Prostate cancer is second only to lung cancer as the leading cause of cancer deaths in American men. In 1997, approximately 209,900 new cases of prostate cancer were diagnosed, and more than 41,800 deaths were attributed to this malignancy.¹ At present, chemotherapy and immunotherapy cannot cure prostate cancer once it has spread beyond the gland. Therefore, curative treatment for localized tumors may be the best hope of lowering the mortality rate for prostate cancer.¹ According to this viewpoint, the primary focus of prostate cancer management should be the detection and aggressive treatment of tumors while they are still confined to the prostate.

The discovery of prostate-specific antigen (PSA) has made it possible to detect tumors before they become palpable on rectal examination. Improvements in radiotherapy and surgical techniques have decreased the complications of treatment and provided acceptable cure rates. However, the enthusiasm for prostate cancer screening must be tempered by the lack of evidence that its routine use can improve the quality and quantity of life for the overall population. Furthermore, a prostate cancer screening program is expensive, and the present treatments for this malignancy can be associated with significant side effects.

The controversial aspects of prostate cancer screening are reviewed in this article. An attempt is also made to identify the patient groups that definitely would benefit from prostate cancer screening. Current treatment approaches for tumors confined to the prostate are also reviewed.

Prostate Cancer Screening Controversy

The effectiveness of a cancer screening program depends on a number of factors. The malignancy must be detectable with minimal harm and cost, and early diagnosis must be able to improve the quantity and quality of the patient's life. An effective treatment for the cancer must be available, and this treatment should have few side effects. Finally, treatment of the asymptomatic patient must provide a better outcome than treatment after the disease has become clinically evident.

At this time, prostate cancer screening does not fulfill all of the requirements for an effective screening program. Some evidence shows that, compared with screening by rectal examination alone, routine screening of asymptomatic patients with PSA testing and digital rectal examinations detects a higher percentage of cancers that are localized to the prostate.² However, both the American Academy of Family Physicians³ and the U.S. Preventive Services Task Force⁴ recently recommended against the use of routine prostate cancer screening for two reasons: (1) early prostate cancer detection has no proven benefit and (2) the potential side effects of treatment may outweigh the benefits. In contrast, the American Cancer Society and the American Urological Association⁵ recommend the use of a PSA-based screening program to detect prostate cancer in men 50 years of age and older.

The main problem with prostate cancer screening is that even though this malignancy is extremely common, it is the actual cause of death in only a small proportion of patients who have histologic evidence of prostate cancer. Although data from autopsies indicate that approximately 70 percent of 80-year-old men have prostate cancer,⁶ this malignancy is the cause of death in only 3 percent of all men.⁷ Prostate cancer is often an incidental finding in elderly patients. The tumor grows so slowly that no symptoms appear; in essence, patients often die of other causes before the cancer causes serious problems. Thus, prostate cancer screening programs may result in the detection and treatment of many asymptomatic cancers that will have no impact on length of life.

In the era of medical cost containment, the expense of a prostate cancer screening program must be considered, especially because other preventive health care measures, including smoking cessation programs, colon cancer screening, vaccination programs and prenatal care programs, may have greater impact on the overall health of the total population. These potentially more useful programs compete for funding with prostate cancer detection programs.

Although an individual PSA test is relatively inexpensive ($20 to $40), expenses multiply when a patient with an abnormal PSA test must be evaluated. Transrectal ultrasound examination costs approximately $100 per patient, and random biopsies cost another $150. Pathologic evaluation of the biopsy specimens costs approximately $300 per patient. When compounded by the fact that three patients without cancer must be evaluated for each cancer that is detected,⁸ the estimated overall cost of initiating a nationwide prostate cancer screening and treatment program for all eligible men ranges from $8.5 to $25.7 billion per year.⁹

Prostate cancer screening does have a number of potential benefits. Evidence exists that screening programs based on PSA testing will detect only clinically significant malignancies (i.e., larger and more aggressive tumors that will cause significant symptoms or decrease the patient's life span if they are left untreated).¹⁰ Furthermore, it is clear that every year more than 40,000 men die from prostate cancer. At present, early detection and treatment are the only effective measures for decreasing the mortality rate for this malignancy. Finally, some evidence shows that the aggressive diagnosis and treatment of prostate cancer is having an effect: 1997 was the first year in which the mortality and incidence rates for prostate cancer were expected to decrease.^11,12 It is too early to attribute these changes to prostate cancer screening programs initiated in the mid-1980s. However, screening programs that use PSA testing have been shown to reduce the number of patients who present with metastatic tumors or markedly elevated PSA levels.²

Indications for Prostate Cancer Evaluation

It is reasonable to search for prostate cancer in the male patient who is having difficulty voiding (slow stream, urgency) or hematuria, or who has signs and symptoms of metastatic cancer (bone spread resulting in an elevated alkaline phosphatase level and progressive back pain, sciatica or lower extremity neurologic impairment). Either curative treatments for cancers confined to the prostate (radical prostatectomy or radiotherapy) or palliative treatments for metastatic disease (orchiectomy to eliminate androgen stimulation to the tumor) are likely to decrease symptoms and improve quality of life.

Routine prostate cancer screening in asymptomatic patients is more controversial. The eventual decision to offer prostate cancer screening must be tempered by several factors: (1) prostate cancer has no cure once it has spread beyond the prostate, (2) prostate cancer treatment has potential complications, including impotence and incontinence, and (3) screening may identify a cancer that may never cause symptoms or decrease life expectancy.

The decision to offer prostate cancer screening must be made on an individual basis, depending on the patient's age, health status, family history, risk of prostate cancer and personal beliefs. The patient must be informed about the risks and potential benefits of screening. The patient also must be helped to realize that while prostate cancer can grow quickly, it generally grows quite slowly. In most men, a high-fat diet, smoking, lack of exercise and excessive alcohol intake can have a greater impact on life span than prostate cancer.

The risk of dying from prostate cancer is higher in certain patients, including all African-American men and men who have a first-degree relative with prostate cancer.¹³ Since these men may be genetically predisposed to the development of prostate cancer, the American Urological Association⁵ recommends that they be evaluated with annual PSA testing and rectal examinations, beginning at 40 years of age.

For all other men, prostate cancer screening should be performed at the age of 50 years in those who wish to undergo evaluation. Annual examinations can then be considered. Changes in the rectal examination or a rise in the PSA level of greater than 0.7 ng per mL per year are suggestive of cancer.

Prostate cancer screening probably should not be done once patients are over the age of 70 or if they develop a significant underlying medical illness or other incurable malignancy that will decrease their life expectancy to less than 10 years.

Approach to Prostate Cancer Screening

Patients generally should be evaluated by a urologist if physical examination of the prostate reveals any area of asymmetry, nodularity or induration, because up to 50 percent of these findings will be caused by prostate cancer.⁸ The problem with using only the digital rectal examination as a screening tool is that it does not detect cancers before they have spread beyond the prostate. More than 50 percent of prostate cancers diagnosed by digital rectal examination have spread locally or have metastasized to lymph nodes or bone.

The approach to screening has been revolutionized by the discovery of PSA as a serum marker that is 70 to 80 percent sensitive for prostate cancer. This serum marker is a protein made only by prostate cells. Serum PSA levels are proportional to either the total volume of prostate tissue or the amount of irritation in the prostate (such as occurs with carcinoma or inflammation). Either increased volume or irritation causes PSA to spill from the prostate into the bloodstream.

When PSA testing is used alone, it can detect up to 80 percent of prostate cancers. However, the PSA test is not very specific, since only one third of men with an abnormal serum PSA level actually have cancer.⁸ Numerous attempts have been made to enhance the ability of PSA to distinguish between benign and malignant disease. The test enhancements that have been tried include the following: the free PSA test, which looks at the amount of PSA that is not bound to plasma proteins; the PSA density test, in which PSA levels are adjusted to the size of the prostate; the PSA velocity test, in which PSA changes are observed over time; and PSA age-adjusted ranges, because the PSA level can rise with age. Of all these methods, the use of age-adjusted ranges appears to be the most useful, since this enhances cancer detection in younger patients, who benefit most from early diagnosis and treatment, and decreases the number of biopsies performed in older men, who are at less risk of dying from prostate cancer (Table 1).¹⁴

Once initial prostate cancer screening has been performed, the physician must decide how often the patient should be reevaluated. Compared with one-time screening, yearly digital rectal examinations and PSA testing detect a higher proportion of organ-confined cancers. Almost 75 percent of patients with prostate cancer detected on serial screenings are found to have organ-confined and therefore potentially curable cancer, compared with 66 percent of patients who undergo only a single screening.¹⁵

Before serial screening is performed in an asymptomatic patient, the risks and benefits of diagnosis should be discussed, and informed consent should be obtained. Another important consideration is the presence or absence of competing co-morbid conditions.¹⁶ The authors of this article believe that serial screening should be performed in all patients who have a family history of prostate cancer. Biopsy specimens should be obtained if the PSA level rises more than 0.7 ng per mL per year or the contour of the prostate gland changes.

Guidelines on serial screening have recently been published.^2–5 It should be remembered, however, that these recommendations are based on limited scientific information. The American Cancer Society¹ recommends that, beginning at the age of 50 years, men with a life expectancy of at least 10 years should be offered annual digital rectal examinations and PSA tests. Alternatively, some investigators have suggested that examinations may need to be performed only every other year in patients with a serum PSA level of less than 2 ng per mL, given the extremely low incidence of cancer found in this group.¹⁷

Once a patient reaches 70 years of age or competing comorbid conditions limit survival beyond 10 to 15 years, consideration can be given to terminating prostate screening as long as the patient remains asymptomatic.

Indications for Urologic Referral

If abnormalities are detected on the digital rectal examination or PSA test, patients should undergo urologic evaluation with transrectal ultrasound-guided prostate biopsy. No further urologic evaluation is necessary in patients who have an unremarkable digital rectal examination and a normal serum PSA level, because the incidence of prostate cancer is only 0.4 percent in this group.¹⁵

Transrectal ultrasound examination and guided prostate biopsies are office-based procedures that are well tolerated by patients. The procedures require no adjuvant sedation or analgesia. Rare complications of transrectal prostate biopsy include rectal bleeding and sepsis. Most patients report only mild rectal spotting, hematospermia or hematuria after the test.

Before transrectal prostate biopsy is performed, the patient should stop taking warfarin (Coumadin), aspirin and other nonsteroidal anti-inflammatory medications for 10 days and should not have a urinary tract infection. On the morning of the examination, the patient should have a saline laxative enema (Fleet or other brand). The patient should also be given an oral dose of a broad-spectrum antibiotic.

Treatment Options

The standard treatment options for prostate cancer include radical prostatectomy, radiotherapy and watchful waiting (Table 2). Unfortunately, the choice of treatment cannot be based on firm scientific evidence that one form of treatment works better than another, since no studies to date have compared these options in similar patient populations. Thus, treatment decisions are based more often on the side effects, long-term risks, and financial and emotional costs of the different therapies.

Young healthy patients most often are encouraged to undergo radical prostatectomy, and older patients are steered toward observation or radiotherapy. This general approach has been justified by the risks and benefits associated with radical prostatectomy, radiotherapy and observation. In the end, however, the treatment choice has to be based on the patient's preference, given his understanding of the benefits and side effects of each option. Through discussions with his family physician, a radiotherapist and a urologist, the patient should be able to obtain the information needed to make an informed decision.

Because prostate cancer usually grows slowly, the patient can postpone treatment for one to two months without an increased risk of spread. This should give the patient ample time to obtain multiple medical opinions about treatment options.

Radical Prostatectomy

The prostate is wrapped around the urethra like a doughnut. In radical prostatectomy, the entire prostate is excised from the urethra and bladder, which are then reconnected. Currently, the average hospital stay after radical prostatectomy is two to three days. Most patients are able to eat a regular diet within two days of surgery. Full activity usually can be resumed by one month after radical prostatectomy.

Side Effects

Severe complications from radical prostatectomy are relatively uncommon. However, damage to the urinary sphincter and penile nerves during surgery can result in postoperative urinary incontinence and impotence. According to our review of most current series, only 20 percent of patients who undergo radical prostatectomy have any degree of stress urinary incontinence following surgery, and fewer than 1 percent have severe leakage (Table 3).

Impotence is a more common problem after radical prostatectomy. Although the technique of peeling the erectile nerves away from the lateral edge of the prostate has markedly improved the surgeon's ability to preserve the patient's sexual function, our review indicates that the return of normal erections also depends on the patient's age and his preoperative sexual function (Table 4). Overall, postoperative impotence rates are high. However, even if the erectile nerves are removed during radical prostatectomy, penile sensation and the ability to have an orgasm are preserved.

Therapies for erectile dysfunction are now available. Minimally invasive approaches include vacuum constriction devices, intra-urethral prostaglandin pellets and sildenafil (an oral medication for erectile dysfunction currently being evaluated by the U.S. Food and Drug Administration). With these therapies, the impact of postoperative erectile dysfunction can be minimized.

Cancer Control After Surgery

Cancer can recur after radical prostatectomy. A tumor recurrence may become detectable on physical examination or by radiologic evaluation (clinical recurrence), or it may be suggested by a rising PSA level (biochemical recurrence). The postoperative serum PSA level should be less than 0.1 ng per mL, which represents the lower limit for which most laboratory assays can reliably measure PSA. A PSA level that is above 0.1 ng per mL after surgery is definitive proof that prostate cells are growing somewhere in the patient and implies that the cancer persists.

Overall cure rates for radical prostatectomy generally fall between 60 and 70 percent.^18,19 Although these cure rates are similar to those for radiotherapy, two factors related to cancer recurrence must be considered. First, the rate of clinically detectable recurrence in the pelvis after radical prostatectomy has been very low (5 percent).¹⁹ Radical prostatectomy appears to provide better local control of cancer than radiotherapy. Furthermore, this surgical procedure is not associated with the complications of bleeding, urinary obstruction and perineal pain that can occur if the tumor comes back after radiotherapy. Second, PSA-based cancer recurrence after surgery does not necessarily imply that a clinically significant cancer relapse will follow or that death from recurrent cancer is inevitable.²⁰ It has been shown that a significant proportion of patients with a rising PSA level (especially when the level is rising very slowly) remain free of any signs or symptoms of the recurrent cancer, despite the presence of a detectable PSA level. Many such patients are likely to outlive the recurrent cancer without needing additional treatment.²⁰

Radiotherapy for Localized Prostate Cancer

External-beam radiotherapy appears to be as effective as surgery in curing prostate cancer, at least for the first 10 years after treatment.²¹ Radiotherapy is well tolerated, and it is associated with no hemorrhagic or anesthetic risks. Furthermore, this treatment option does not require hospitalization or a significant recovery period. Normal activity can usually be maintained during radiotherapy. However, treatment is administered daily for four to six weeks, and many patients report feeling fatigued at the end of this period.

Compared with surgery, radiotherapy has several potential disadvantages. Radical prostatectomy provides more definitive information about long-term prognosis, because the size of the tumor, the presence of cancer spread and the presence of cancer in the lymph nodes can be determined from the surgical specimen. With radiotherapy, the post-treatment status of the tumor is unknown; serial PSA levels serve as surrogate markers to determine whether the treatment was curative.

Radiotherapy can also have significant side effects (Table 5).²² It is associated with severe bladder irritation (urgency, pain and frequency) in as many as 5 percent of patients. Rectal irritations (diarrhea, urgency, tenesmus and bleeding) occur in 3 to 10 percent of patients who receive radiotherapy for prostate cancer, and impotence is a problem in 40 to 50 percent of patients receiving this treatment.²²

The two types of radiotherapy are external-beam irradiation and implantation of radioactive pellets (seeds). Although neither approach has been shown to be superior in terms of long-term outcome, seed implant therapy has been gaining in popularity since its introduction a few years ago. Theoretically, seed implants can deliver a higher dose of radiation to the prostate with fewer side effects. However, seed implant radiotherapy is not yet widely available, and it may be associated with a higher incidence of rectal pain.

Over a period of more than 10 years, the chance of cure may not be as great with radiotherapy as with surgery.²³ In patients treated with radical prostatectomy, most cancer recurrences occur within the first four years after surgery. With radiotherapy, however, cancers can recur over a much longer period of time, because the prostate cancer may not be completely destroyed by external-beam or seed-implant treatment.

Watchful Waiting

The term “watchful waiting” implies that the patient undergoes a program of observation, with palliative treatments initiated if symptoms of progressive cancer appear. Palliative measures may include orchiectomy or hormone deprivation therapy using agents such as leuprolide (Lupron). Watchful waiting is a reasonable option in elderly patients, patients with low-grade tumors and patients with other medical illnesses that reduce life expectancy to less than 10 years.

The main advantage of watchful waiting is that it has no side effects. Because life expectancy is similar in men who have untreated low-grade cancers and men who do not have cancer, watchful waiting avoids both the overtreatment of indolent cancers and the occurrence of treatment side effects.²⁴

Watchful waiting does have limitations and risks. By its very nature, this approach prevents the patient from receiving potentially curative therapy, in that treatment decisions are deferred until the cancer has progressed. Once cancer progression occurs, only palliative treatments such as hormone deprivation therapy can be instituted, and death from prostate cancer usually occurs within two years of the appearance of metastatic disease. Although many patients do well under watchful waiting programs, some patients have cancer progression, develop symptoms and eventually die from prostate cancer. In Sweden, where watchful waiting is the rule, the per capita death rate from prostate cancer is one of the highest in the world.²⁵

When watchful waiting is being considered, it's important to be sure patients understand the following: (1) their risk of cancer progression and death from prostate cancer is increased if treatment is deferred; (2) only palliative treatments can be employed if their cancer progresses; and (3) PSA levels must be checked every three to six months to determine if the cancer has progressed. Despite these factors, watchful waiting is definitely a reasonable option in older patients with low-grade prostate cancer and significant comorbidity. This approach may allow these patients to live a normal life span without the side effects and expense of aggressive treatment programs.²⁶