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)


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