Author: Dr Charles J. Ryan University of California San Francisco 2008-07-28
Introduction
Approximately 230,000 new cases of prostate
cancer are diagnosed in the United States annually, making it the most
common cancer affecting American men besides superficial skin cancers.
Although it is a highly curable malignancy when treated in its early
stages, approximately 50-60,000 men experience a relapse of the disease
annually, and approximately 5-10% harbor advanced disease at the time of
diagnosis, and are thus considered unable to be cured with surgery or
radiation. Approximately 30,000 American men die of the disease every
year. Death rates from prostate cancer have been steadily declining
since the 1990s, a result of the combination of early detection and
improved treatment of localized disease as well as improved therapies
for men with advanced disease.
Prostate cancer is a disease of the aging male, and the risk of developing the disease persists throughout a man’s lifetime. While only 1 in 10,000 men under age 40 will develop prostate cancer, the odds increase to 1 in 103 for those between the ages of 40-59, and 1 in 8 for those between the ages of 60-79. Certain population groups are at higher risk, including African Americans and those with a family history of the disease. Men with a first degree relative (brother, father, uncle) with prostate cancer have a higher likelihood of developing the disease, however mortality from the disease is not different from those with the sporadic form.
The epidemiology of the disease was altered substantially in the early 1990s with the onset of PSA (prostate-specific antigen) blood screening – which resulted in a significant increase in the incidence of the disease. The “spike” in the incidence of the disease is mitigated, however, by the development of stage migration – an effect where more men are diagnosed with earlier stage disease.
The successful management of prostate cancer is accomplished through a multidisciplinary approach that utilizes the expertise of urologists and medical and radiation oncologists. This article will focus on the types of cancer that arise in the prostate and the variety of treatment options that are available to men diagnosed with the disease. Some of the controversies and novel developments in the area of the management of localized disease will be discussed, as will the use of hormonal and chemotherapies.
Pathology
The prostate gland is approximately the size of a walnut and is located at the base of the bladder. The primary role of the prostate gland in male physiology is the secretion of the fluid components of semen. Thus, the most common type of cancer arising from the prostate comes from the glandular tissue – a type of cancer known as an adenocarcinoma. Over 95% of prostate cancers are adenocarcinomas. Unlike adenocarcinomas that develop in other parts of the body (e.g., lung and colon), adenocarcinomas that arise in the prostate are stimulated to grow through the stimulation of androgen (e.g., testosterone) and express in high concentrations the androgen receptor (AR) – which is activated by testosterone. Unless otherwise specified, all discussions of prostate cancer will concern adenocarcinoma. The remainder of prostate cancers are neuroendocrine (a.k.a. small cell) cancers and transitional cell carcinomas (arising from the special lining cells of the urinary tract - similar to bladder cancer). Sarcomas can also arise in the prostate gland but are exceedingly rare.
Natural History
The
vast majority of diagnosed prostate cancers are confined within the
prostate gland - and are thus termed “localized” disease – a situation
in which curative treatment is possible. The fatal form of the disease
arises from the situation where the cancer has spread through the blood
or lymph system to the bones (most commonly) or to other organs, such as
the liver and lung (less common). Many patients who are diagnosed and
treated for localized disease may harbor occult metastatic (distantly
spread) disease in one or more of these other organs, which accounts for
the 50,000 or so relapses that occur in the US every year, and the vast
majority of the 30,000 annual deaths. Figure 1 shows the varied
clinical “states” that are seen in the progression of prostate cancer.
Tumors that spread outside of the prostate gland typically do so by penetrating the capsule of the prostate along the routes of the nerves and/or invade the seminal vesicles (ducts for the transit of sperm to the urethra) and/or through the blood and lymph system. When the disease spreads “locally,” it can invade the bladder or the rectum, which is nearby.
Tumors that spread outside of the prostate gland typically do so by penetrating the capsule of the prostate along the routes of the nerves and/or invade the seminal vesicles (ducts for the transit of sperm to the urethra) and/or through the blood and lymph system. When the disease spreads “locally,” it can invade the bladder or the rectum, which is nearby.
The most common site of distant spread (metastasis) is bone, particularly the lumbar spine, femur, and pelvis. The development of metastatic disease in the bone represents a complex interplay between the tumor cells themselves, the bony tissues that harbor their growth, as well as hormones in the circulation and, as recent studies suggest, an attempt by the immune system to control the spread of the disease. In most situations when tumors grow in the bone, it begins as a painless process, however bone complications such as pain, fractures, and compression of the spinal cord can occur if the disease is not properly controlled. In many situations, the development of such bony complications can be prevented or delayed through the use of hormonal therapy, medicines such as bisphosphonates (e.g., Zoledronic acid), and radiation to metastatic sites with the potential to threaten the spinal cord.
Causes and Risk Factors of Prostate Cancer
It
is likely that there is more than one underlying cause of prostate
cancer, as there appear to be both genetic and environmental factors
that contribute to its development. The role of genetics is an area of
active investigation that will likely lead to significant advances in
our ability to predict who will develop clinically significant prostate
cancer. Such advances may lead to more accurate and detailed screening
methods as well as molecular targeted therapies.
Testosterone (the male sex hormone) plays a critical role in the growth of prostate tumors but not necessarily in its onset. Prostate cells contain a special compound (enzyme) which is able to convert regular testosterone into a much more potent form, dehydrotestosterone (DHT). There are two drugs available that block the conversion of Testosterone to DHT, finasteride and dutasteride. There is good evidence from a large trial that finasteride can prevent prostate cancer in certain men who are at risk of developing the disease.
Further, blocking the interaction of testosterone and its derivatives with the androgen receptor (AR) form the basis for the most effective means of controlling the growth of advanced disease. The Nobel Prize for medicine was awarded to Huggins and Hodges, the two physicians who demonstrated in the 1940s, that castration (removal of the testicles) could improve the symptoms and prolong the lives of men with advanced prostate cancer. Many of the new medical therapies that have been developed or are in development for prostate cancer are derivations of this original approach.
Environmental influences also play a role in the development of the disease. Certain areas of the world (e.g., Asia) have a low incidence of prostate cancer, although individuals who migrate from such regions of low prostate cancer incidence to regions of higher incidence (e.g., North America) develop an increasing risk for prostate cancer, suggesting a dietary or environmental link. Factors common to the low incidence areas include a primarily low-fat, plant-based diets. Increased dietary amounts of animal fat, in particular, appear to be directly associated with prostate cancer.
Dietary components that potentially decrease the risk of prostate cancer:
• lycopene ( present in cooked tomatoes)
• selenium (a naturally occurring mineral)
• omega-3 fatty acids (present in fish)
• Vitamin E
Should Healthy Men be Screened for Prostate Cancer?
The
majority of cases of prostate cancer are detected through combination
of the PSA blood test along with the digital rectal exam (DRE) - the two
components that form the basis of screening for the disease. Although
it is generally accepted that the widespread use of PSA testing has led
to a stage migration in the disease (more patients with low risk disease
that is amenable to surgical or radiation treatment) there is
controversy amongst the various public health associations as to whether
PSA screening is to be recommended. The current recommendation of the
Agency for Healthcare Research and Quality’s US Preventive Services Task
Force is that insufficient evidence exists to recommend for or against
routine prostate cancer screening. This view is shared by the American
College of Physicians, but differs from the recommendations of the
American Urological Association, whish recommends yearly screening for
men after the age of 50 who have a life expectancy >10 years, and for
those age 40 and older with a family history and for African American
men. The AUA suggests offering screening as an option for patient in
light of the potential risks (morbidity of biopsy and possible treatment
methods) and benefits (finding a potentially curable cancer),
ultimately leaving the decision up to the patient.
The crux of the issue regarding screening is that there may be a tendency for this procedure to “over diagnose” the disease - that is to diagnose early stage and non-aggressive disease that would, if not treated, have little effect on the quality of life and survival of the patient. As a result of this over-detection, many men face morbidity from the treatment (e.g., incontinence, impotence, bleeding and other surgical risks) of a disease that would be unlikely to harm them if left untreated.
The pace of change in a physician’s ability to assess the disease risk of men with newly diagnosed prostate cancer, as well as the decline in the major side effects of treatment (incontinence, for example, is becoming less common with improved surgical techniques) have reduced the strength of this argument to some extent. That said, the results of randomized trials to determine the efficacy (or lack thereof) of PSA screening on decreasing the death rate from this disease are anticipated in the next few years.
A useful algorithm for screening has been developed by the National Comprehensive Cancer Network (NCCN - http://www.nccn.org ). These recommendations suggest that men undergo a baseline evaluation, including a medical history and physical examination, as well as a discussion of the risks and benefits of screening starting at age 40. Men who wish to pursue an early detection strategy should be offered a digital rectal exam (DRE) and a serum PSA test. If this first PSA is < 0.6, the panel recommends repeating the PSA at age 45. If the PSA is ≥ 0.6, the panel recommends annual follow-up with DRE and PSA testing. Following this algorithm, as long as the DRE remains normal, the PSA remains < 2.5 ng/mL, and the PSA velocity remains < 0.5 ng/mL/year, annual DRE and PSA testing should continue. A biopsy should be considered for those in whom the DRE remains normal but the PSA is between 2.5 ng/mL and 4.0 ng/mL or the PSA velocity is ≥ 0.5 ng/mL/year (factoring in age, comorbid conditions, family history, and racial background). For patients with a negative DRE but a PSA in the 4 ng/mL to 10 ng/mL range, the panel recommends proceeding to biopsy, or performing a test of “free” PSA (lower levels of which are associated with cancer) in cases where the biopsy may present a risk to the patient or if he has other comorbid conditions. All individuals with a PSA > 10 ng/mL and those with a suspicious DRE should undergo biopsy.
The range of the ”normal” PSA increases with age. Because of this, recent recommendations suggest lowering the upper limit of normal to 2.5 ng/mL for men in their 40s and 50s. Others have recommended the use of age-adjusted PSA ranges whereby the upper-limit of normal is 2.5 ng/mL for men in their 40s, 3.5 ng/mL for men in their 50s, 4.5 ng/mL for men in their 60s, and 6.5 ng/mL for men in their 70s.
Diagnostic Testing
Symptoms
- Most patients with early-stage prostate cancer do not have any
symptoms of the disease and are diagnosed on the basis of screening.
Urinary symptoms can occur which can be confused with the symptoms of
benign prostatic hypertrophy (BPH) SPELL OUT. Bone pain, loss of
appetite, weight loss, and fatigue are symptoms that can accompany
metastatic disease. In rare but severe cases, nerve damage can occur,
causing altered levels of sensation in the arms and legs, weakness in
the legs, or a change in the level of bowel or bladder control.
Biopsy – A prostate biopsy is considered when there is reasonable clinical suspicion based on DRE and PSA results that prostate cancer exists. Further considerations regarding the biopsy are that the patient have at least a 10-year life expectancy and he would consider a form of treatment if, in fact, prostate cancer were detected. Prostate biopsy is performed as a simple outpatient procedure with local anesthesia under ultrasound guidance. An enema is given prior to the procedure and it is followed by a short course of antibiotics. The procedure involves the insertion of a trans-rectal ultrasound (TRUS) probe into the patient’s rectum, allowing visualization of the gland. Subsequently 8-16 “cores” are obtained with a 15mm long core biopsy needle. It is recommended that, at a minimum, 12 core biopsy be used. Biopsy results may show cancer or other conditions that are not cancer per se but will require surveillance: these include atypical small acinar proliferation (ASAP) and high-grade prostatic intraepithelial neoplasia (HG PIN). Either one of these conditions merits close follow-up and repeat biopsies, as they may suggest a high risk for the development of cancer.
IMAGING
A
variety of radiographic (X-ray) approaches are utilized in the workup
of newly diagnosed and suspected prostate cancer. Many patients will
undergo a bone scan to rule out the presence of metastatic disease in
the bone prior to proceeding with local therapy with curative intent, or
to determine the extent of disease outside of the prostate gland.
Similarly, CT scans are often performed to exclude the presence of
suspicious pelvic lymph nodes and metastases in the liver, in addition
to being useful in the planning of treatment with radiation. A
comprehensive TRUS (trans-rectal ultrasound) can also yield valuable
information on the extent of the disease evidenced by the size of the
prostate gland as well as the nearby seminal vesicles. An endorectal MRI
scans can also be utilized to create accurate images of the prostate
gland, but is currently utilized only in specialized centers. The
ProstaScint scan utilizes a radioactively labeled monoclonal antibody to
identify prostate cancer tissue, however due to relatively high
false-positive and false-negative rates, this test is not used widely.
STAGING/GRADING
Tumor
grade describes the appearance of prostate cancer under the microscope
and the extent to which the tumor cells conform to the normal
architecture of the gland or not. The most common grading system is the
Gleason grading system in which 2 scores are derived and then
“summed.” The tumors are assigned a number 1-5, where 1 represents the
least aggressive appearing pattern and 5 represents the most aggressive
appearing pattern. The Gleason score (or sum) is the combination of the
primary and secondary Gleason grade, and is often quoted as such (e.g.,
“Gleason 3 + 3=6”) rather than simply stating the sum. The reason for
this is that the primary Gleason has a very strong prognostic value, and
therefore a Gleason 3+3 would be considered less aggressive than a
Gleason 4+2. Gleason patterns 1 and 2 are very rarely found.
Tumor stage refers to the extent of cancer within the prostate gland and beyond. As with most cancers, the American Joint Committee on Cancer’s TNM (T = primary tumor, N = regional nodes, M = distant metastasis) staging system is utilized. The TNM staging system for prostate cancer was last revised in 2002. Appendix 1 shows the AJCC staging system for prostate cancer.
Tumor stage refers to the extent of cancer within the prostate gland and beyond. As with most cancers, the American Joint Committee on Cancer’s TNM (T = primary tumor, N = regional nodes, M = distant metastasis) staging system is utilized. The TNM staging system for prostate cancer was last revised in 2002. Appendix 1 shows the AJCC staging system for prostate cancer.
Treatment Strategies
Localized Prostate Cancer
Many treatment options are available for patients with localized, early stage prostate cancer. There is no clear, single treatment that is best applied to all patients, making this a much-debated topic because of successful outcomes with the various forms of treatment. Further, it would be nearly impossible to devise a randomized, head-to-head study that would assign patients to various treatment modalities and determine which is the most effective.
The vast majority of treatment decisions are made by clinicians in conjunction with their patients, taking into consideration the extent of the disease, the life expectancy of the patient, and the anticipated side-effect profile of the various treatment modalities. Treatment options include surgery (radical prostatectomy), radiation (external beam, brachytherapy with permanent implants, brachytherapy with temporary implants, cryotherapy, high-intensity focused ultrasound (HIFU), hormonal therapy, and active surveillance. Prediction tools called nomograms are available (online at www.nomograms.org), which can help patients and clinicians predict patients’ responses to the various forms of treatment based on the pretreatment parameters discussed above (Clinical stage, biopsy Gleason score, and diagnostic PSA level).
Watchful Waiting or Active Surveillance
The risk of disease progression is low in patients with Gleason scores 2-6 (with no pattern 4 or 5 present), T1 or T2a disease, and a serum PSA that is low and stable. Men with these features can be followed carefully and treated at the first sign of progression. Critical to the success of this approach is diligent surveillance and repeat biopsies (approximately yearly). Progression of the disease is determined by a significant rise in the PSA, a change in the DRE, or an increase in the Gleason sum. With this approach, approximately 20-40% of men will require treatment (surgery or radiation) within a 5-year period. Thus, active surveillance offers an opportunity to avoid, or delay the side effects of radical treatment. The standards of care for surveillance (e.g., when to treat and how frequently to repeat biopsies) are in the process of development. A study conducted in Sweden in which patients were randomly selected to have surgery or active surveillance found that by 10 years there was a significant difference in the death rate from prostate cancer, and an improvement overall in younger men (<65 years old). Despite this, it is still possible that men with low risk disease who are diligent in their followup can undergo active surveillance and deferred therapy. The optimal settings in which to recommend this approach are being defined.
Radical Prostatectomy
Radical prostatectomy involves the surgical removal of the prostate and seminal vesicles. Several surgical approaches are utilized, including the radical retropubic prostatectomy (an incision is made from the waist level down to the pubic bone), radical perineal prostatectomy (the incision is made between the scrotum and the anus), and approaches that utilize a laparoscopic or robotic technique in which 5 or 6 small incisions are made in the abdomen and the procedure is done with the aid of cameras and trocars (hollow cylinders through which surgical equipment is passed to avoid inserting the surgeons hand into the surgical field). The advantage of laparoscopic and robotic approaches is that with the smaller incisions, the post surgery hospitalization may be shortened by several days. Despite this advantage, these newer approaches have not been proven to be superior in terms of cancer control – although neither have they been shown to be inferior. At the time of surgery, the surgeon may elect to remove the pelvic lymph nodes in higher risk cases or if there is an intra-operative finding suggesting more advanced disease. Following prostatectomy, a urinary catheter is held in place for several days and patients are back to full activity within 2.5 to 3 weeks.
Loss of erectile function and urinary incontinence are commonly feared complications of prostate surgery. The likelihood and severity of these depend on the extent of the disease, the experience of the surgeon, and the general health of the patient. During surgery the urethra is transected, allowing removal of the prostate, and then re-connected (the surgical term is re-anastomosis) to the base of the bladder. Most patients will regain full continence within days to weeks of the removal of the catheter after surgery. Although complete loss of urinary continence is rare, up 20% of patients will have some degree of stress incontinence (loss of small amounts of urine with straining, coughing, etc). Preservation of erectile function potency is related to patient age, sexual function before surgery, and the ability of the surgeon to preserve the neurovascular bundles which are located immediately alongside the prostate. In men under age 60 with both neurovascular bundles preserved, postoperative potency rates are approximately 40-82%. This figure drops to 20-60% if one bundle is resected. Full potency can take 6-18 months to return after surgery and can be improved with the early use of erectile medications (e.g., Sildenafil) and other approaches.
Radiation Therapy – external beam therapy
Several approaches in the management of localized prostate cancer involve the delivery of radiation to the cancerous tissue. Two principal concepts are taken into consideration: The dose of the radiation and the field size (how widely radiation is spread throughout the region of the tumor). As with surgery, the goal is control of the cancer while minimizing the toxicity to normal tissues near the prostate. Given this, the range of radiation approaches includes standard external beam radiation therapy (the radiation comes from a machine and is aimed at the prostate while the patient lies on a table), to the more modern techniques of 3-dimensional conformal radiation therapy [3DCRT] and intensity modulated radiation therapy [IMRT]), which allow radiation treatment to be given at higher doses in the prostate and lower doses elsewhere. The application of 3DCRT and IMRT has led to improved tumor control and decreased side effects. Proton beam radiation is a newer approach which has not yet been widely adopted in which the energy is theoretically directed more precisely to the prostate compared to conventional radiation therapy - reliable data on the superiority of this approach is currently lacking, however.
There is some debate about field size and whether radiation should be directed at the lymph node chains around the prostate in addition to the prostate itself. There is ample evidence to suggest, however, that patients with high-risk disease (Gleason sum >7, PSA >10 and larger tumors) appear to benefit from the inclusion of the pelvic lymph nodes in the radiation field.
For some patients, the results of radiation therapy can be further enhanced with the addition of Androgen Deprivation Therapy (ADT - see below) before and during radiation treatment.[1] In particular, ADT has been proven to improve the overall survival following radiation in patients with intermediate-risk (PSA 10 – 20, ng/ml, T2b, or Gleason score 7) or high-risk (PSA > 20 ng/ml, T3, or Gleason score 8, 9 or 10) disease. Relatively short term (4 – 6 months) of neoadjuvant and concurrent ADT is utilized for patients with intermediate risk disease, whereas those with higher risk features benefit from longer periods of therapy (24-36 months).
Radiation therapy also has side effects – typically related to urinary, bowel, and sexual function. While men who undergo surgery are more likely to experience incontinence, men treated with radiation are more likely to suffer obstructive urination and bowel symptoms (diarrhea, rectal bleeding, hemorrhoids etc). Further, while surgery tends to have an early effect on sexual function, the effect of radiation on sexual function may not occur for up to 18 to 24 months. The sexual side effects of radiation are frequently exacerbated by the concurrent use of ADT.
Radiation Therapy – brachytherapy; permanent implants.
Brachytherapy is a form of radiation in which “seeds” containing the radiation are permanently placed in the prostate gland. Permanent implants in the form of iodine-125 or palladium-103 radioactive seeds may be used. The procedure itself can be performed as an outpatient procedure, and no incisions are necessary. During the procedure, several needles loaded with the radioactive seeds are placed through the skin of the perineum. The radioactivity of the seeds decay rather quickly, reaching half-strength in 17 days (Palladium) or 60 days (Iodine).
Patients who are most likely to benefit from seed implantation are those with a small gland size (<60 cc), minimal lower urinary tract symptoms, PSA <10 ng/mL, and Gleason score ≤ 6. Many patients with these features are cured with brachytherapy as monotherapy and do not require additional therapy to the prostate. Patients with higher PSA levels and/or higher Gleason grade tumors may receive seed implants plus external beam radiation to the prostate and/or regional lymph nodes as well as ADT. Side effects of brachytherapy by itself are minimal, and include irritative urinary symptoms (burning, frequency, and urgency), which are temporary. Cumulative effects on erectile function can also be seen as with other forms of radiation.
High-dose rate (HDR) brachytherapy is a form of temporary radioactive seed implantation and is typically utilized in patients with higher risk disease in combination with external beam radiation and/or androgen deprivation. The difference from standard brachytherapy is that a series of hollow-bore catheters are placed in the prostate gland while the patient is sedated and are subsequently filled with radioactive rods that deliver a very high dose of radiation (iridium-192) over a short period of time, and are then removed. Typically the patient receives two treatment sessions and is discharged home the following day.
Because there have been no definitive, long-term clinical trials in which similar patients were randomly chosen to be treated with surgery or radiation therapy, it cannot be stated which of these various approaches is superior. The best that can be said is that radiation therapy, delivered in adequate doses and, when indicated, with ADT, appears to result in similar long-term, relapse-free outcomes as does surgery. Currently, the treatment choice is made following a discussion of the pros and cons of each approach between the patient and physician. It is recommended that patients with newly diagnosed, localized prostate cancer consult with radiation oncologists, urologists, and medical oncologists while considering the various options.
Other Approaches to Localized Prostate Cancer
Cryosurgery
Cryosurgery
involves freezing the tumor with the placement of small probes
containing argon gas or liquid nitrogen. Cancer cells are destroyed
when the prostate reaches -40 degrees C. The side effects of cryosurgery
can be significant, including damage to the nerve bundles responsible
for normal erectile function and sloughing of normal tissue from the
urinary tract, causing significant urinary difficulty. Because of this,
and because the long-term efficacy of this approach is not known, it is
not recommended as the sole form of treatment of the cancer. Cryosurgery
may be useful in certain cases where the cancer has recurred (following
radiation, for example) in a very discrete location in the prostate
gland for cases of extremely focal recurrence.
High-Intensity Focused Ultrasound (HIFU)
High-intensity
focused ultrasound (HIFU) can be utilized to kill normal and cancerous
prostate tissue by heating the tissues to 85 degrees C. This treatment
is not currently available in the United States outside of clinical
trials, although preliminary data suggest that this may be associated
with clinical outcomes similar to those seen with cryotherapy. Radiation
or surgery is possible as a second treatment if this therapy fails.
Further study of this approach is needed prior to widespread
implementation.
Hormonal Therapy – Androgen Deprivation Therapy (ADT)
Hormonal
therapy in prostate cancer refers to any therapy that seeks to block
the stimulation of the tumor(s) by testosterone. Hormonal therapy may be
used at all stages of the disease and can induce prostate cancer cells
into a prolonged state of hibernation and/or death.
Medications known as LHRH (leuteinizing hormone releasing hormone) agonists are used to decrease testosterone production. They manipulate a natural feedback system in the body that normally maintains a circulating level of testosterone, leading the testes to completely shutdown testosterone production. This is frequently referred to as medical castration. LHRH agonists are given by injection and are available in preparations that exert their effect for periods ranging from 1 to 12 months. An equally effective alternative to taking hormonal medications altogether is to stop the production of testosterone by having an orchiectomy (surgical removal of the testes). When the testosterone level has been lowered, the PSA tends to drop quickly and the prostate shrinks. There are additional androgens produced in the adrenal glands. In some situations, the addition of oral medications called antiandrogens that prevent androgens from entering the prostate cells may be beneficial. The combination of these two types of hormonal medications is known as total androgen blockage or complete androgen deprivation.
These medications are occasionally used as primary treatment in many older patients with localized prostate cancer who do not undergo surgery or radiation. The duration of therapy with these medications varies. They may be taken anywhere from three months to three years, or indefinitely, depending upon the clinical indication. A commonly used strategy known as intermittent androgen deprivation is used to minimize the side effects of the ADT. In this strategy, the therapy is administered for an initial period of 6 to 12 months, then stopped. Following withdrawal of the medication, PSA typically declines and then begins to rise as the testosterone rises. ADT can be resumed when the PSA rises. The interval between these intermittent cycles can range from months to years.
One alternative to medical castration is high-dose antiandrogen therapy (bicalutamide 150 mg/day). This applies to men with locally advanced and metastatic disease who are interested in maintaining libido and erectile function. This approach can be used to control disease progression in patients who experience a rising PSA following surgery or radiation. Because of inconsistent results in a large multinational study, high dose bicalutamide is not considered a standard of care.
Androgen deprivation poses a substantial risk of side effects. The absence of testosterone (caused by LHRH agonists or orchiectomy) can produce a loss in the desire for sex, weight gain, hot flashes, loss of muscle strength, fatigue, osteoporosis, and occasionally depressive symptoms An important recent observation is that ADT may increase the risk of stroke and heart attacks. This is a consequence of the metabolic changes that occur with ADT and is not specific to the drugs being given. Antiandrogen medications may produce gastrointestinal symptoms, breast tenderness, breast enlargement, and liver problems. Calcium and Vitamin D supplements should also be used to prevent bone loss in patients on ADT. All patients on androgen deprivation for long periods of time should be screened for osteoporosis or osteopenia.
Medications known as LHRH (leuteinizing hormone releasing hormone) agonists are used to decrease testosterone production. They manipulate a natural feedback system in the body that normally maintains a circulating level of testosterone, leading the testes to completely shutdown testosterone production. This is frequently referred to as medical castration. LHRH agonists are given by injection and are available in preparations that exert their effect for periods ranging from 1 to 12 months. An equally effective alternative to taking hormonal medications altogether is to stop the production of testosterone by having an orchiectomy (surgical removal of the testes). When the testosterone level has been lowered, the PSA tends to drop quickly and the prostate shrinks. There are additional androgens produced in the adrenal glands. In some situations, the addition of oral medications called antiandrogens that prevent androgens from entering the prostate cells may be beneficial. The combination of these two types of hormonal medications is known as total androgen blockage or complete androgen deprivation.
These medications are occasionally used as primary treatment in many older patients with localized prostate cancer who do not undergo surgery or radiation. The duration of therapy with these medications varies. They may be taken anywhere from three months to three years, or indefinitely, depending upon the clinical indication. A commonly used strategy known as intermittent androgen deprivation is used to minimize the side effects of the ADT. In this strategy, the therapy is administered for an initial period of 6 to 12 months, then stopped. Following withdrawal of the medication, PSA typically declines and then begins to rise as the testosterone rises. ADT can be resumed when the PSA rises. The interval between these intermittent cycles can range from months to years.
One alternative to medical castration is high-dose antiandrogen therapy (bicalutamide 150 mg/day). This applies to men with locally advanced and metastatic disease who are interested in maintaining libido and erectile function. This approach can be used to control disease progression in patients who experience a rising PSA following surgery or radiation. Because of inconsistent results in a large multinational study, high dose bicalutamide is not considered a standard of care.
Androgen deprivation poses a substantial risk of side effects. The absence of testosterone (caused by LHRH agonists or orchiectomy) can produce a loss in the desire for sex, weight gain, hot flashes, loss of muscle strength, fatigue, osteoporosis, and occasionally depressive symptoms An important recent observation is that ADT may increase the risk of stroke and heart attacks. This is a consequence of the metabolic changes that occur with ADT and is not specific to the drugs being given. Antiandrogen medications may produce gastrointestinal symptoms, breast tenderness, breast enlargement, and liver problems. Calcium and Vitamin D supplements should also be used to prevent bone loss in patients on ADT. All patients on androgen deprivation for long periods of time should be screened for osteoporosis or osteopenia.
Clinical States of Prostate Cancer
For
most patients who develop recurrent prostate cancer after undergoing
local therapy with radiation or surgery, prostate cancer is managed as a
chronic medical condition. The contemporary classification of the
disease reflects the fact that it typically involves the progression
through a series of distinct clinical “states” (See Figure 1), defined
by the presence or absence of metastatic disease as well as detailing
whether or not the disease is progressing in the context of a normal or
low testosterone level (referred to as the “castrate state”)[2]. The
principal reason for the increasing heterogeneity of clinical states
stems, in part, from the widespread practice of PSA monitoring after
definitive local therapy, coupled with the frequent utilization of ADT
in patients who have experienced a “PSA only relapse” - in which the
only sign of recurrent disease is a rise in the PSA following surgery
(approximately one-third of patients who have a PSA relapse after
radical prostatectomy are treated within 12 months of relapse)[3]. The
earlier use of hormonal therapy coupled with changes in PSA as a measure
of the success or failure of a given treatment has generated a new form
of androgen-independent prostate cancer, characterized by a rising PSA
in the presence of castrate testosterone levels without radiographic
evidence of disease dissemination.
One of the most important aspects of the clinical states model is that it allows for uniform grouping of patients with respect to clinical trials aiming to develop new therapies. For example, the results of a trial of chemotherapy would be very different in patients who are treated during the time when they have only a rising PSA and have not been treated with ADT, yet are compared with those who have metastatic prostate cancer that has progressed after ADT, so called Castration resistant prostate cancer, the setting in which chemotherapy is currently used most commonly (see below).
The remainder of the Knol will discuss the treatment approaches for patients in each of the clinical states beyond localized disease.
One of the most important aspects of the clinical states model is that it allows for uniform grouping of patients with respect to clinical trials aiming to develop new therapies. For example, the results of a trial of chemotherapy would be very different in patients who are treated during the time when they have only a rising PSA and have not been treated with ADT, yet are compared with those who have metastatic prostate cancer that has progressed after ADT, so called Castration resistant prostate cancer, the setting in which chemotherapy is currently used most commonly (see below).
The remainder of the Knol will discuss the treatment approaches for patients in each of the clinical states beyond localized disease.
Rising PSA
Each
year approximately 50-60,000 American men develop a rising PSA after
having already received local therapy with “curative intent.” Patients
in this clinical state are generally offered one of three treatment
options: radiation therapy to eliminate cancer in the prostate bed,
hormonal therapy in some form, or observation. Not all men who
experience a relapse of the disease in the form of a rising PSA will go
on to develop metastatic prostate cancer and many may be able to be
cured with radiation therapy (if they have previously undergone radical
prostatectomy).
The primary issues that must be taken into account for patients with a rising PSA as their only manifestation of disease include the risk of developing bone metastases, the patient’s risk for death from prostate cancer, other medical conditions that may outweigh this risk, as well as any new therapies under development that may delay the need for ADT.
The rate of change in PSA over time (usually expressed as the PSA doubling time or PSADT) is the single most accurate predictor of both metastases and death in the rising PSA clinical state. One study demonstrated that one half of the patients with a PSADT <3 developed metastatic tumors in the bone within 2.25 years, whereas it took approximately four years in those with a PSADT of 3-6 months (p<0.001). [4]
Other factors in addition to the PSADT may be of particular use in helping to identify patients who are likely to benefit from further local therapy such as salvage radiotherapy. An analysis by Stephenson, for example, demonstrated that the rate at which the PSA is rising – expressed as a “doubling time” in months. are a critical component of outcome in patients thus treated. Other important factors indicating favorable outcome after salvage radiotherapy include the presence of positive surgical margins, a Gleason score below 8, and a pre-radiation PSA below 2.0 ng/mL.[5] In this study, patients with a low Gleason score, a positive surgical margin at the time of radical prostatectomy, and a slowly rising PSA had an approximately 80% likelihood of having their PSA reduced to zero with radiation alone.
Many patients with a rising PSA will ultimately require hormonal therapy in one form or another, and a substantial number will go on to hormonal therapy before they develop metastases.
The primary issues that must be taken into account for patients with a rising PSA as their only manifestation of disease include the risk of developing bone metastases, the patient’s risk for death from prostate cancer, other medical conditions that may outweigh this risk, as well as any new therapies under development that may delay the need for ADT.
The rate of change in PSA over time (usually expressed as the PSA doubling time or PSADT) is the single most accurate predictor of both metastases and death in the rising PSA clinical state. One study demonstrated that one half of the patients with a PSADT <3 developed metastatic tumors in the bone within 2.25 years, whereas it took approximately four years in those with a PSADT of 3-6 months (p<0.001). [4]
Other factors in addition to the PSADT may be of particular use in helping to identify patients who are likely to benefit from further local therapy such as salvage radiotherapy. An analysis by Stephenson, for example, demonstrated that the rate at which the PSA is rising – expressed as a “doubling time” in months. are a critical component of outcome in patients thus treated. Other important factors indicating favorable outcome after salvage radiotherapy include the presence of positive surgical margins, a Gleason score below 8, and a pre-radiation PSA below 2.0 ng/mL.[5] In this study, patients with a low Gleason score, a positive surgical margin at the time of radical prostatectomy, and a slowly rising PSA had an approximately 80% likelihood of having their PSA reduced to zero with radiation alone.
Many patients with a rising PSA will ultimately require hormonal therapy in one form or another, and a substantial number will go on to hormonal therapy before they develop metastases.
Non-Metastatic (but) Castration-Resistant Prostate Cancer.
Earlier use of hormonal therapy coupled with using PSA as a means of identifying recurrent prostate cancer has generated a new form of castration-resistant prostate cancer, a condition characterized by a rising PSA in the presence of low testosterone with no radiographic evidence of metastatic disease. Relatively little is known about the natural history of this disease state. In the only analysis of its kind, Smith and colleagues described the natural history of 201 such patients who participated in a randomized controlled trial but received placebo. Overall, 33% of patients developed bone metastases within 2 years and one half developed bone metastases within 30 months. Patients with a baseline PSA > 10 ng/ml and a rapid PSADT experienced shorter time to the first bone metastasis, metastases-free survival, and overall survival. [6] There is no standard therapy for such patients, although it is generally accepted that ADT be continued (otherwise the testosterone may rise and further stimulate the tumor) and in many cases patients are treated with so called “secondary hormonal therapies.”
A variety of secondary hormonal therapies are available and typically aim to further interrupt the ability of testosterone and its related hormones’ ability to stimulate the androgen receptor. A widely utilized drug is ketoconazole, which lowers the levels of testosterone-like hormones made by the adrenal glands. Other anti-androgens such as nilutamide or flutamide may be useful if a patient has received bicalutamide. Steroid drugs like prednisone and dexamethasone are also used, as are estrogens such as diethylstilbestrol or estradiol. The biology of secondary hormonal signaling, and other new therapies are an active area of research. New drugs, such Abiraterone acetate, are showing promise in this area.
Treatment of Metastatic Disease
Patients
with prostate cancer that has spread to the bones, lymph nodes, or
other organs are generally considered to have an incurable form of the
disease, however the disease is highly treatable with a variety of
hormonal and chemotherapy-based strategies.
As described above, the standard initial treatment is ADT. There is some evidence to suggest that patients with metastatic disease who are treated with total androgen blockade demonstrate increased survival compared with patients treated with medical castration (LHRH agonist only). Other studies have failed to prove a survival advantage to either hormonal approach. In any event, patients with metastatic disease tend to demonstrate significant clinical improvement when given hormonal therapy. In the event a patient with metastatic disease is being treated with hormonal therapy and develops new bone pain, these lesions can be treated effectively (for palliation) with a short (3-day) course of radiation.
Ultimately, a population of prostate cancer cells adapts to and grows despite low levels of androgens and this modality becomes ineffective in controlling the disease. This is known as castration-resistant prostate cancer (or hormone-refractory prostate cancer). As stated above, many patients may benefit from the use of secondary hormonal therapies such as ketoconazole, anti-androgens, and estrogens once initial ADT proves insufficient. These approaches can be useful in either the non-metastatic or metastatic disease setting.
For many patients with advanced prostate cancer, pain and bone complications (e.g., fractures) become a substantial risk. For such patients, an approach that combines bone protection with chemotherapy is frequently utilized[7]. One drug, zoledronic acid, has been shown to reduce the rate of complications in the bone and is in widespread use in this setting. It is administered intravenously approximately once per month.
As described above, the standard initial treatment is ADT. There is some evidence to suggest that patients with metastatic disease who are treated with total androgen blockade demonstrate increased survival compared with patients treated with medical castration (LHRH agonist only). Other studies have failed to prove a survival advantage to either hormonal approach. In any event, patients with metastatic disease tend to demonstrate significant clinical improvement when given hormonal therapy. In the event a patient with metastatic disease is being treated with hormonal therapy and develops new bone pain, these lesions can be treated effectively (for palliation) with a short (3-day) course of radiation.
Ultimately, a population of prostate cancer cells adapts to and grows despite low levels of androgens and this modality becomes ineffective in controlling the disease. This is known as castration-resistant prostate cancer (or hormone-refractory prostate cancer). As stated above, many patients may benefit from the use of secondary hormonal therapies such as ketoconazole, anti-androgens, and estrogens once initial ADT proves insufficient. These approaches can be useful in either the non-metastatic or metastatic disease setting.
For many patients with advanced prostate cancer, pain and bone complications (e.g., fractures) become a substantial risk. For such patients, an approach that combines bone protection with chemotherapy is frequently utilized[7]. One drug, zoledronic acid, has been shown to reduce the rate of complications in the bone and is in widespread use in this setting. It is administered intravenously approximately once per month.
Chemotherapy for Castration-Resistant Prostate Cancer (CRPC)
Until recently, chemotherapy has been utilized with relatively little frequency in prostate cancer. This has had less to do with the effectiveness of chemotherapy against prostate cancer (many patients benefit significantly from chemotherapy) and more to do with the fact that definitive data from clinical trials of chemotherapy in this disease were lacking until the early part of this decade. It wasn’t until 2004 that an approach that utilized chemotherapy was shown to improve the survival of prostate cancer patients - a fact that had contributed to an environment of skepticism regarding the utility of this approach.
Two simultaneously conducted phase III studies were presented in 2004 that compared docetaxel chemotherapy to mitoxantrone, a drug that had been approved for use in prostate cancer for its potential to palliate pain and improve quality of life, but not to improve survival. The most important of the two studies was the multinational “Tax 327” study, which utilized 3 treatment arms: docetaxel (35 mg/m2) administered intravenously once per week, versus docetaxel (75 mg/m2) given intravenously every 3 weeks, versus mitoxantrone 12 mg/m2, which was also administered every 21 days. In Tax 327, 90% of the patients had metastatic disease in the bone and approximately one half had disease-related pain requiring opiod pain medications (e.g., morphine). An important fact to consider in the interpretation of this study is that “crossover” was allowed - meaning that patients who were treated with one chemotherapy were allowed to receive the second chemotherapy if the first failed to control the cancer.
The results of the Tax 327 study demonstrated that the median survival of all docetaxel treated patients was 18.2 months, compared with 16.4 months for those treated with mitoxantrone, a difference that was statistically significant. An analysis of the survival in the docetaxel every 3 weeks arm was 18.9 months, which was significant when compared with the 16.4 month survival in those treated with M/P, and translated into a hazard ratio of 0.76 and a p value of 0.009 – in laymen’s terms this means that patients who received docetaxel first lived 24% longer. The docetaxel given every 21 days was also superior to mitoxantrone with respect to pain response rate (35% versus 22%; p=0.01) and PSA response rate (45% versus 32%; p = 0.0005). Based on the improvement in survival observed in patients receiving the docetaxel/prednisone every 21 days in Tax 327, the US Food and Drug Administration (FDA) approved the use of docetaxel (75 mg/m2 every 21 days) together with prednisone as front-line therapy for metastatic HRPC in May 2004.[8, 9]
Although these results have led to the establishment of docetaxel as the standard of care for CRPC, several new approaches to improving the efficacy of chemotherapy-based approaches are in development. Results are anticipated from an ongoing Phase III randomized double-blinded study comparing standard docetaxel therapy to docetaxel/ prednisone plus bevacizumab, a monoclonal antibody therapy targeting the vascular endothelial growth factor (VEGF) receptor. VEGF is the principal signal allowing growing tumors to grow new blood vessels, a process known as angiogenesis. The addition of bevacizumab to chemotherapy in other cancers has led to improvements in survival and responses to chemotherapy. It is thought that by reducing the effect of VEGF on blood vessel formation and development, more chemotherapy will be able to reach the tumor, leading to a greater proportion of the tumor being killed by the chemotherapy.
Therapies that seek to augment the body’s immune reaction against prostate cancer are also in late-stage clinical trials. In therapy based on the Provenge® vaccine, dendritic cells (the cells that initiate an immune response) are removed from the body and incubated with a prostate cancer antigen (prostatic acid phosphatase) and re-infused into the body three times. Prior studies suggested (but did not prove) that patients who received this vaccine had a longer survival than patients who received a placebo, and the confirmatory studies are underway. In a distinct series of vaccine studies also in phase III trials, the cell-based tumor vaccine GVAX® is being compared with chemotherapy with docetaxel. With this approach, prostate cancer cells grown outside the body (and radiated so that they cannot grow) are injected under the skin as a form of a “live” vaccine, similar to those that are utilized in infectious diseases. Should these approaches prove useful in late-stage disease, it is possible that these vaccines may be used to prevent or delay recurrence in patients who have been treated with radiation or surgery with curative intent.
As a result of the fact that docetaxel has found widespread use in the management of hormone refractory prostate cancer, an increasing number of patients have developed chemotherapy-refractory disease, and thus may require second-line chemotherapeutic approaches. A variety of such approaches are currently in development, however there is currently no accepted standard of care in this setting.
Conclusion
Prostate cancer is a very common disease with an extremely varied natural history. The optimal management of patients with prostate cancer is highly individualized, based on the varied aggressiveness of the disease ranging from one that is capable of being observed without therapy to one that is lethal for many patients. The optimal treatment program for an individual patient is one in which a multidisciplinary team of clinicians is involved in clinical decision making and treatment planning. Further, the aging of the population raises the possibility that more men than ever will deal with advanced prostate cancer, highlighting the urgency for the development of new therapies. Investigation of new therapies in the forms of clinical trial enrollment is a critical factor in proving their success or failure and should be encouraged whenever possible.
Figure 1: Clinical States of Prostate Cancer: The following diagram demonstrates schematically the distinct form the disease takes through its long natural history which vary based on the presence or absence of metastases as well as the use of androgen deprivation therapy (See text).
Appendix 1: Prostate Cancer Staging - adapted from the American Joint Committee on Cancer Staging Manual, 6th Edition).
T1 tumors are those tumors that are not clinically palpable on DRE or visible on TRUS.
T1a – incidental finding of cancer in ≤ 5% of the tissue resected during a trans-urethral resection of the prostate.
T1b - incidental finding of cancer in ≥ 5% of the tissue resected during a trans-urethral resection of the prostate.
T1c – tumor identified by needle biopsy (performed because of an elevated PSA).
T2 tumors are confined to the prostate, identified by DRE or TRUS.
T2a – tumor involves one-half of one lobe or less.
T2b – tumor involves more than one-half of one lobe, but not both lobes.
T2c – tumor involves both lobes.
T3 tumors extend through the prostatic capsule.
T3a – extracapsular extension (unilateral or bilateral)
T3b – tumor invades seminal vesicle(s)
T4 tumors are fixed or invade adjacent structures such as: bladder neck, external sphincter, rectum, levator muscles, or pelvic wall.
N1 refers to regional lymph node metastasis
M1 refers to distant metastasis
M1a – non-regional lymph nodes
M1b – bone(s)
M1c – other site(s)
Useful Web Resources for Patients:
American Cancer Society
www.cancer.org/
Prostate Cancer Foundation
www.prostatecancerfoundation.org
National Cancer Institute’s (PDQ) Website for patients www.cancer.gov
National Comprehensive Cancer Network www.nccn.org
Clinical Trials.gov
cancertrials.nci.nih.gov
References
1. Ryan, C.J. and E.J. Small, Early versus delayed androgen deprivation for prostate cancer: new fuel for an old debate. J Clin Oncol, 2005. 23(32): p. 8225-31.
2. Scher, H.I. and G. Heller, Clinical states in prostate cancer: towards a dynamic model of disease progression. Urology, 2000. 55: p. 323-327.
3. Mehta, S., D. Lubeck, and N. Sadetsky, Patterns of secondary cancer treatment for biochemical failure following radical prostatectomy: data from CaPSURE. . J Urol, 2004. 171: p. 215-219.
4. Zelefsky, M.J., et al., Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer. J Clin Oncol, 2005. 23(4): p. 826-31.
5. Stephenson, A.J., et al., Salvage radiotherapy for recurrent prostate cancer after radical prostatectomy. Jama, 2004. 291(11): p. 1325-32.
6. Smith, M.R., et al., Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol, 2005. 23(13): p. 2918-25.
7. Ryan, C.J. and M. Eisenberger, Chemotherapy for hormone-refractory prostate cancer: now it's a question of "when?" J Clin Oncol, 2005. 23(32): p. 8242-6.
8. Tannock, I.F., et al., Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med, 2004. 351(15): p. 1502-12.
9. Petrylak, D.P., et al., Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med, 2004. 351(15): p. 1513-20.