Zanmbeel

Saturday, October 13, 2007

Treatment for early prostate cancer

INTRODUCTION — Prostate cancer is a malignancy of the prostate gland, an organ that forms a ring around the urethra, near its connection to the bladder (show figure 1). The urethra is the tube that carries urine from the bladder to the outside of the body.

Prostate cancer is the most common cancer affecting men. Every year, more than 200,000 American men are diagnosed with prostate cancer, and nearly 30,000 die from this disease. Over the last 15 years, the increasing use of prostate cancer screening with blood levels of prostate-specific antigen (PSA) has led to more cases being diagnosed at an early stage, when the cancer is still limited to the prostate gland and is highly curable.

There are three standard approaches to treating early prostate cancer: surgical removal of the prostate gland, radiation therapy with or without hormone therapy, and "active surveillance," a term that describes the decision to delay definitive treatment while carefully monitoring for evidence of progression or growth of the cancer. Hormone therapy has traditionally been reserved for men with advanced or metastatic prostate cancer, although new applications of hormonal therapy as a supplement to active surveillance, surgery, or radiation show promise.

The ultimate choice of treatment is dependent upon several factors. The likelihood that the prostate cancer is confined to the prostate gland and therefore, potentially curable The volume and histologic grade (ie, degree of aggressiveness) of the cancer A man's age and overall health, including any other medical conditions The outcomes and potential side effects associated with the different forms of treatment

This topic discusses the evaluation of men with early prostate cancer, and describe the available treatment options, outcomes from therapy, and treatment-related side effects. A separate topic review is available about advanced prostate cancer. (See "Patient information: Advanced prostate cancer").

PRETREATMENT EVALUATION — Prior to selecting the best treatment option, it is critically important that the disease extent be determined. Although this is most accurately determined by surgically removing the prostate, several pretreatment factors can be used to predict whether a prostate cancer is likely to be confined to the prostate gland itself (termed organ-confined disease) or spread beyond the prostate gland, and therefore, more advanced.

The most important pretreatment factors are the clinical stage, the level of the serum PSA, the tumor volume (as determined by the number of positive biopsy samples, and the extent of cancer involvement within each biopsy sample) and the degree of aggressiveness of the tumor, referred to as the Gleason grade.

Prostate cancer stage — Physicians use a common notation to describe the extent, or stage of a cancer. The tumor-node-metastasis (TNM) system is the most common method used to stage prostate cancer (show table 1).

In this system, T1 tumors are microscopic and cannot be felt during rectal examination (show figure 2) T2 tumors can be felt with a rectal examination, but appear to be confined to the prostate gland T3 tumors have grown beyond the prostate into the capsule of connective tissue that surrounds the gland, or into the seminal vesicles (glands near the prostate that secrete fluid into the reproductive tract) (show figure 1) T4 tumors have grown locally beyond the prostate, and involve nearby tissues

The finding of a T3 or T4 tumor suggests a more advanced tumor that is not likely to be cured, even with aggressive surgery. The stage assigned by a rectal examination is termed a clinical or "c" stage, while a man who has undergone surgical removal of the prostate with microscopic evaluation will be assigned a pathologic, or "p" stage.

Endorectal coil MRI — Endorectal coil MRI uses magnetic resonance imaging to assess the prostate and its surrounding tissues. Although this technique is not yet widely available, it has been shown to be particularly helpful in evaluating the possibility of extension outside of the prostate capsule or into the seminal vesicles in men who are considering surgery. This procedure may also help to determine if a nerve-sparing prostate operation is appropriate.

Serum PSA level — The vast majority of men with prostate cancer have elevated levels of PSA in the blood. The PSA level at the time of diagnosis provides important information about the likelihood of finding that prostate cancer has spread beyond the prostate. As PSA levels increase, the likelihood of disease spread to tissues beyond the prostate gland rises. Men with a PSA concentration less than 10 ng/mL have a 70 to 80 percent chance of having organ-confined disease, compared to 50 percent for those with PSA levels 10 to 50 ng/L, and only 25 percent with higher PSA levels [1].

The pretreatment PSA level can also predict the likelihood of a cancer recurrence after treatment. Men with a lower PSA concentration are more likely to be cancer-free five years after treatment than those with a higher pretreatment PSA level.

Biopsy grade — A prostate biopsy, in which a small amount of tissue is removed from the prostate and examined under a microscope, is performed when prostate cancer is suspected. This examination allows the physician to confirm the diagnosis, and also assess the volume and level of aggressiveness (called the Gleason grade) of the tumor.

The pathologist typically reports a primary grade (between 1 to 5) and a secondary grade, also between 1 and 5. The higher the Gleason grade, the more aggressive (fast-growing) the tumor appears. These two numbers are then combined together to form the Gleason score. If the cancerous tissue shows primarily grade 3 and secondarily grade 4 areas of tumor involvement, the combined Gleason score is "3 plus 4" or 7. Gleason score 2 to 4 tumors are typically referred to as low grade (also called well-differentiated), Gleason 8 to 10 tumors are high grade (or poorly differentiated), and the Gleason scores between 5 to 7 are referred to as intermediate grade.

Predictive models — These pretreatment factors, and combinations of these factors can be used by physicians in two ways: they are useful to predict the likelihood that a man has an organ-confined cancer that may be potentially curable, and they can also be used to predict the outcome of either surgery or radiation therapy.

Predicting organ-confined cancer — Combinations of pretreatment factors are more accurate than any one of the individual factors to predict the likelihood of a man having organ-confined disease. One such predictive model combines the clinical tumor (T) stage, the Gleason score from the tumor biopsy, and the serum PSA to construct tables that allow an estimation of the likelihood of finding organ-confined, and thus, potentially curable disease at the time of surgery (show table 2).

Another potentially useful tool to estimate outcome of therapy is a nomogram or graph, which consists of parallel scales that are calibrated for different prognostic variables. Once the numerical risk is calculated for each variable, a final single calibrated scale is then used to determine the overall risk of prostate cancer recurrence based upon all of the factors. Many of these published nomograms are designed for use after therapy such as surgery (show table 3), but some use pretreatment variables.

Predicting treatment outcome — In addition to predicting the likelihood of organ-confined disease, pretreatment models utilizing PSA, biopsy Gleason score, and clinical T stage can also be used to predict the chance of being cancer-free following either surgery or radiation. In general, these models stratify patients into one of three defined prognostic groups: Low-risk — Clinical stage T1c or T2a, serum PSA concentration <10>20 ng/mL, and a biopsy Gleason score of 8 or higher. Men with high-risk prostate cancer have an approximately 33 percent chance of being cancer-free five years after treatment.

TREATMENT OPTIONS — The three standard therapies for men with organ-confined prostate cancer are surgery (radical prostatectomy), RT, and active surveillance. To date, no good study has directly compared these three options. Young, healthy men are typically encouraged to undergo radical prostatectomy, while older patients tend to be steered toward RT or observation. This fact makes it difficult to compare outcomes in men treated with either surgery or radiation.

Radical prostatectomy — Radical prostatectomy (referred to as prostatectomy) is a complete removal of the prostate gland. This treatment is thought to offer the best chance for long-term survival (beyond ten years). Selected men with low-risk early stage prostate cancer who undergo prostatectomy have an 80 to 85 percent chance of remaining cancer-free up to 15 years after surgery.

During a prostatectomy, the surgeon removes the entire prostate and then reconnects the urethra and bladder. The prostate gland may be removed from two different approaches: the perineal approach (through the perineum, the tissue between the penis and anus), or the retropubic approach (through the lower abdomen). One advantage of the retropubic approach is that it allows tissue to be removed from the lymph nodes in the pelvis prior to removal of the prostate. Men with low-risk disease may not need a lymph node dissection, since there is a low likelihood that disease has spread to these nodes.

Newer prostatectomy techniques include the use of a laparoscope (an instrument in inserted through a small incision) or a robotic arm. These methods do not have a proven advantage over the open approach, except for possibly less blood loss.

Complications — The most common complications of prostatectomy are urinary incontinence (uncontrolled leakage of urine) and erectile dysfunction (ED, the inability to have an erection sufficient for sexual intercourse). Most men have some degree of urinary incontinence and ED immediately following surgery, although both usually improve over time.

Age is an important factor in the risk of urinary incontinence after prostatectomy. In a large study, severe urinary incontinence was experienced by almost 14 percent of men between 75 and 79, but in fewer than 4 percent of younger men [2]. Almost one-half of the affected men had only occasional incontinence, often related to stresses on the bladder such as sneezing, coughing, or laughing.

The likelihood of experiencing ED after prostatectomy also increases with age. In one review, the potency rate after surgery was 100 percent for men in their 40s, and 55, 43, and 0 percent for men in their 50s, 60s, and 70s, respectively [3]. Men who have nerve-sparing surgery and who had a high level of sexual functioning before surgery are less likely to have ED after surgery (see "Nerve sparing procedures" below). Medications (eg, Viagra®, sildenafil) are effective in the majority of men. Early, preventive use of these drugs may also promote the return of a man's ability to have an erection. (See "Patient information: Sexual problems in men").

Nerve sparing procedures — A procedure that avoids the nerves responsible for urinary and sexual function (called nerve-sparing prostatectomy) has reduced the incidence of these conditions. However, this procedure is not recommended for all men, including men with large tumors, high Gleason grade cancers, or a high PSA before treatment. With these exceptions, there is no evidence that a nerve-sparing operation compromises control of the cancer.

Radiation therapy (RT) — Two forms of RT are used to treat prostate cancer: external beam RT and interstitial implantation, also called brachytherapy.

External beam radiation — External beam RT (EBRT) uses a machine called a linear accelerator that moves around the patient, directing x-rays (also called gamma rays) at the pelvis. EBRT is typically administered daily, five days per week. Treatment lasts five to eight weeks, depending upon whether it is used alone or in combination with other treatments. EBRT can be done on an outpatient basis, and men can usually continue their normal activities during treatment. The dose of radiation delivered to the prostate tumor is important, and is determined in part by the pretreatment factors discussed above.

Whether results with EBRT are comparable to those obtained with surgery is controversial. It is difficult to compare outcomes among similar groups of men who have received these two different treatments for the following reasons: As noted above, young, healthy men are typically encouraged to undergo surgery, while older men often receive RT. During prostatectomy, the pelvic lymph nodes and the tissues around the prostate gland can be directly evaluated for evidence of cancer spread, but this is not possible in men undergoing RT. As a result, men receiving RT may actually have more extensive disease than expected from the pretreatment evaluation, compared to those undergoing surgery.

Nevertheless, some generalizations can be made. For men with low-risk, organ-confined prostate cancer, surgery and EBRT result in approximately equivalent rates of cancer control at five years, approximately 80 percent [4]. Men with high-risk organ-confined tumors (eg, high pretreatment serum PSA and high Gleason score) may do better with surgery. In the same report, 62 percent of surgically treated men with high-risk tumors were cancer-free at five years, compared to only 26 percent after EBRT[4]. However, these men were treated with relatively low doses of EBRT, and at least one study suggests that higher doses of RT preferentially benefit men with high-risk disease [5]. Furthermore, other reports show that long-term treatment results from surgery and RT are similar in men with either low-risk or high-risk disease when higher doses of EBRT are used (72 Gray or higher) (show table 4) [6]. Complications — Clinicians are careful to limit the amount of radiation that is directed at healthy tissue around the prostate tumor, although some surrounding normal tissues can be damaged. The risk of damage may be lower when newer treatment planning techniques such as conformal RT are utilized (see "Conformal radiation" below).

Possible side effects of EBRT include urinary urgency and/or frequency, bladder pain, sexual impotence (erectile dysfunction, ED), and bowel problems such as proctitis (inflammation of the rectum). Compared to prostatectomy, urinary problems and ED are less common following RT, but bowel problems such as diarrhea, bowel urgency, and painful hemorrhoids are more common. In contrast to surgically treated men, ED rates increase over time after RT.

These differences in treatment-related complications continue to be evident up to five year following treatment [7,8]. As an example, in one study, men undergoing prostatectomy had a more than twofold higher risk of urinary incontinence compared to those treated with EBRT (9.6 versus 3.5 percent) and were more likely to have ED (80 versus 62 percent) [7]. On the other hand, men receiving EBRT reported more difficulties with bowel function (diarrhea, bowel urgency, and painful hemorrhoids).

Viagra and other related drugs may be beneficial for men with radiation-related ED.

Conformal radiation — Three-dimensional conformal radiation therapy, or 3D-CRT, uses sophisticated computer modeling to precisely outline the tumor and deliver larger doses of RT while minimizing damage to surrounding normal tissues. This technique is more expensive than EBRT, and has not been proven more effective than conventional RT. However, it may allow a higher dose to be given to the prostate, which produces fewer side effects, particularly bowel problems.

Intensity modulated radiation therapy — Intensity modulated radiation therapy (IMRT) is an advanced form of 3D-CRT in which the radiation dose to the prostate gland, a complex and irregular target, is varied by changing the intensity of the beam during therapy. The major advantage of IMRT over 3D-CRT is a reduction in the dose received by nearby organs, particularly the bowel, resulting in fewer side effects. The advantage may be greatest in men who require RT of the pelvic lymph nodes in addition to the prostate gland. IMRT requires special expertise and equipment, and is becoming more available in treatment centers within the United States.

Brachytherapy — Brachytherapy involves placing a radioactive source directly into the prostate gland under ultrasound guidance. The procedure is done with general anesthesia (the patient is given medicine to induce sleep) or regional anesthesia (epidural or spinal medications block pain below the waist). There are two types of brachytherapy. Low-dose-rate (LDR) brachytherapy implants rice-sized radioactive seeds or pellets into the prostate, which emit radiation from within the gland for a specified period of time. The radioactivity of the seeds diminishes over time, and the dose of radiation to surrounding tissues is limited.

Some men have questions or fears about the possibility of exposing family members to unsafe levels of radiation. The risk of radiation exposure to people around the patient after the seeds are placed is not clearly understood. However, radiation exposure to family members is thought to be low. One study examined radiation levels in the home of a man who had undergone seed placement [9]. Radiation levels were measured in four rooms of the man's home for three weeks. The study revealed that, even for spouses living in the same home, the level of radiation exposure was low, and similar to that of a transcontinental airplane flight.

Nevertheless, as an added margin of safety, most men are advised to avoid prolonged, direct contact with children and pregnant women (eg, by sitting on the patient's lap) for three months after seed placement. High-dose rate (HDR) brachytherapy uses a catheter or needle inserted into the prostate to temporarily implant a radioactive source into the prostate gland over a period of several hours. The catheter or needle is placed while a patient is under general anesthesia, but anesthesia not necessary to load the radioactive source or while the source is in place. There is no risk of radiation exposure to family or friends after the catheter/needle is removed.

When it is used, HDR brachytherapy is usually combined with EBRT. At least one study suggests that there are fewer side effects with HDR as compared to LDR brachytherapy [10]. However, HDR brachytherapy is not as widely available as LDR brachytherapy.

Brachytherapy versus EBRT — The major advantage of brachytherapy over EBRT is convenience; brachytherapy (at least the more common LDR procedure) is a one-time procedure while EBRT requires five to eight weeks of treatment. Brachytherapy is often used alone in men with low-risk disease, and has effectiveness similar to other treatments for this group of men. Up to 86 percent of men with a Gleason score less than 7 and serum PSA less than 10 ng/mL remain free of progression for up to 15 years [11]. Brachytherapy is usually combined with EBRT for men with higher risk disease.

Complications — Men who undergo brachytherapy usually experience inflammation and swelling of the prostate gland, which can lead to urinary urgency (needing to void urgently), frequency (needing to void frequently), and burning, and occasionally retention of urine (being unable to empty the bladder completely, which requires temporary use of a catheter). In addition, damage to nearby tissue can cause bowel urgency and frequency, rectal bleeding, and the development of rectal ulcers; these symptoms are rare when brachytherapy is used alone.

The risk of short-term urinary incontinence may be less with brachytherapy than with EBRT as long as pati are selected carefully. Selection criteria have been developed by the American Brachytherapy Society on the basis of pretreatment clinical features [12]. The guidelines suggest that the combination of clinical stage T2a or better, biopsy Gleason score of 6 or less, and serum PSA less than 10 ng/mL identifies a group of low-risk patients who are most likely to have excellent long-term oncologic outcomes. Most men who have brachytherapy-related urinary and bowel symptoms improve significantly over time, whereas symptoms may become more severe in men who have EBRT. The risk of ED is similar to other treatments.

Active surveillance — Some men elect to delay treatment in favor of a program of observation, also called active surveillance (previously called watchful waiting). Active surveillance may be preferred over treatment to avoid treatment-related side effects. However, prostate cancer itself can cause urinary incontinence, sexual impotence, and obstruction of the flow of urine as the tumor grows and the cancer progresses. In the United States, less than 10 percent of men with early stage prostate cancer choose active surveillance.

A large study from Sweden directly compared surgery to active surveillance, and showed that men who chose active surveillance were significantly more likely to die within 10 years [13]. The risk of dying was highest among men 65 years of age and younger who chose active surveillance. In addition, many fewer surgically treated men developed metastatic prostate cancer at 10 years (15 versus 25 percent). Despite the fact that many men who delay treatment do not die of prostate cancer, even those with low-grade cancers are at risk of developing incurable bone metastases.

When is active surveillance appropriate? — Active surveillance is most appropriate for men with a limited life expectancy (less than 10 years, based upon their age) who have small tumors, low Gleason scores (less than 7), and a slowly rising PSA level, particularly if they have another medical condition that might limit their life expectancy to less than 15 years. Younger men and men over the age of 70 who are otherwise healthy and who have aggressive (eg, Gleason score 7) or large tumors should be encouraged to receive immediate treatment. These men have more rapid tumor growth, and are more likely to die of prostate cancer if their disease is left untreated.

Monitoring during active surveillance — Men who choose active surveillance should have monitoring every three to six months, including a rectal examination and blood test to determine PSA level. A repeat prostate biopsy should be done within the first year after the initial diagnosis to make certain that a more aggressive tumor (ie, with a higher Gleason grade) was not missed.

There are no guidelines in place that define what, if any, criteria should be used to decide when to intervene with treatment. Definitive therapy (ie, radiation or surgery) may be recommended if there is a significant change in the PSA level, rectal examination, or Gleason grade on follow-up biopsy. Some clinicians use a PSA doubling time of less than three years as a trigger to prompt therapy. However, none of these criteria are firm recommendations based upon scientific studies.

In reality, many men will go on to receive treatment because of anxiety about the continually rising PSA level. Approximately 50 percent of men who choose active surveillance will proceed to treatment within three years, either because of disease progression or anxiety.

Androgen deprivation therapy — Male hormones (androgens, the most common of which is testosterone) fuel the growth of prostate cancer. Treatments that decrease the body's levels of androgens (androgen deprivation therapy, ADT) decrease the size of a normal prostate and prostate cancer. ADT can be accomplished either by removing the testicles, where many of the body's androgens are produced (called an orchiectomy), or by using medicines that interfere with androgen production or its action in the body.

The available data suggest that ADT is useful for men who are undergoing RT. The addition of ADT to EBRT improves outcomes for men with intermediate-risk and high-risk localized prostate cancer, but not those with low-risk disease. The optimal duration of therapy is controversial, but men with intermediate-risk disease (see "Biopsy grade" above) appear to benefit from four to six months of ADT, given for two months before and during EBRT, while those with higher-risk disease benefit from an additional two years of ADT after completing EBRT.

ADT alone versus active surveillance — The use of ADT alone (rather than active surveillance) in men with early stage disease has risks and benefits that are not completely understood. ADT alone is increasingly recommended to men who prefer to avoid surgery and radiation therapy, and some studies suggest that this offers modest cancer control.

However, these studies do not consider treatment-related side effects and long-term follow up data are not yet available. Potential side effects of long-term ADT are sexual dysfunction, breast tenderness and enlargement, hot flashes, muscle loss, osteoporotic bone fractures, and accelerated coronary artery disease.

Side effects of ADT — Side effects of ADT are related to the decreased levels of male hormones, and include decreased libido (sex drive), impotence (erectile dysfunction), and symptoms similar to those of menopause (eg, hot flashes, temporary enlargement of the breast tissue). ADT can also lead to loss of muscle and bone, the latter resulting in osteoporosis (thinning of the bones) and an increased risk of bone fractures. Treatments are available to reduce the risk of osteoporosis. (See "Patient information: Osteoporosis prevention and treatment").

Cryotherapy — Cryotherapy is a local treatment for prostate cancer in which tumor cell destruction is accomplished by freezing. Although early trials showed unacceptably high complication rates, there has been a resurgence of interest in cryotherapy because of improvements in technique that have reduced treatment-related side effects, and possibly improved outcomes [14].

Cryotherapy is performed in the operating room under anesthesia. Using ultrasound guidance, multiple cryoprobes (thin needles) are placed within the prostate gland. Liquid nitrogen or argon gas is then infused into the gland, freezing the tissues. After the gland has been frozen and allowed to thaw, the tumor is refrozen and again allowed to thaw (the "double freeze-thaw" technique). Following therapy, men are discharged home with a urinary catheter in place for at least three weeks.

The available data suggest that with newer techniques, the same men who benefit from radical prostatectomy or RT (ie, those with low-risk disease) are likely to have favorable outcomes from cryotherapy. However, cryotherapy cannot be recommended with the same sense of confidence as radical prostatectomy or RT because long-term data on outcomes are not available.

CLINICAL TRIALS — Progress in treating prostate 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/

SUMMARY Surgery and RT offer fairly equivalent survival outcomes in well selected patients for the first ten years or so after therapy; beyond that time, there may be a higher risk of recurrence with RT. However, radiation techniques continue to improve, and it is likely that results using higher doses, more precise delivery techniques, and combined use with androgen deprivation therapy (for men with higher risk disease) will improve outcomes (see "Intensity modulated radiation therapy" above). Often, the decision between radiation and surgery is a matter of patient preference. The pattern of treatment-related toxicity is different. Surgery is associated with more early urinary and sexual side effects, which tend to improve over time, while RT causes more bowel problems, and worse urinary and sexual dysfunction over time. Although brachytherapy alone offers some advantages over external beam radiotherapy, it is best reserved for men with low-risk disease and those with small prostate glands. Men with higher-risk disease who choose brachytherapy are usually treated with a combination of brachytherapy and external beam RT (see "Brachytherapy" above).. Watchful waiting (active surveillance) is appropriate only for older men (over the age of 70 or 75) with a small tumor, a low Gleason score, and a life expectancy of 15 years or less. Monitoring with PSA blood tests, a rectal examination, and follow up biopsies are recommended at regular intervals during active surveillance. Treatment with surgery or radiation may be recommended if the tumor is thought to be rapidly growing (see "Active surveillance" above). Clinical trials (particularly those that compare surgery to different forms of radiation therapy) are needed to improve outcomes among men with clinically localized prostate cancer (see "Clinical trials" above).

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.patients.uptodate.com). 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. National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
US TOO! International, Inc

(www.ustoo.org)

[1-8,10,11,13-18]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Partin, AW, Yoo, J, Carter, HB, et al. The use of prostate specific antigen: Clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150:110.
2. Stanford, JL, Feng, Z, Hamilton, AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283:354.
3. Naitoh, J, Zeiner, RL, Dekernion, JB. Diagnosis and treatment of prostate cancer [see comments]. Am Fam Physician 1998; 57:1531.
4. Kupelian, P, Katcher, J, Levin, H, et al. External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: Therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am 1997; 3:78.
5. Pollack, A, Zagars, GK, Starkschall, G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002; 53:1097.
6. Kupelian, PA, Potters, L, Khuntia, D, et al. Radical prostatectomy, external beam radiotherapy <72> or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004; 58:25.
7. Potosky, AL, Legler, J, Albertsen, PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the prostate cancer outcomes study. J Natl Cancer Inst 2000; 92:1582.
8. Potosky, AL, Davis, WW, Hoffman, RM, et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 2004; 96:1358.
9. Michalski, J, Mutic, S, Eichling, J, Ahmed, SN. Radiation exposure to family and household members after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 56:764.
10. Grills, IS, Martinez, AA, Hollander, M, et al. High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate palladium seeds. J Urol 2004; 171:1098.
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12. Nag, S, Beyer, D, Friedland, J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789.
13. Bill-Axelson, A, Holmberg, L, Ruutu, M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352:1977.
14. Han, KR, Cohen, JK, Miller, RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol 2003; 170:1126.
15. Wei, JT, Dunn, RL, Sandler, HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 2002; 20:557.
16. Miller, DC, Sanda, MG, Dunn, RL, et al. Long-term outcomes among localized prostate cancer survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol 2005; 23:2772.
17. Chodak, GW, Thisted, RA, Gerber, GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:242.
18. Albertsen, PC, Hanley, JA, Gleason, DF, Barry, MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer [see comments]. JAMA 1998; 280:975.

Prostate cancer screening

INTRODUCTION — Prostate cancer screening involves testing for cancer in men who have no symptoms of the disease. This testing can find cancer at an early stage, when it may be more easily and effectively treated. However, medical experts disagree about whether prostate cancer screening is right for all men, and it is not clear if the benefits of screening outweigh the risks.

This topic review is designed to discuss the advantages and disadvantages of prostate cancer screening. Men should talk with their healthcare provider to decide what is best in their individual situation.

WHAT IS PROSTATE CANCER? — Prostate cancer is a malignancy of the prostate, a small gland in men that is located below the bladder and above the rectum (show figure 1). The prostate produces seminal fluid that helps carry sperm during ejaculation.

According to the American Cancer Society, about 234,000 men in the United States will be diagnosed with prostate cancer in 2006, and over 27,000 will die from this disease. Prostate cancer is the second most commonly diagnosed malignancy after skin cancer.

Although many men are diagnosed with prostate cancer, most of them do not die from their cancer. While the lifetime risk of being diagnosed with prostate cancer is about 17 percent, only 3 percent of men die from the disease. Furthermore, autopsies show that 30 percent of men 50 years and older die with undiagnosed prostate cancer. This suggests that prostate cancer may grow so slowly that many men die of other causes before they even develop symptoms of prostate cancer.

RISK FACTORS

Age — All men are at risk for prostate cancer, but the risk greatly increases with older age. Doctors rarely find prostate cancer in men younger than 50 years old.

Ethnic background — Black men develop prostate cancer more often than white men. They also are more likely to die of prostate cancer than white men.

Family medical history — Men who have a first-degree relative (a father or brother) with prostate cancer are more likely to develop the disease.

Diet — A diet high in animal fat may increase a man's risk of prostate cancer.

PROSTATE CANCER SCREENING — Prostate cancer screening involves two tests: A physical test called a digital rectal exam (DRE) A blood test that measures prostate specific antigen (PSA).

Digital rectal examination — The DRE is performed by a healthcare provider in the office by inserting a gloved, lubricated finger into the rectum to feel for any lumps or irregularities in the prostate gland (show figure 2). DRE can detect some cancers that are missed by the PSA test. However, because it is not possible to reach all areas of the prostate, some tumors can go undetected using this screening method alone. Additionally, microscopic prostate cancers are impossible to detect by touch, no matter where they are located.

Prostate specific antigen — PSA is a protein produced by the prostate. The serum PSA test measures the amount of PSA in a sample of blood. Although many men with prostate cancer have an elevated PSA concentration (greater than 4.0 ng/mL), a high level does not necessarily mean there is a cancer. The most common cause for an elevated PSA is benign prostatic hyperplasia (BPH), a noncancerous enlargement of the prostate. Other benign causes include prostate infection (prostatitis) and trauma. Trauma may be caused by bicycle riding or sexual activity; thus, the PSA should not be measured for 48 hours after these activities.

Generally speaking, the higher the PSA, the greater the chance that a cancer is present. However, in some studies, over 20 percent of men with prostate cancer had a normal PSA (false-negative test), while up to 40 percent of men without cancer had an abnormal PSA (false-positive test). Overall, only 30 percent of men with abnormal values will have prostate cancer.

Thus, the PSA test is not 100 percent accurate. False-negative results can delay diagnosis until the cancer is more advanced and less likely to be curable. False-positive results, which are common, can cause anxiety and lead to further testing that is more expensive to perform and is uncomfortable for patients.

Refinements in PSA blood testing such as measuring PSA velocity (rate of change over time), PSA density (PSA per volume of prostate tissue), free (unbound) PSA, and complex (bound to protein) PSA are intended to increase the accuracy of PSA tests, but there is not general agreement about the additional benefits of these tests.

If the DRE or PSA test is positive — A positive DRE or PSA test is not a reason to panic; benign conditions are the most common causes for an abnormal test, particularly for PSA tests. On the other hand, a positive test should not be ignored. Other tests, like transrectal ultrasound and prostate biopsy, are needed to evaluate a positive DRE or PSA.

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

Prostate biopsy — Prostate biopsy is also performed without sedation or anesthesia. It is done by inserting a small device into the rectum that can take a small sample of any suspicious areas (found either with DRE or ultrasound). Tissue samples are also taken from the base, middle, and tip of each side of the prostate. Some men experience temporary, mild rectal bleeding or blood in the urine or semen after this procedure. Rarely, biopsy can cause heavy bleeding or infection.

Up to one in five men with a negative result on an initial biopsy may have cancer diagnosed after subsequent biopsies. In addition, prostate biopsy can detect clinically unimportant cancers that are unlikely to cause illness or death; subsequent treatment for these cancers can ultimately cause more harm than good.

Summary — No screening test for prostate cancer is perfect. Experts who favor it suggest that the best screening strategy combines DRE with PSA testing, followed by transrectal ultrasound-guided prostate biopsy if either test is positive.

PROS AND CONS OF SCREENING — There are a number of arguments for and against prostate cancer screening.

Arguments for screening — Experts in favor of prostate cancer screening cite the following arguments: Even though many men with prostate cancer have nonaggressive tumors and do not die of the disease, the cancer is so common that a substantial number of men die from the cancer every year and many more suffer from the complications of advanced disease. For men with an aggressive prostate cancer, the best chance for curing it is probably by finding it at an early stage through screening and then treating it with surgery or radiation. Studies have shown that men who have prostate cancer detected by PSA screening tend to have earlier-stage cancer than men who have a cancer detected by other means. (See "Patient information: Advanced prostate cancer" and see "Patient information: Treatment for early prostate cancer"). The five-year survival for men who have prostate cancer confined to the prostate gland (early stage) is nearly 100 percent; this drops to 30 percent for men whose cancer has spread to other areas of the body. Chemotherapy and radiation therapy are relatively ineffective once prostate cancer has spread outside the prostate gland. The available screening tests are not perfect, but they are fairly good compared with screening tests for some other cancers, and they are easy to perform. The death rate due to prostate cancer has declined in recent years. This may be due to increased screening or improvements in prostate cancer treatment, particularly for advanced cancers. The death rate may also have declined due to changes in the ways that physicians complete death certificates.

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

Other arguments have also been made against screening: Because of the relatively high number of false-positive DRE and PSA tests, a number of screened men will undergo unnecessary further testing with transrectal ultrasound and prostate biopsy. These secondary tests are relatively safe to perform, but they are not totally without side effects, and they add further costs. The side effects of treatment for early prostate cancers that are detected with screening may be substantial. Surgery and radiation therapy are the most popular therapies, and both can cause erectile dysfunction, urinary incontinence, and bowel problems. Although there are some tools to predict which cancers are more aggressive than others, these tools are not always accurate.

Many prostate cancers detected with screening are unlikely to cause death or disability. Thus, a number of men will have to experience the side effects of surgery and radiation for cancers that would never have bothered them had they gone undetected. In other words, even if the screening process works and a cancer is detected, it is not clear in all cases that the treatment is more beneficial than harmful.

PREVENTION OF PROSTATE CANCER

Supplements — Studies suggest that vitamin E and selenium supplements may protect against prostate cancer, but there is not enough evidence to recommend these supplements to all men.

Medications — Finasteride (Proscar®) has been shown to reduce the risk of developing prostate cancer by about 25 percent. However, aggressive cancers were diagnosed more frequently during the first year in men treated with finasteride than in those taking a placebo (look-alike substitute that contains no medication) pill. The reasons for this finding are not clear. It is not clear if finasteride should be offered to men at high risk for prostate cancer.

RECOMMENDATIONS

Professional organizations — Major medical associations and societies have issued conflicting recommendations regarding screening, making it difficult for an individual to decide if screening is right. The United States Preventive Services Task Force [2] and many European cancer societies have not endorsed routine serum PSA screening for the early detection of prostate cancer, while the American Cancer Society [3] and American Urological Association [4] do recommend screening. With currently available data, it is not possible to determine if the benefits of screening outweigh the significant risks associated with treatment.

A number of studies are expected to be completed over the next several years that should help clarify this controversy. In the meantime, the American Cancer Society, American Urological Association, and American College of Physicians recommend that men have an open discussion with their clinician.

The best way to decide if prostate cancer screening is right is to: Consider individual prostate cancer risk factors Know the potential benefits and harms of screening, diagnosis, and treatment Talk to a clinician about concerns or questions.

For men who choose screening — If a man chooses to have screening, he should begin at age 50. Men with risk factors for prostate cancer (such as black men or a man with a father or brother who had prostate cancer) may want to begin screening at the age of 45.

Screening should continue yearly once it is started, though less frequent testing may be appropriate for some men with a low PSA. For men who choose screening, we suggest that those with a PSA level below 1.0 ng/mL consider having PSA testing every four years and that those with a higher PSA level consider having PSA testing annually. We suggest that men who choose screening have an annual digital rectal exam, regardless of their PSA level.

Screening not recommended — Screening should not be performed in men who are 75 years and older or who have serious health problems; these men are unlikely to live long enough to benefit from screening and/or treatment.

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.patients.uptodate.com). 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. National Cancer Institute

1-800-4-CANCER
(www.cancer.gov/cancertopics/screening/prostate)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
US TOO! Prostate Cancer Education and Support

(www.ustoo.com/Early_Detection.asp)

[1-6]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Prostate cancer. National Cancer Institute. Web site: http://cancernet.nci.nih.gov/cancertopics/types/prostate.
2. Screening for prostate cancer: recommendation and rationale. Ann Intern Med 2002; 137:915.
3. Smith, RA, von Eschenbach, AC, Wender, R, et al. American Cancer Society Guidelines for the early detection of cancer: update of early detection guidelines for prostate, colorectal, and endometrial cancers. CA Cancer J Clin 2001; 51:38.
4. Prostate-specific antigen (PSA) best practice policy. American Urological Association (AUA). Oncology (Williston Park) 2000; 14:267.
5. Whittemore, AS, Cirillo, PM, Feldman, D, Cohn, BA. Prostate specific antigen levels in young adulthood predict prostate cancer risk: results from a cohort of Black and White Americans. J Urol 2005; 174:872.
6. Carter, HB. Prostate cancers in men with low PSA levels--must we find them?. N Engl J Med 2004; 350:2292.

Prostate cancer screening

Advanced prostate cancer

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 serum 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, and in some men, symptomatic progression of prostate cancer will never occur. Despite this fact, many men are uncomfortable with an untreated rising serum 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 aggresive cancers (ie, lower Gleason grade and lower serum PSA level), and a slowly rising PSA level. (See "Salvage local therapy for a rising serum 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: Treatment for early prostate cancer").

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). Various combinations of T, N, and M stage are then 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).

According to this system, 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 molecule 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®). They are all administered 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 [11]. 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 while orchiectomy is a one-time surgical procedure. For men without health insurance prescription drug coverage, GnRH agonist therapy can be expensive.

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. Antiandrgens 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 [11].. (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 initiating 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 deferred until symptoms develop.

Some research results suggest that earlier ADT decreases the likelihood of dying from prostate cancer and delays the onset of symptoms [7,8]. Neither of these studies was performed in men with a rising serum 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 [7]. 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) [8]. 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 [9]. 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").

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. Studies show that regular injections of a bisphosphonate medication (eg, zoledronic acid, Zometa®) can prevent bone loss during long-term ADT [1], and regular exercise may also delay the loss of lean muscle. Most experts recommend that all men beginning ADT increase their calcium intake to 1200 to 1500 mg daily and take vitamin D supplements. (See "Patient information: Calcium for bone health" and see "Patient information: Osteoporosis causes, diagnosis, and screening").

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 serum PSA), stopped, then restarted when the serum 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 [10].

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 [11]. Some experts consider a temporary discontinuation of treatment if the serum 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 and their effectiveness as sole therapy for advanced prostate cancer is controversial. However, antiandrogens alone are attractive as a treatment option for men with minimal 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 monotherapy with an antiandrogen be discussed, but the guidelines do not specifically recommend this strategy over conventional methods of ADT (such as orchiectomy or a GnRH agonist) [11].

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 the first approach should be to discontinue ADT, particularly antiandrogens. Research shows that withdrawal of antiandrogen therapy often results in improvements in the symptoms and signs of the disease. The time it takes for improvements to be noticed depends upon the drugs being used. When antiandrogens are withdrawn, a man must wait several weeks or months before knowing if this approach has been effective.

Another approach for androgen-resistant prostate cancer is to use 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, the antifungal medication ketoconazole, and corticosteroids (eg, dexamethasone [Decadron®] or prednisone).

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.

In the past, chemotherapy was considered ineffective in treating prostate cancer, but newer research suggests that this is not necessarily true. Newer chemotherapy regimens include active drugs such as docetaxel. In 2004, two landmark trials were published that showed that docetaxel-containing regimens were associated with significantly longer survival compared to other regimens [1,2].

Because of these data, most physicians consider docetaxel plus prednisone the standard chemotherapy regimen for men with HRPC.

SALVAGE LOCAL THERAPY FOR A RISING SERUM 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 aggresive cancers (ie, lower Gleason grade and lower serum 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 immediate postoperative EBRT was not administered. 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 serum PSA (optimally 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 8, T2b disease, show table 1), or if the post-prostatectomy PSA doubling time is 10 months, the addition of 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 prostatectomy — Selected men with a rising serum 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 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 (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 also receive 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 [14].

The optimal duration of ADT in this setting is controversial; some studies suggest that four months is sufficient (two months before and during EBRT) while others show benefit from an additional two or three years of ADT following EBRT. Some research findings suggest that men with more aggressive prostate cancers (those men with a higher Gleason grade and higher pretreatment serum PSA level) may benefit from a longer duration of ADT [].

EBRT plus brachytherapy — 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 []. 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 [,].

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.patients.uptodate.com). 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.plwc.org/portal/site/PLWC)
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)

[13,14]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Smith, MR, McGovern, FJ, Zietman, AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345:948.
2. Bolla, M, Gonzalez, D, Warde, P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295.
3. Roach, M, Lu, J, Pilepich, MV, et al. Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int J Radiat Oncol Biol Phys 2000; 47:609.
4. Ward, JF, Slezak, JM, Blute, ML, et al. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005; 95:751.
5. Van Poppel, H, Goethuys, H, Callewaert, P, et al. Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer. Eur Urol 2000; 38:372.
6. Gerber, GS, Thisted, RA, Chodak, GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997; 32:385.
7. 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.
8. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 1997; 79:235.
9. Dotan, ZA, Cho, D, Rhee, AC, et al. The role of hormonal treatment for biochemical recurrence in patients following radical prostatectomy (abstract). Proc Amer Soc Clin Oncol 2003; 22:381a.
10. Goldenberg, SL, Bruchovsky, N, Gleave, ME, et al. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 1995; 45:839.
11. 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.
12. Picus, J, Halabi, S, Hussain, M, et al. Long term efficacy of peripheral androgen blockade on prostate cancer: results of CALGB 9782 (abstract). J Clin Oncol 2006; 24:234s. (Abstract available online at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed August 22, 2006).
13. Tannock, IF, de Wit, R, Berry, WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351:1502.
14. Petrylak, DP, Tangen, CM, Hussain, MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351:1513.

Pages

Saturday, October 13, 2007

Treatment for early prostate cancer

Prostate cancer screening

Prostate cancer screening

Advanced prostate cancer