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Previous Volume 331:996-1004 October 13, 1994 Number 15 Next

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Prostate cancer is the second leading cause of death from cancer among men; 25 percent of men with prostate cancer die of the disease¹. Moreover, many patients who do not die of prostate cancer require treatment to ameliorate symptoms such as pain, bleeding, and urinary obstruction. Thus, prostate cancer is also a major cause of suffering and of health care expenditures.

The high rate of mortality from prostate cancer may be due to late detection. In recent studies, screening for prostate cancer has combined the measurement of serum prostate-specific antigen (PSA) -- the most accurate single test for the detection of prostate cancer -- with the more traditional approach of digital rectal examination. As compared with other diagnostic approaches, these two procedures, in conjunction with ultrasound-guided biopsy of the prostate, increase the overall rate of cancer detection by 70 percent, double the detection rate for organ-confined cancers, and avoid detection of most medically unimportant cancers (only 7 percent of detected cancers are microfocal and low in grade)^2,3,4. The National Cancer Institute has initiated a large trial to determine whether screening for prostate cancer with serum PSA measurements and digital rectal examination will reduce morbidity and mortality, but this study will take several years to complete.

The American Cancer Society and the American Urological Association recommend that men who are 50 years of age or older undergo annual measurement of serum PSA and rectal examination for early detection of prostate cancer and that men at high risk for prostate cancer, such as blacks and those with a strong family history, undergo annual screening starting at the age of 40 years. Although there is uncertainty about the natural history of the cancers detected by screening, the available evidence suggests that most are clinically important⁴. Because treatment in the early stages of cancer is less costly than treatment in advanced stages, early detection with the use of these two procedures may be cost effective^5,6.

The management of prostate cancer may include watchful waiting, curative treatment, and palliation. Categorical recommendations for individual patients cannot be made on the basis of the medical literature, since valid comparisons of various strategies are lacking and since, owing to recent advances in detection and treatment, much of the existing literature is outdated. Thus, in making decisions about treatment, clinicians should give less weight to information about the established value of various treatments than to the patient's age and general health, the clinical stage^7,8 and histologic grade⁹ of the cancer, factors concerning the quality of life (e.g., the immediate risks associated with treatment vs. the subsequent risks associated with advanced cancer), and available resources (Table 1, Table 2, and Table 3) ¹⁰. In this regard, the treatment recommendations presented in Table 4 are intended as general guidelines.

View this table: [in this window] [in a new window]   Table 1. Tumor-Node-Metastasis (TNM) Classification of Prostate Cancer.

 

View this table: [in this window] [in a new window]   Table 2. Gleason System for Histologic Grading of Prostate Cancer.

 

View this table: [in this window] [in a new window]   Table 3. Complications of Treatments for Prostate Cancer.

 

View this table: [in this window] [in a new window]   Table 4. Recommended Treatment of Prostate Cancer According to the Stage of the Disease and Qualifying Conditions.

 
Treatment of Patients with Clinically Localized Disease (Stage T1 or T2)

In selected groups of patients with clinically localized prostate cancer, all the available treatments result in rates of survival that are comparable to the expected survival rate for the general population^11,12,13. These uniformly good results can be attributed to the favorable natural history of indolent cancers, the early detection and effective treatment of aggressive cancers, the confounding effects of competing causes of death, and the equalizing effect of hormonal therapy for relapses.

Watchful Waiting and Hormonal Therapy

Watchful waiting is appropriate for men with a life expectancy of less than 10 years who have low-grade, low-stage prostate cancer discovered at the time of a partial prostatectomy for benign hyperplasia (stage T1a). These cancers rarely progress during the first 5 years after they have been detected, but in 10 to 25 percent of patients they progress within 10 years^14,15.

Watchful waiting has resulted in low rates of death from prostate cancer (9 to 15 percent) among men with localized disease, raising a question about the need to treat all men with localized disease^13,16,17. Although these results pertain to patients who are in low-risk categories, they do not necessarily apply to younger men at higher risk, who are underrepresented in the studies of watchful waiting^17,18. The high rates of disease progression (34 to 80 percent) in the studies of watchful waiting indicate that few clinically evident prostate cancers are dormant. Younger men with stage T1a tumors, who have a longer projected period of risk than do older men with the same stage of disease, are candidates for potentially curative treatment.

Because prostate cancer is an androgen-dependent tumor, primary hormonal therapy is an option for men with clinically localized disease, especially older men who are not suitable candidates for more aggressive treatment.

Radical Prostatectomy

In men with clinically localized prostate cancer whose life expectancy is 10 years or more, the goal of treatment should be to eradicate the disease. For those whose cancers are confined to the prostate, radical prostatectomy offers the best chance of achieving this goal. In the only randomized trial comparing radical prostatectomy with radiation therapy, prostatectomy resulted in a higher rate of progression-free survival at five years¹⁹. This trial has been criticized because some patients did not receive the treatment they were randomly assigned to receive and the results in the patients treated with radiation were less favorable than those reported at most centers²⁰.

In uncontrolled studies, the 15-year survival rates among patients with clinically localized disease who were treated with radical prostatectomy were excellent: 86 to 93 percent^12,21,22. A National Institutes of Health consensus conference concluded that the 10-year survival rates with radical prostatectomy and radiation therapy were similar. In the studies reviewed at the conference, however, the cancers were not detected as early, characterized as accurately, or treated as effectively as cancers that are diagnosed and treated with current methods.

Until recently, the major drawback of radical prostatectomy was that most cancers had spread beyond the bounds of the operation by the time they were detected²³. This has become less of a problem since the introduction of PSA testing to detect cancer in the early stages. Early detection also allows less extensive surgery, with fewer complications. For example, nerve-sparing radical retropubic prostatectomy, which preserves erectile function in many men by avoiding injury to the cavernosal neurovascular bundles, can be performed in men with tumors detected at an early stage^24,25.

Nerve-sparing prostatectomy may compromise the adequacy of cancer excision,²⁶ but in appropriately selected patients (i.e., those likely to have disease confined to the prostate), the results of treatment are not compromised. The single study of the control of cancer after nerve-sparing prostatectomy reported results that were as good as or better than any previously reported²⁷.

The advisability of radical prostatectomy in men with bulky, high-grade tumors (T2b) has been questioned²⁸. These tumors are the least likely to be cured with surgery and are also the least likely to be treated effectively with radiation. The prognosis is excellent after radical prostatectomy if the tumor is confined to the prostate²¹. Men with stage T2b disease treated with nerve-sparing surgery, as compared with those undergoing standard radical prostatectomy, have a higher risk of cancer at the margins of the excised tissue²⁷.

A pelvic lymphadenectomy is usually performed before a radical prostatectomy in order to determine the stage of the disease. In patients with low-stage, low-grade tumors and serum PSA concentrations under 10 µg per liter, lymphadenectomy is optional because of the low risk of metastases.

Salvage Therapy after Radical Prostatectomy

Serum PSA concentrations rise within five years after radical prostatectomy in 3 to 11 percent of men with pathologic evidence of tumors confined to the prostate (pT1 or pT2 disease) and in 15 to 40 percent of men with pathological evidence of focal, extracapsular tumor extension (pT3 disease)^26,29,30. Extensive positive margins and invasion of the seminal vesicles are associated with even higher rates of relapse (30 to 66 percent)^26,28,29.

Detectable serum PSA concentrations after surgery indicate persistent cancer or, in rare cases, retained prostatic tissue. Men with serum PSA concentrations that remain detectable after surgery or are undetectable initially after surgery but later rise may benefit from radiation therapy to the prostatic bed. This treatment reduces serum PSA concentrations to the undetectable range in 30 to 80 percent of men, the response rate being at the higher end of the range if the increase in the serum level is delayed. In 30 to 60 percent of men who have a response to radiation therapy, however, the serum PSA concentration will rise again within two years^31,32,33,34.

Adjuvant radiation therapy reduces the rate of local recurrence but has little effect on survival^35,36,37. For men with extensive, high-grade cancer, who are at high risk for distant metastases, hormonal therapy is more appropriate than radiation therapy.

Radiation Therapy

Radiation therapy has been widely used for clinically localized (T1 or T2) disease, with 15-year rates of disease-free survival of 45 to 85 percent³⁸. Radiation has been used preferentially in older, less healthy patients and those with higher-grade, more clinically advanced tumors. Like radical prostatectomy, radiation therapy does not cure men with occult metastases, nor does it consistently eradicate all cancer cells within the treatment field³⁹. Impotence occurs in 40 to 60 percent of patients after external-beam radiation therapy^37,40.

The best results have been achieved with external-beam therapy^11,37,39. Serum PSA concentrations may rise transiently during treatment⁴¹ but almost always decline during the first year after treatment. Unfortunately, serum PSA concentrations rise again, often without suspicious findings on rectal examination, in 50 to 75 percent of patients within 5 years and in 80 percent within 10 years^42,43. This rate of biochemical relapse is higher than that after radical prostatectomy (3 to 40 percent), except in patients treated with prostatectomy who have had evidence of seminal-vesicle or lymph-node involvement^26,28,29,44. Biopsies reveal cancer in 20 to 63 percent of patients 18 months or more after radiation treatment. Positive biopsy specimens are frequently associated with rising serum PSA concentrations and subsequent distant metastases⁴⁵.

For patients with stage T1 disease, the overall rate of survival with radiation therapy is equivalent to that of the general population. There is conflicting evidence on the question of whether complications of radiation -- especially urethral stricture and incontinence -- occur more frequently after partial prostatectomy⁴⁶. For patients with stage T2 tumors, survival ranges from a rate equivalent to that of the general population to a rate about 20 percent below that of the general population^11,47.

Conformal radiation therapy is a new method in which the field of radiation is designed to conform to the volume of tissue treated⁴⁸. This method involves a computerized three-dimensional reconstruction of the prostate, and the patient must be immobilized during treatment. Morbidity is reduced, and the dose of radiation to the tumor can be increased by about 10 percent. Other experimental approaches include the use of heavy-particle radiation,⁴⁹ hypoxic sensitizers,⁵⁰ and hyperthermia⁵¹.

Interstitial-radiation therapy, once popular because of its favorable results in preserving potency, is now used less frequently. With early techniques involving the use of seeds containing iodine-125 and gold-198, the dose of radiation was unevenly distributed, with poor results^52,53. New techniques have been developed in which seeds containing iridium-192⁵⁴ or palladium-103⁵⁵ are implanted with the guidance of ultrasonography, but the long-term results are not yet known.

Cost-Benefit Analysis of Potentially Curative Treatment

The results of a study using decision analysis suggest that only younger men with high-grade tumors benefit from radical prostatectomy or radiation therapy⁵⁶. However, this study focused on potent men over the age of 60 years -- those most likely to have side effects from either treatment -- and the natural history of prostate cancer was oversimplified in the statistical model. The data used to estimate the probability of cancer progression were derived mainly from patients with stage T1 disease. Moreover, the data used to predict the outcome of treatment did not reflect the results attainable with current methods of detection⁴ and treatment,^26,47 and the model did not incorporate patients' opinions about various outcomes. With watchful waiting, there is the risk that an opportunity for a cure will be missed, and until this approach is proved to be as effective as treatment in representative populations, it should not be recommended for men with a life expectancy of 10 years or more.

Treatment of Patients with Locally Advanced Disease (Stage T3)

It is questionable whether men with cancer that has spread beyond the prostate can be cured with a wide excision of the tumor or radiation therapy, because most such men also have occult distant metastases. Thus, the survival rates, which are often determined by the most common final treatment, hormonal therapy, are similar with all treatments -- that is, about 25 to 50 percent lower than the rate in the general population¹¹.

Conservative Management

In some patients, low-grade, stage T3 tumors have been managed with watchful waiting or transurethral resection, with acceptable results⁵⁷. The results of hormonal therapy, another conservative treatment, are equivalent to those of more aggressive approaches, but it is infrequently chosen by patients as the primary therapy because it does not offer a chance for a cure.

Radical Prostatectomy

In about 20 percent of men in whom small, stage T3 tumors have been identified, the clinical stage has been overestimated, and the cancer is therefore amenable to complete excision⁵⁸. Adjuvant hormonal therapy improves the results of radical prostatectomy for stage T3 disease, but equivalent results may be achieved with hormonal therapy alone⁵⁷.

Preoperative Hormonal Therapy and Radical Prostatectomy

The use of hormonal therapy before radical prostatectomy may reduce the percentage of stage T2 tumors with positive surgical margins -- or perhaps just make them more difficult for the pathologist to identify. It is doubtful, however, that hormonal therapy converts extracapsular tumors to those confined to the prostate⁵⁹.

Radiation Therapy

The 15-year survival rate after radiation therapy for stage T3 tumors is about half the normal survival rate^11,37,60,61. Nearly 90 percent of patients have rising serum PSA concentrations within 10 years after radiation therapy^41,42.

Adjuvant hormonal therapy has been used to improve survival after radiation therapy⁶². Although the early results are encouraging, it is uncertain whether the rate of cure will be increased.

Salvage Treatment after the Failure of Radiation Therapy

Radical prostatectomy is occasionally performed as salvage treatment in patients whose tumors recur after radiation therapy; however, the complication rate is 10-fold higher than that among patients who do not undergo radiation, and the probability of a cure without major complications is less than 20 percent^63,64,65. External-beam and interstitial radiation have also been used as salvage therapy in patients with recurrent tumors after radiation, with marginal results^66,67. Hormonal therapy in such patients provides equivalent therapeutic benefits with fewer side effects⁶².

Treatment of Patients with Lymph-Node Metastases

Less than 15 percent of patients with lymph-node metastases (stages N1 through N3) are cured with any treatment^11,37,68. Therefore, most clinicians recommend performing a pelvic lymphadenectomy to determine the nodal stage of the disease before proceeding with a radical prostatectomy -- and sometimes before radiation therapy. In patients at high risk, the nodal stage may be determined laparoscopically⁶⁹.

In patients with nodal metastases, treatment options include hormonal therapy, radical prostatectomy, and radiation therapy. Hormonal therapy delays the progression of cancer and provides local control. Although local control is not durable in one third of patients,⁷⁰ transurethral resection is usually effective in relieving an obstruction of the bladder outlet caused by the primary tumor.

Because lymphadenectomy is not therapeutic, many surgeons do not perform a radical prostatectomy if there are nodal metastases. Others recommend radical prostatectomy to provide local control of the primary tumor. In a retrospective study comparing radical prostatectomy, radiation therapy, and watchful waiting in patients with positive lymph nodes, those treated with prostatectomy fared best, but they also had less advanced disease than the other patients⁷⁰. Favorable survival rates have been reported with radical prostatectomy and postoperative hormonal therapy in patients with positive nodes and diploid tumors; however, equivalent results may be achieved with hormonal therapy alone⁷¹. There is no evidence that radiation therapy benefits men with nodal metastases^11,37,68.

Treatment of Patients with Disseminated Disease

Hormonal Therapy

Hormonal therapy is the mainstay of treatment for men with disseminated prostate cancer. Though unequivocal evidence of a survival benefit is lacking, about 85 percent of patients have an objective response⁷². A change in the serum PSA concentration is a good indicator of a response⁷³.

Orchiectomy, a minor, outpatient operation that can be performed under local anesthesia, is a time-honored method of reducing serum testosterone concentrations. It avoids the problem of compliance with medication regimens but is not accepted by all patients. Estrogen therapy is as effective as orchiectomy, and there is no benefit from combining the two treatments⁷⁴. Diethylstilbestrol in daily doses of 3 mg or more causes cardiovascular toxicity⁷²; a daily dose of 1 mg is effective without excessive toxic effects but does not reliably reduce serum testosterone concentrations to the range associated with castration⁷⁵.

The timing of hormonal therapy is controversial, because patients with metastatic disease who are not treated may have long intervals without symptoms, and the side effects of androgen deprivation (e.g., hot flashes and diminished muscle mass, libido, and sexual potency) are not trivial in asymptomatic, sexually active men. There is at best equivocal evidence that early hormonal therapy is more effective than delayed hormonal therapy^74,76.

Men with disseminated disease who have symptoms should be treated immediately. Younger, asymptomatic men with high-grade tumors should also be considered for early treatment, whereas older men can be followed until they become symptomatic. Patients with rising serum PSA concentrations usually request immediate treatment.

            Gonadotropin-Releasing Hormone Agonists

Gonadotropin-releasing hormone agonists, when administered over a long period, stimulate pituitary gonadotropin secretion for four to five days, after which gonadotropin, especially luteinizing hormone, secretion is suppressed. Testosterone secretion rises and then declines, resulting in very low serum testosterone concentrations after two to three weeks⁷⁷. The initial rise in serum testosterone concentrations may stimulate tumor growth; therefore, patients who have spinal cord compression, pathological fracture, or urinary obstruction from tumor growth should receive antiandrogen therapy during the testosterone surge⁷⁸. Treatment with gonadotropin-releasing hormone agonists is as effective as treatment with diethylstilbestrol⁷⁴ or orchiectomy⁷⁹ and offers the psychological advantage of avoiding castration; a disadvantage is its high cost.

            Nonsteroidal Antiandrogens

Flutamide is a nonsteroidal antiandrogen agent that acts by blocking the binding of testosterone (and dihydrotestosterone) to its intracellular receptors. Flutamide also blocks the inhibitory effect of testosterone on gonadotropin secretion, and therefore serum luteinizing hormone and testosterone concentrations increase, so that many patients remain potent. It is approved for use only in combination with gonadotropin-releasing hormone agonists but has been used alone or in combination with finasteride in men who wish to retain sexual potency⁸⁰. Flutamide is also very expensive.

            Other Hormonal Agents

Progestins, such as megestrol acetate, act primarily by inhibiting the release of luteinizing hormone; they also block androgen receptors. With all progestins, an escape phenomenon occurs in which serum testosterone concentrations gradually rise after 6 to 12 months of treatment. Escape can be prevented by adding a low dose of estrogen (0.1 mg of diethylstilbestrol daily), which by itself is insufficient to suppress testosterone secretion, but which, by synergizing with the progestin, maintains testosterone suppression⁸¹.

Finasteride is a 5-alpha-reductase inhibitor that is only marginally effective in the treatment of prostate cancer⁸².

            Maximal Androgen Ablation

The most controversial issue concerning hormonal therapy for prostate cancer is maximal androgen ablation -- that is, combined therapy to reduce the effects of both gonadal and adrenal androgens, such as the use of a gonadotropin-releasing hormone agonist plus flutamide. Combined therapy may confer at most a six-month overall survival benefit^83,84; however, for patients with early metastatic disease, survival may be increased by as long as 20 months^83,85. These results have not been confirmed in other trials,⁸⁶ and the question has been raised whether blocking the response to the early surge of testosterone secretion with flutamide accounted for the survival advantage associated with combined treatment. To address this issue, a follow-up trial comparing orchiectomy plus flutamide with orchiectomy plus placebo has been initiated.

In a trial evaluating orchiectomy with and without antiandrogen therapy, there was a significant (six-month) delay in the progression of disease, but the survival advantage (three months) was not significant⁸⁷. In a trial comparing orchiectomy with and without flutamide, there was a significant (10-month) delay in the progression of disease and a significant (10-month) survival advantage among the patients who received combined therapy⁸⁸.

Maximal androgen ablation is an option for patients requiring hormonal therapy, but further information is needed before it can be recommended for all patients. Combination therapy with a gonadotropin-releasing hormone agonist and flutamide is prohibitively expensive for many patients.

Treatment of Patients with Disease Refractory to Hormonal Therapy

Secondary Hormonal Therapy

The results of secondary hormonal therapy with high-dose estrogen, an antiandrogen, or an inhibitor of androgen synthesis are poor. Though subjective responses occur in 10 to 20 percent of patients, they last only about six months. Because cancers that have recurred after hormonal therapy are still responsive to androgenic stimulation, lifelong androgen suppression should be maintained. The one exception is patients who have been treated with flutamide. In these patients, flutamide should be discontinued. Objective responses lasting about six months have been reported after discontinuation of flutamide in patients with hormone-refractory disease⁸⁹.

Palliative Radiation Therapy

External-beam radiation therapy is usually effective in patients with symptomatic soft-tissue or osseous metastases. Objective responses occur in approximately 80 percent of such patients, but about half have a relapse. Patients with pain from multiple metastases that is not controlled with analgesic drugs may have improved pain control with hemibody irradiation⁹⁰.

Patients with Spinal Cord Compression

Patients with spinal cord compression should be treated with high-dose corticosteroids⁹¹. In patients not previously treated with hormonal therapy, androgen suppression should be initiated with orchiectomy or ketoconazole, because these treatments rapidly lower testosterone secretion. If the symptoms are mild, radiation alone may be used. Surgical decompression of the spinal cord is appropriate in patients with severe or rapidly progressive lesions, those who have previously undergone irradiation, and those with spinal instability.

Cytotoxic Chemotherapy for Hormone-Refractory Disease

Cytotoxic chemotherapy is largely ineffective in treating prostate cancer. Objective responses are uncommon, complete responses are rare, and survival is not increased. A combination of agents is no more effective than a single agent, and the addition of chemotherapy to hormonal therapy does not improve survival⁹².

The combination of estramustine and vinblastine, both of which affect the function of mitotic spindles, is the most effective current regimen. In trials combining these two agents as a treatment for patients with hormone-refractory disease, there was a 30 to 50 percent response rate, with a response defined as a decrease of 50 percent or more in serum PSA concentrations on three successive biweekly measurements^93,94.

Anti-Growth Factor Treatment

Suramin is an investigational agent with an antitumor effect that may be related to its ability to bind to heparin-binding growth factors; it also has adrenolytic activity. Although there have been no reports of a complete response to suramin therapy, about a third of patients have had objective responses. Several have had responses that lasted for more than one year, making suramin one of the most active agents against hormone-refractory disease. Survival was significantly longer among patients whose serum PSA values decreased by more than 75 percent during treatment than among those with a smaller decrease in serum PSA values. The median interval between treatment and the progression of disease was about six months, and the median survival was about one year. In patients with objective responses, the interval between treatment and the progression of disease was about one year⁹⁵.

Supportive Therapy

Supportive treatment includes the administration of analgesics, antidepressants, corticosteroids, antiemetics, and stool softeners, the use of urologic procedures to alleviate urinary tract obstruction, and the provision of psychological support.

Current and Future Research

Basic research in prostate cancer is focused on the roles of hormones, growth factors, oncogenes, tumor-suppressor genes, and apoptosis (programmed cell death) in the development and progression of prostate cancer. Drug studies are evaluating agents that modulate growth factor activity (e.g., inhibit tyrosine kinase or induce transforming growth factor ), induce terminal-cell differentiation (e.g., retinoids and phenylacetate), and inhibit invasion and metastasis (e.g., a tissue inhibitor of metalloproteinase-2). Clinical drug studies that are in process or planned include the evaluation of high-dose lovastatin (to block cholesterol synthesis in cancer cells), taxol, retinoids, and interferon. In addition, clinical trials will evaluate radical prostatectomy as compared with watchful waiting, hormonal therapy before either prostatectomy or radiation therapy, and adjuvant radiation therapy or hormonal therapy after radical prostatectomy⁹⁶. This research will provide important insights to help resolve the current controversies concerning the treatment of patients with prostate cancer and may lead to reduced morbidity and mortality rates among such patients.

Source Information

From the Department of Surgery, Division of Urologic Surgery, Washington University School of Medicine, 4960 Children's Pl., St. Louis, MO 63110, where reprint requests should be addressed to Dr. Catalona.

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