the breast tissue. (See "Patient information: Sexual problems in men"). A decrease in the size of the penis and/or testicles is a common side effect of ADT and hair (body and head) often becomes thinned.

ADT can also lead to a reduction in muscle and bone strength; loss of bone can lead to osteoporosis (thinning of the bones), and bone fractures.

Treating side effects of ADT — A number of treatments are available to decrease the side effects of ADT.

Most experts recommend that all men beginning ADT increase their calcium intake to 1200 to 1500 mg daily, take a vitamin D supplement, and undergo a screening test for osteoporosis. (See "Patient information: Calcium and Vitamin D for bone health" and see "Patient information: Osteoporosis causes, diagnosis, and screening"). Although some studies show that regular injections of a bisphosphonate medication (eg, zoledronic acid, Zometa®) can prevent bone loss during long-term ADT [5], the best time to begin this therapy is controversial.
Regular exercise may delay the loss of lean muscle and decrease replacement of muscle with fat.
Treatments for hot flashes include hormonal medications such as estrogen or progesterone, antidepressant medications (selective serotonin reuptake inhibitors or SSRIs), or an antiepileptic drug (gabapentin). Each of these treatments has risks and benefits that must be considered individually.
For men receiving treatment with an antiandrogen alone, preventive radiation therapy to the chest can help to prevent swelling of breast tissue. Preventive radiation treatment is not usually recommended for men who undergo orchiectomy or for those who take other forms of hormone therapy.
Loss of libido and difficulty maintaining an erection may be less of a problem with alternate treatment regimens (see "Alternatives to conventional ADT" below).
Alternatives to conventional ADT — Some men find that the side effects of ADT (particularly impotence, hot flashes and fatigue) significantly affect their quality of life. As a result, attempts have been made to find alternative hormone therapies that have fewer side effects. Many of these have been studied in men whose only evidence of advanced disease is a rising PSA.

Intermittent ADT — Intermittent ADT (called IAD) is given over a period of time and then stopped temporarily. It is a controversial alternative to continuous ADT. The main benefit is that some men have an improved sense of well-being and a return of libido and sexual ability (if these were present prior to treatment) while ADT is stopped.

Typically, IAD (with or without an antiandrogen) is continued until a maximal response is achieved (usually a predetermined, low value of blood PSA), stopped, then restarted when the blood PSA rises to a predetermined threshold (eg, 10 to 20 ng/mL).

Men receiving IAD can expect to spend approximately 35 to 50 percent of their time off-therapy. Time off treatment in the first cycle ranges from 6 to 15 months, and may be longer for men with less advanced disease compared to those with metastatic disease. Time off therapy decreases with each consecutive cycle [6].

The impact of this approach on long-term outcomes, particularly survival, is not yet known. The ASCO expert panel concluded that there was insufficient evidence to support the use of intermittent as compared to continuous ADT [1]. Some experts consider a temporary discontinuation of treatment if the blood PSA level becomes undetectable during initial ADT, and if side effects (usually hot flashes) are significant. However, a man who chooses IAD must understand that his survival may be reduced; further study is needed. Men who are interested in IAD are encouraged to enroll in a clinical trial testing the benefit of IAD versus conventional ADT. (See "Clinical trials" below).

Antiandrogen monotherapy — As noted above, antiandrogens alone are not considered a form of ADT because they do not lower the body's production of androgens. In addition, their effectiveness as a single therapy for advanced prostate cancer is controversial. However, antiandrogens alone are attractive as a treatment option for men with minimally advanced disease (eg, only a rising PSA after local therapy) because they can be given orally, and they are associated with a better quality of life during therapy than other forms of hormone therapy because they cause fewer problems with sexual dysfunction and loss of bone mass.

ASCO guidelines suggest that single antiandrogen therapy is discussed, but the guidelines do not specifically recommend this strategy over conventional methods of ADT (such as orchiectomy or a GnRH agonist) [1].

Oral sequential hormone therapy — Peripheral or sequential androgen blockade involves the use of an oral anti-androgen (usually flutamide or bicalutamide) combined with another oral drug that blocks the conversion of testosterone to dihydrotestosterone. Such drugs are called 5-alpha reductase inhibitors. Most studies have used finasteride (Proscar@), although dutasteride (Avodart@) is also available.

Although early studies of this regimen show promising results, long-term follow-up is lacking and the impact on survival is unknown. Furthermore, oral hormone therapy is associated with a high frequency of painful and progressive enlargement of breast tissue. This problem can be prevented with radiation therapy to the breasts prior to starting treatment. However, if breast enlargement develops, surgery may be required to remove excessive tissue. (See "Managing the side effects of androgen deprivation therapy").

Secondary hormone therapy — When advanced prostate cancer becomes androgen-resistant, other hormone treatments may be tried. Current guidelines recommend that for men receiving combined androgen blockade (CAB), that the first approach should be to discontinue the antiandrogen (flutamide, nilutamide, bicalutamide). Research shows that withdrawal of antiandrogen therapy may improve symptoms of the disease and temporarily lower the PSA level.

Another approach for androgen-resistant prostate cancer in men receiving CAB is to try a different type of antiandrogen. Cancer that is resistant to one antiandrogen treatment may not be resistant to another. There are two groups of antiandrogens, the steroidal antiandrogens and the nonsteroidal or "pure" antiandrogens. Steroidal antiandrogens include cyproterone acetate and megestrol acetate. Nonsteroidal antiandrogens include flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®). All of these drugs block androgen receptors and alter the levels of other hormones in the body, eventually lowering the high testosterone levels that contribute to the growth of prostate cancer.

Other drugs that function to block the activity of androgen in the body can also be used to treat androgen-resistant prostate cancer, including estrogens, steroids (eg, dexamethasone [Decadron®] or prednisone, or the antifungal medication ketoconazole).

Chemotherapy — Eventually, even with secondary hormone treatment, nearly all men with advanced prostate cancer stop responding to all forms of hormone treatment. This situation is referred to as hormone-refractory prostate cancer (HRPC). The next step in treatment is determined by an individual's characteristics and preferences, and often includes chemotherapy.

Docetaxel — In the past, chemotherapy was considered ineffective in treating prostate cancer, but newer research suggests that this is not necessarily true. The most active newer chemotherapy regimens are those that include the drug docetaxel. Several trials have confirmed that docetaxel-containing regimens are associated with significantly longer survival compared to other regimens [7,8].

Because of these data, most experts consider docetaxel plus prednisone to be the standard chemotherapy regimen for first-line treatment of men with HRPC [9]. Docataxel is usually given into a vein every three weeks and prednisone is taken by mouth every day.

Satraplatin — Satraplatin is an oral chemotherapy drug that is being developed as a second-line treatment for men whose tumors are no longer responding to hormone therapy or the first-line chemotherapy treatment. In one study, the addition of satraplatin to a steroid drug (prednisone) reduced the risk of disease progression by more than 30 percent compared to prednisone alone [10].

Satraplatin is not yet available commercially. It is currently available only by participating in a clinical trial (www.clinicaltrials.gov/ct/search?term=satraplatin).

SALVAGE LOCAL THERAPY FOR A RISING PSA AFTER SURGERY OR RADIATION — As noted above, some men with a rising PSA as the only sign of disease recurrence may be curable with further local therapy. Men who have the best chance of long-term control of the prostate cancer with local-only therapy are those who have less aggressive cancers (ie, lower Gleason grade and lower PSA level), and a slowly rising PSA level.

The best treatment for this situation depends upon a number of factors.

Salvage radiation — Some men who initially had prostate surgery may be successfully treated with radiation therapy, as long as EBRT was not given immediately after surgery. The best candidates for this approach are men who meet all of the following criteria:

A positive surgical margin, and/or Gleason score <8, and no evidence of lymph node involvement at the time of initial prostatectomy
A low PSA (optimally &#8804;1.5 ng/mL) at the time of recurrence
At least one year elapsed between the surgery and the rise in PSA
For men who had unfavorable risk factors at the time of radical prostatectomy (eg, PSA >10 ng/mL, Gleason score &#8805;8, T2b disease, show table 1), or if the post-prostatectomy PSA doubling time is &#8804;10 months, short-term androgen deprivation therapy (two months before and during salvage EBRT) may be recommended.

Men who do not meet these criteria are usually offered hormone therapy alone without radiation therapy (see "Androgen deprivation therapy" below).

Salvage brachytherapy — Men who were initially treated with radiation therapy have several treatment options, including salvage prostatectomy, salvage cryotherapy, and salvage brachytherapy. EBRT is not usually recommended if it was given previously due to the high risk of radiation-related side effects. Brachytherapy is described in detail below (see "Brachytherapy plus EBRT" below).

However, the side effects of salvage brachytherapy can be significant, and may include gastrointestinal or urinary complications or the need for a temporary colostomy (to empty the bowels through the abdomen into a bag) or urostomy (to empty the bladder through the abdomen into a bag).

Salvage prostatectomy — Selected men with a rising PSA following radiation therapy for a localized prostate cancer may be able to undergo prostatectomy (termed "salvage" prostatectomy). However, salvage prostatectomy can be associated with serious side effects, and all men are not good candidates.

Optimal candidates are men who are unlikely to have tumor spread outside the prostate, have a life expectancy of at least 10 years, and who had a Gleason score &#8804;6, a pretreatment serum PSA <10 ng/mL, and T1c or T2a tumor stage at initial diagnosis. At the time when the recurrence is found, similar conditions should also be met (ideally, with a serum PSA <4.0 ng/mL).

Men at the highest risk for having disease outside of the prostate include those with a rapid PSA doubling time (particularly less than three to six months), high Gleason score tumors, and a short interval between the original treatment and the time when the PSA begins to rise again; these men are not good candidates for salvage prostatectomy. These men may be offered cryotherapy or androgen deprivation therapy.

Cryotherapy — Cryotherapy is sometimes recommended for men who have a rising PSA after EBRT, and who meet the criteria for salvage prostatectomy, but have more advanced tumor in the region of the prostate (ie, T3 disease, show table 1) at the time of initial diagnosis or recurrence.

Androgen deprivation therapy — For men who are not suitable candidates for local therapy because they have metastases, a short PSA doubling time (&#8804;3 months), significant underlying medical illness, or an unfavorable balance of risks and benefits for definitive salvage therapy, traditional androgen deprivation therapy (ADT) is usually the treatment of choice. The general aspects of ADT are discussed in detail above (see "Androgen deprivation therapy" above).

TREATMENT FOR LOCALLY ADVANCED CANCERS — Experts are not in complete agreement about the best way to manage locally advanced prostate cancer (most often T3 tumors; T4 disease is rare); treatment options include:

External beam radiation treatment (EBRT) with or without brachytherapy (see "Radiation therapy" below).
Transurethral resection of the prostate (TURP), a conservative type of surgery that aims only to relieve obstruction to the urine flow that is caused by the tumor
Radical prostatectomy, in which the entire prostate gland is removed surgically in an attempt to provide a cure
Hormone therapy that eliminates the effect of male hormones (androgens such as testosterone) on the growth of the prostate cancer cells. The term "hormone therapy" refers to any treatment that decreases the amount of androgens in a man's body or prevents the body (particularly the prostate cells) from responding to them. More commonly used terms for this type of therapy are androgen ablation or androgen deprivation therapy (ADT).
ADT alone is not a common form of therapy for men with locally advanced prostate cancer. However, it is often used in combination with radiation therapy, which is the most commonly recommended approach for men with locally advanced prostate cancer. Prostatectomy may be a reasonable option for young, otherwise healthy men. Your doctor will take into account your age, general health, and the particular characteristics of your cancer when making a treatment recommendation.

As noted above, antiandrogen therapy is rarely used alone (ie, without a GnRH antagonist) in men with locally advanced prostate cancer. ADT is not as effective as radiation or surgery for local tumor control, and there is a high risk of developing urinary obstruction from an enlarging prostatic tumor if ADT is used alone.

Radiation therapy — There are two forms of radiation therapy used to treat prostate cancer: external beam radiation therapy (EBRT) and brachytherapy (also called interstitial implantation).

External beam radiation therapy — The majority of men with locally advanced prostate cancer are treated with EBRT, usually in conjunction with ADT (see "ADT plus EBRT" below). EBRT uses an accelerator, which makes x-rays and then delivers radiation to the area of the prostate and pelvis (where the regional lymph nodes are located) from outside of the patient. The level or dose of EBRT that is directed to the prostate is important; higher doses may give better results.

EBRT does not require hospitalization and men can usually continue with normal activities during the course of treatment, typically administered once daily for approximately eight weeks. Although the radiation therapist attempts to limit the amount of radiation that hits healthy tissue, this is difficult; noncancerous tissue around the prostate (such as the rectum or bladder) may be damaged during treatment.

The most precise way to give higher doses of EBRT to the prostate uses a method called intensity modulated radiation therapy or IMRT. This technique uses sophisticated computer modeling to precisely outline the tumor, allowing larger doses of radiation to be delivered precisely to the tumor while minimizing damage to surrounding normal tissues. This technique is more expensive than conventional EBRT, and is not available in all radiation treatment facilities. Although it has not yet been proven to be more effective at controlling prostate cancer, IMRT is associated with fewer side effects, particularly bowel problems.

Side effects of EBRT — Side effects of EBRT can include urinary urgency, frequency, bladder pain, bowel problems, sexual impotence (inability to have an erection sufficient for intercourse), and proctitis (inflammation of the rectum, resulting in rectal pain or bleeding). Compared to men undergoing radical prostatectomy for prostate cancer, urinary problems tend to be less common after EBRT, but bowel problems such as diarrhea, bowel urgency, and painful hemorrhoids may be more common.

ADT plus EBRT — Most men who have EBRT for locally advanced prostate cancer are also given androgen deprivation therapy (ADT). The benefits of combined therapy include better control of disease within the prostate, better control throughout the rest of the body, and improved survival [11]. Most experts recommend treatment with ADT for at least two years after the radiation therapy is completed [8].

Brachytherapy plus EBRT — Brachytherapy is a several hour-long procedure done in the hospital. Brachytherapy is given after the man receives anesthesia, and involves placement of a radioactive source directly into the prostate gland with ultrasound guidance. There are two types: low-dose-rate (LDR) brachytherapy implants many radioactive seeds or pellets (each about the size of a grain of rice) into the prostate. These emit radiation within the gland for a specified period of time and then become inactive. This type of brachytherapy is most commonly used for men with earlier stage disease. This procedure rarely requires an overnight stay in the hospital.

In contrast, men with locally advanced prostate cancer are more likely to be offered high-dose rate (HDR) brachytherapy. This typically requires general anesthesia and an overnight hospital stay. With HDR brachytherapy, a catheter or needle is inserted into the prostate temporarily to deliver radiation to the prostate gland for a period of several hours. HDR brachytherapy is not considered effective in treating locally advanced prostate cancer when used alone; it must be combined with EBRT.

Whether combining HDR brachytherapy with EBRT (with or without ADT) is better than treating a man with optimal doses of EBRT plus ADT is controversial. Although combined brachytherapy plus EBRT has the advantage of a shorter course of EBRT (4 to 5 weeks versus 8.5 weeks if EBRT is given without brachytherapy), it is also more likely to cause urinary side effects.

Side effects of brachytherapy — Complications of brachytherapy are predominantly urinary. Men who undergo this treatment may experience inflammation and swelling of the prostate gland, which can cause an inability to pass urine (urinary retention). Thus, men with a very large prostate gland (particularly those with significant urinary symptoms or a high "urinary symptom score", show table 2) are not good candidates for brachytherapy.

Surgery

Transurethral resection of the prostate — Commonly referred to as a TURP, this form of surgery involves removal of a part of the prostate gland by inserting thin instruments into the urethral canal of the penis. This procedure can prevent the prostate tumor from growing for a time, and helps relieve the blockage of urine flow caused by the tumor. However, this provides only a temporary fix, and studies show that TURP is not as effective over the long-term compared to radical prostatectomy.

Radical prostatectomy — Radical prostatectomy refers to complete surgical removal of the prostate gland. Although this treatment option is widely used in cases of early prostate cancer, it is not used as often for men with locally advanced prostate cancer for two reasons: it is more difficult to remove all the cancer, and it is more likely that the cancer has already spread to the lymph nodes or other tissues. If this happens, the chance of radical surgery curing the cancer is extremely low.

Nonetheless, in selected healthy men with locally advanced prostate cancer, radical prostatectomy may be an appropriate option. In one of the largest studies to date, 842 men with locally advanced prostate cancer underwent prostatectomy; two thirds were still alive without evidence of spread of their prostate cancer at 15 years, although more than one-half had a rising PSA [11]. This is an early indicator of cancer recurrence.

It is possible to select those men who have the greatest chance of benefiting from radical surgery. Men who have a pretreatment serum PSA below 10 ng/mL, a low to moderate Gleason score (a measure of the microscopic degree of tumor aggressiveness), and no evidence of tumor spread to the seminal vesicles (an area that lies above the prostate gland) have the best long-term outcomes with radical prostatectomy. The likelihood of a successful outcome with radical prostatectomy is twice as high for men with these characteristics compared to men without them [12,13].

Some men who undergo prostatectomy for locally advanced prostate cancer may be offered postoperative radiation therapy, particularly if the tumor could not be removed entirely (often termed positive margins). Although this approach decreases the chance of a tumor recurrence, its influence on survival is less clear, and there is some disagreement as to whether the benefits outweigh the risks.

Side effects of prostate surgery — Serious or life-threatening complications from prostate surgery are rare. The most common complications are urinary incontinence and sexual impotence. Rates of incontinence and impotence are highest immediately after surgery and tend to improve over time. In recent years, advances in surgical techniques have reduced the incidence of both of these conditions by avoiding (sparing) the nerves responsible for urinary and sexual function, although this nerve-sparing surgery is not always an appropriate option for men with locally advanced prostate cancer.

Age is an important factor in the risk of urinary incontinence after prostatectomy. Older men are more likely to have problems. The likelihood of impotence after radical prostatectomy also increases with age. A man's previous level of sexual functioning and the use of nerve-sparing surgery also influence this complication. Several treatments have been shown to be effective for men who experience impotence after surgery, including sildenafil (Viagra®), vardenafil (Levitra®) and tadalafil (Cialis®). (See "Patient information: Sexual problems in men").

Hormone therapy — The rationale for using androgen deprivation therapy (ADT) for locally advanced prostate cancer is the same as for metastatic disease. Male hormones (androgens such as testosterone) promote or stimulate tumor growth; when deprived of these hormones, the cancerous cells of the prostate gland (as well as normal cells) die and the prostate gland shrinks in size. ADT is effective against cancer cells within the prostate gland as well as for any cancer cells that may have spread outside of the prostate.

ADT is rarely used alone (ie, without any form of local treatment) in men with locally advanced prostate cancer. ADT is not as effective as radiation or surgery for local tumor control, and there is a high risk of developing urinary obstruction from an enlarging prostatic tumor if ADT is used alone. More commonly, ADT is used in conjunction with RT. (See "ADT plus EBRT" above).

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.uptodate.com/patients). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable.

People Living With Cancer: The official patient information website of the American Society of Clinical Oncology
(www.cancer.net/portal/site/patient)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.cancer.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
US TOO!
(www.ustoo.com)
[8,11-19]


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REFERENCES

Loblaw, DA, Virgo, KS, Nam, R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2007; 25:1596.
Messing, EM, Manola, J, Sarosdy, M, et al. Immediate hormonal therapy vs. observation for node positive prostate cancer following radical prostatectomy and pelvic lymphadenectomy: A randomized Phase III Eastern Cooperative Oncology Group trial. N Engl J Med 1999; 341:1781.