Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

TNM Definitions AJCC Stage Groupings Jewett Staging System

Treatment Option Overview

Surgical Complications Radiation Therapy Complications Cryotherapy Complications Hormone Therapy Complications

Stage I Prostate Cancer

Current Clinical Trials

Stage II Prostate Cancer

Current Clinical Trials

Stage III Prostate Cancer

Current Clinical Trials

Stage IV Prostate Cancer

Current Clinical Trials

Recurrent Prostate Cancer

Current Clinical Trials

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Changes to This Summary (07/02/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Diagnostic variables.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information

Note: Separate PDQ summaries on Prostate Cancer Prevention and Prostate Cancer Screening are also available.

Note: Estimated new cases and deaths from prostate cancer in the United States in 2008:[1]

• New cases: 186,320.
• Deaths: 28,660.

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites such as bone. Because the median age at diagnosis is 72 years, many patients—especially those with localized tumors—may die of other illnesses without ever having suffered significant disability from the cancer. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management. Controversy exists in regard to the value of screening, the most appropriate staging evaluation, and the optimal treatment of each stage of the disease.[2]

A complicating feature of any analysis of survival after treatment of prostate cancer and comparison of the various treatment strategies is the evidence of increasing diagnosis of nonlethal tumors as diagnostic methods have changed over time. Nonrandomized comparisons of treatments may therefore be confounded not only by patient-selection factors but also by time trends. For example, a population-based study in Sweden showed that from 1960 to the late 1980s, before the use of prostate-specific antigen (PSA) for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the nonlethal variety.[3][Level of evidence: 3iB] With the advent of PSA screening, the ability to diagnose nonlethal prostate cancers may increase further. Another issue complicating comparisons of outcomes among nonconcurrent series of patients is the possibility of changes in criteria for histologic diagnosis of prostate cancer.[4] This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004.[5,6] The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval [CI], 0.79–0.91; P < .001) than the same slides read in 1990 to 1992. As a result, Gleason score-standardized prostate cancer mortality for these men was artifactually improved from 2.08 to 1.50 deaths per 100 person years—a 28% decrease even though overall outcomes were unchanged.

The issue of screening asymptomatic men for prostate cancer with digital rectal examination (DRE), PSA, and/or ultrasound is controversial.[7,8] Serum PSA and transrectal ultrasound are more sensitive and will increase the diagnostic yield of prostate cancer when used in combination with rectal examination; however, these screening methods are also associated with high false-positive rates and may identify some tumors that will not threaten the patient’s health.[9-11] The issue is further complicated by the morbidity associated with work-up and treatment of such tumors and the considerable cost beyond a routine DRE. Furthermore, because a high percentage of tumors identified by PSA screening alone have spread outside the prostate, PSA screening may not improve life expectancy. In any case, the clinician who uses PSA for the detection of prostate cancer should be aware that no uniform standard exists; if a laboratory changes to a different assay kit, serial assays may yield nonequivalent PSA values.[12] In addition, the upper limit of the normal range of PSA, and therefore the threshold at which to biopsy, is not well-defined.[13] A multicenter trial (PLCO-1) sponsored by the National Cancer Institute is under way to test the value of early detection in reducing mortality. (Refer to the PDQ summary on Prostate Cancer Screening for more information.)

Survival of the patient with prostatic carcinoma is related to the extent of the tumor. When the cancer is confined to the prostate gland, median survival in excess of 5 years can be anticipated. Patients with locally advanced cancer are not usually curable, and a substantial fraction will eventually die of the tumor, though median survival may be as long as 5 years. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most such patients will die of prostate cancer. Even in this group of patients, however, indolent clinical courses lasting for many years may be observed.

Other factors affecting the prognosis of patients with prostate cancer that may be useful in making therapeutic decisions include histologic grade of the tumor, patient’s age, other medical illnesses, and level of PSA.[14-18] Poorly differentiated tumors are more likely to have already metastasized by the time of diagnosis and are associated with a poorer prognosis. For patients treated with radiation therapy, the combination of clinical tumor stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse.[19][Level of evidence: 3iDii] In most studies, flow cytometry has shown that nuclear DNA ploidy is an independent prognostic indicator for progression and for cause-specific survival in patients with pathologic stages III and IV prostate cancer without metastases (Jewett stages C and D1). Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques and histogram analysis to determine prognosis will require standardization.[20-23]

Often, baseline rates of PSA changes are thought to be markers of tumor progression. Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor and therefore of very limited utility in making therapeutic decisions. For example, baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting in the control arm of a randomized trial comparing radical prostatectomy to watchful waiting.[24,25] Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.

Several nomograms have been developed to predict outcomes either prior to [26-29] or after [30,31] radical prostatectomy with intent to cure. Preoperative nomograms are based on clinical stage, PSA, Gleason score, and the number of positive and negative prostate biopsy cores. Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated.[32,33] In addition, the nomograms use nonhealth (intermediate) outcomes such as PSA rise or pathologic surgical findings and subjective endpoints such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy.[27]

Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses because younger men are more likely to die of prostate cancer than older men or men with major comorbid medical illness. Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. PSA, an organ-specific marker with greater sensitivity and high specificity for prostate tissue, is often used as a tumor marker.[16,17,34-39] After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[36] however, a substantial proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time.[40] Biochemical evidence of failure on the basis of elevated or slowly rising PSA alone therefore may not be sufficient to alter treatment. For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence. Of these 315 men, 103 men (34%) developed clinical evidence of recurrence. The median time to development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years.[41]

After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[42,43] It is difficult to base decisions about instituting additional therapy on biochemical failure. The implication of the various definitions of PSA failure for overall survival (OS) is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.[44,45]

Using surrogate endpoints for clinical decision making is controversial. Preliminary data from a retrospective cohort of 8,669 patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short posttreatment PSA doubling time (<3 months in this study) fulfills some criteria as a surrogate endpoint for all-cause mortality and prostate cancer mortality after surgery or radiation therapy.[46] Likewise, a retrospective analysis has shown that PSA declines of 20% to 40% (but not 50%) at 3 months and 30% or more at 2 months after initiation of chemotherapy for hormone independent prostate cancer, fulfilled several criteria of surrogacy for OS.[47] These observations should be independently confirmed in prospective study designs and may not apply to patients treated with hormonal therapy. In addition, there are no standardized criteria of surrogacy or standardized cutpoints for adequacy of surrogate endpoints, even in prospective trials.[48]

After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status;[16] however, decreases in PSA of less than 80% may not be very predictive.[16] Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Clinicians, therefore, cannot rely solely on the serum PSA level to monitor a patient’s response to hormone therapy; they must also follow clinical criteria.[49]

References

1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 
   
   
2. Garnick MB: Prostate cancer: screening, diagnosis, and management. Ann Intern Med 118 (10): 804-18, 1993.  [PUBMED Abstract]
   
   
3. Helgesen F, Holmberg L, Johansson JE, et al.: Trends in prostate cancer survival in Sweden, 1960 through 1988: evidence of increasing diagnosis of nonlethal tumors. J Natl Cancer Inst 88 (17): 1216-21, 1996.  [PUBMED Abstract]
   
   
4. Berner A, Harvei S, Skjorten FJ: Follow-up of localized prostate cancer, with emphasis on previous undiagnosed incidental cancer. BJU Int 83 (1): 47-52, 1999.  [PUBMED Abstract]
   
   
5. Albertsen PC, Hanley JA, Barrows GH, et al.: Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 97 (17): 1248-53, 2005.  [PUBMED Abstract]
   
   
6. Thompson IM, Canby-Hagino E, Lucia MS: Stage migration and grade inflation in prostate cancer: Will Rogers meets Garrison Keillor. J Natl Cancer Inst 97 (17): 1236-7, 2005.  [PUBMED Abstract]
   
   
7. Krahn MD, Mahoney JE, Eckman MH, et al.: Screening for prostate cancer. A decision analytic view. JAMA 272 (10): 773-80, 1994.  [PUBMED Abstract]
   
   
8. Kramer BS, Brown ML, Prorok PC, et al.: Prostate cancer screening: what we know and what we need to know. Ann Intern Med 119 (9): 914-23, 1993.  [PUBMED Abstract]
   
   
9. Hinman F Jr: Screening for prostatic carcinoma. J Urol 145 (1): 126-9; discussion 129-30, 1991.  [PUBMED Abstract]
   
   
10. Gerber GS, Chodak GW: Routine screening for cancer of the prostate. J Natl Cancer Inst 83 (5): 329-35, 1991.  [PUBMED Abstract]
    
    
11. Catalona WJ, Smith DS, Ratliff TL, et al.: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 324 (17): 1156-61, 1991.  [PUBMED Abstract]
    
    
12. Takayama TK, Vessella RL, Lange PH: Newer applications of serum prostate-specific antigen in the management of prostate cancer. Semin Oncol 21 (5): 542-53, 1994.  [PUBMED Abstract]
    
    
13. Thompson IM, Pauler DK, Goodman PJ, et al.: Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 350 (22): 2239-46, 2004.  [PUBMED Abstract]
    
    
14. Gittes RF: Carcinoma of the prostate. N Engl J Med 324 (4): 236-45, 1991.  [PUBMED Abstract]
    
    
15. Paulson DF, Moul JW, Walther PJ: Radical prostatectomy for clinical stage T1-2N0M0 prostatic adenocarcinoma: long-term results. J Urol 144 (5): 1180-4, 1990.  [PUBMED Abstract]
    
    
16. Matzkin H, Eber P, Todd B, et al.: Prognostic significance of changes in prostate-specific markers after endocrine treatment of stage D2 prostatic cancer. Cancer 70 (9): 2302-9, 1992.  [PUBMED Abstract]
    
    
17. Pisansky TM, Cha SS, Earle JD, et al.: Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer. J Clin Oncol 11 (11): 2158-66, 1993.  [PUBMED Abstract]
    
    
18. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. N Engl J Med 330 (4): 242-8, 1994.  [PUBMED Abstract]
    
    
19. Pisansky TM, Kahn MJ, Rasp GM, et al.: A multiple prognostic index predictive of disease outcome after irradiation for clinically localized prostate carcinoma. Cancer 79 (2): 337-44, 1997.  [PUBMED Abstract]
    
    
20. Nativ O, Winkler HZ, Raz Y, et al.: Stage C prostatic adenocarcinoma: flow cytometric nuclear DNA ploidy analysis. Mayo Clin Proc 64 (8): 911-9, 1989.  [PUBMED Abstract]
    
    
21. Lee SE, Currin SM, Paulson DF, et al.: Flow cytometric determination of ploidy in prostatic adenocarcinoma: a comparison with seminal vesicle involvement and histopathological grading as a predictor of clinical recurrence. J Urol 140 (4): 769-74, 1988.  [PUBMED Abstract]
    
    
22. Ritchie AW, Dorey F, Layfield LJ, et al.: Relationship of DNA content to conventional prognostic factors in clinically localised carcinoma of the prostate. Br J Urol 62 (3): 245-60, 1988.  [PUBMED Abstract]
    
    
23. Lieber MM: Pathological stage C (pT3) prostate cancer treated by radical prostatectomy: clinical implications of DNA ploidy analysis. Semin Urol 8 (4): 219-24, 1990.  [PUBMED Abstract]
    
    
24. Fall K, Garmo H, Andrén O, et al.: Prostate-specific antigen levels as a predictor of lethal prostate cancer. J Natl Cancer Inst 99 (7): 526-32, 2007.  [PUBMED Abstract]
    
    
25. Parekh DJ, Ankerst DP, Thompson IM: Prostate-specific antigen levels, prostate-specific antigen kinetics, and prostate cancer prognosis: a tocsin calling for prospective studies. J Natl Cancer Inst 99 (7): 496-7, 2007.  [PUBMED Abstract]
    
    
26. Partin AW, Kattan MW, Subong EN, et al.: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 277 (18): 1445-51, 1997.  [PUBMED Abstract]
    
    
27. Partin AW, Mangold LA, Lamm DM, et al.: Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 58 (6): 843-8, 2001.  [PUBMED Abstract]
    
    
28. Kattan MW, Eastham JA, Stapleton AM, et al.: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 90 (10): 766-71, 1998.  [PUBMED Abstract]
    
    
29. Stephenson AJ, Scardino PT, Eastham JA, et al.: Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 98 (10): 715-7, 2006.  [PUBMED Abstract]
    
    
30. Kattan MW, Wheeler TM, Scardino PT: Postoperative nomogram for disease recurrence after radical prostatectomy for prostate cancer. J Clin Oncol 17 (5): 1499-507, 1999.  [PUBMED Abstract]
    
    
31. Stephenson AJ, Scardino PT, Eastham JA, et al.: Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol 23 (28): 7005-12, 2005.  [PUBMED Abstract]
    
    
32. Penson DF, Grossfeld GD, Li YP, et al.: How well does the Partin nomogram predict pathological stage after radical prostatectomy in a community based population? Results of the cancer of the prostate strategic urological research endeavor. J Urol 167 (4): 1653-7; discussion 1657-8, 2002.  [PUBMED Abstract]
    
    
33. Greene KL, Meng MV, Elkin EP, et al.: Validation of the Kattan preoperative nomogram for prostate cancer recurrence using a community based cohort: results from cancer of the prostate strategic urological research endeavor (capsure). J Urol 171 (6 Pt 1): 2255-9, 2004.  [PUBMED Abstract]
    
    
34. Carlton JC, Zagars GK, Oswald MJ: The role of serum prostatic acid phosphatase in the management of adenocarcinoma of the prostate with radiotherapy. Int J Radiat Oncol Biol Phys 19 (6): 1383-8, 1990.  [PUBMED Abstract]
    
    
35. Stamey TA, Yang N, Hay AR, et al.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317 (15): 909-16, 1987.  [PUBMED Abstract]
    
    
36. Stamey TA, Kabalin JN: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. I. Untreated patients. J Urol 141 (5): 1070-5, 1989.  [PUBMED Abstract]
    
    
37. Stamey TA, Kabalin JN, McNeal JE, et al.: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 141 (5): 1076-83, 1989.  [PUBMED Abstract]
    
    
38. Stamey TA, Kabalin JN, Ferrari M: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. III. Radiation treated patients. J Urol 141 (5): 1084-7, 1989.  [PUBMED Abstract]
    
    
39. Andriole GL: Serum prostate-specific antigen: the most useful tumor marker. J Clin Oncol 10 (8): 1205-7, 1992.  [PUBMED Abstract]
    
    
40. Frazier HA, Robertson JE, Humphrey PA, et al.: Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy. J Urol 149 (3): 516-8, 1993.  [PUBMED Abstract]
    
    
41. Pound CR, Partin AW, Eisenberger MA, et al.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281 (17): 1591-7, 1999.  [PUBMED Abstract]
    
    
42. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 37 (5): 1035-41, 1997.  [PUBMED Abstract]
    
    
43. Roach M 3rd, Hanks G, Thames H Jr, et al.: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65 (4): 965-74, 2006.  [PUBMED Abstract]
    
    
44. Kuban DA, el-Mahdi AM, Schellhammer PF: Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 32 (2): 307-16, 1995.  [PUBMED Abstract]
    
    
45. Sandler HM, Dunn RL, McLaughlin PW, et al.: Overall survival after prostate-specific-antigen-detected recurrence following conformal radiation therapy. Int J Radiat Oncol Biol Phys 48 (3): 629-33, 2000.  [PUBMED Abstract]
    
    
46. D'Amico AV, Moul JW, Carroll PR, et al.: Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 95 (18): 1376-83, 2003.  [PUBMED Abstract]
    
    
47. Petrylak DP, Ankerst DP, Jiang CS, et al.: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 98 (8): 516-21, 2006.  [PUBMED Abstract]
    
    
48. Baker SG: Surrogate endpoints: wishful thinking or reality? J Natl Cancer Inst 98 (8): 502-3, 2006.  [PUBMED Abstract]
    
    
49. Ruckle HC, Klee GG, Oesterling JE: Prostate-specific antigen: concepts for staging prostate cancer and monitoring response to therapy. Mayo Clin Proc 69 (1): 69-79, 1994.  [PUBMED Abstract]
    
    

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Cellular Classification

More than 95% of primary prostate cancers are adenocarcinomas, and this discussion is confined to patients with this diagnosis. In general, the degree of tumor differentiation and abnormality of histologic growth pattern directly correlate with the likelihood of metastases and with death. Because of marked variability in tumor differentiation from one microscopic field to another, many pathologists will report the range of differentiation among the malignant cells that are present in a biopsy (Gleason grade).[1,2]

When the cytopathologist is experienced in the technique, and the specimen is adequate for analysis, fine-needle aspiration of the prostate (usually performed transrectally) has been shown to have an accuracy of diagnosis equal to that of traditional core-needle biopsy.[3] Fine-needle aspiration is less painful than core biopsy and, therefore, can be performed as an outpatient procedure and at periodic intervals for serial follow-up. Controversy exists as to whether it is as reliable for grading purposes, particularly with grade range apparent in different fields.[4] Many urologists now use a bioptic gun with ultrasound guidance, which is relatively painless. The risk of complications with this technique is low. A transperineal, ultrasound-guided approach can be used in those patients who may be at increased risk of complications through a transrectal approach.[5] In a series of 670 men undergoing biopsy with an 18-gauge needle, the complication rate was 2% with only 4 patients requiring hospitalization.[6]

References

1. Gleason DF, Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J Urol 111 (1): 58-64, 1974.  [PUBMED Abstract]
   
   
2. Gleason DF: Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M: Urologic Pathology: The Prostate. Philadelphia, Pa: Lea and Febiger, 1977, pp 171-197. 
   
   
3. Ljung BM, Cherrie R, Kaufman JJ: Fine needle aspiration biopsy of the prostate gland: a study of 103 cases with histological followup. J Urol 135 (5): 955-8, 1986.  [PUBMED Abstract]
   
   
4. Algaba F, Epstein JI, Aldape HC, et al.: Assessment of prostate carcinoma in core needle biopsy--definition of minimal criteria for the diagnosis of cancer in biopsy material. Cancer 78 (2): 376-81, 1996.  [PUBMED Abstract]
   
   
5. Webb JA, Shanmuganathan K, McLean A: Complications of ultrasound-guided transperineal prostate biopsy. A prospective study. Br J Urol 72 (5 Pt 2): 775-7, 1993.  [PUBMED Abstract]
   
   
6. Desmond PM, Clark J, Thompson IM, et al.: Morbidity with contemporary prostate biopsy. J Urol 150 (5 Pt 1): 1425-6, 1993.  [PUBMED Abstract]
   
   

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Stage Information

Detection of asymptomatic metastatic disease in prostate cancer is greatly affected by the staging tests performed. Radionuclide bone scans are currently the most widely used tests for metastases to the bone, which is the most common site of distant tumor spread. Magnetic resonance imaging (MRI) is more sensitive than radionuclide bone scans but is impractical for evaluating the entire skeletal system. Some evidence suggests that serum prostate-specific antigen (PSA) levels can predict the results of radionuclide bone scan in newly diagnosed patients. In one series, only 2 of 852 patients (0.23%) with a PSA of less than 20 µg/L had a positive bone scan in the absence of bone pain.[1] In another series of 265 prostate cancer patients, 0 of 23 patients with a PSA of less than 4 μg/L had a positive bone scan, and 2 of 114 patients with a PSA of less than 10 μg/L had a positive bone scan.[2] Prognosis is worse in patients with pelvic lymph node involvement.

Whether to subject all patients to a pelvic lymph node dissection (PLND) is debatable, but in patients undergoing a radical retropubic prostatectomy, the nodal status is ascertained as a matter of course. In patients who are undergoing a radical perineal prostatectomy in whom the PSA value is less than 20 and the Gleason sum is low, however, evidence is mounting that a PLND is probably unnecessary, especially in patients whose malignancy was not palpable but detected on ultrasound.[3,4] A PLND remains the most accurate method to assess metastases to pelvic nodes, and laparoscopic PLND has been shown to accurately assess pelvic nodes as effectively as an open procedure.[5] The exact role of PLND in diagnosis and subsequent treatment is being evaluated, though it has already been determined that the length of hospital stay following laparoscopic PLND is shorter than that following an open procedure. The determining factor when deciding if any type of PLND is indicated is whether definitive therapy may be altered. Likewise, preoperative seminal vesicle biopsy may be useful in patients with palpable nodules who are being considered for radical prostatectomy (unless they have a low Gleason score) because seminal vesicle involvement could affect choice of primary therapy and predicts for pelvic lymph node metastasis.[6]

In patients with clinically localized (stage I or stage II) prostate cancer, Gleason pathologic grade and enzymatic serum prostatic acid phosphatase values (even within normal range) predict the likelihood of capsular penetration, seminal vesicle invasion, or regional lymph node involvement.[3] Analysis of a series of 166 patients with clinical stage I and stage II prostate cancer undergoing radical prostatectomy revealed an association between Gleason biopsy score and the risk of lymph node metastasis found at surgery. The risks of node metastasis for patients grouped according to their Gleason biopsy score was 2%, 13%, and 23% for Gleason scores of 5, 6, and 8, respectively.[7]

Transrectal ultrasound (TRUS) may facilitate diagnosis by directing needle biopsy; however, ultrasound is operator dependent and does not assess lymph node size. Moreover, a prospective multi-institutional study of preoperative TRUS in men with clinically localized prostate cancer felt to be eligible for radical prostatectomy showed that TRUS was no better than digital rectal examination in predicting extracapsular tumor extension or seminal vesicle involvement.[8] Computed tomography (CT) can detect grossly enlarged nodes but poorly defines intraprostatic features;[9] therefore, it is not reliable for the staging of pelvic node disease when compared to surgical staging.[10] Although MRI has been used to detect extracapsular extension of prostate cancer, a positive-predictive value of about 70% and considerable interobserver variation are problems that make its routine use in staging uncertain.[11] Ultrasound and MRI, however, can reduce clinical understaging and thereby improve patient selection for local therapy. Preliminary data with the endorectal MRI coil for prostate imaging report the highest sensitivity and specificity for identification of organ-confined and extracapsular disease.[3,12,13] MRI is a poor tool for evaluating nodal disease.

Two systems are in common use for the staging of prostate cancer. The Jewett system (stages A through D) was described in 1975 and has since been modified.[14] In 1997, the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer adopted a revised tumor, nodes, metastasis (TNM) system that employs the same broad T stage categories as the Jewett system but includes subcategories of T stage, such as a stage to describe patients diagnosed through PSA screening. This revised TNM system is clinically useful and more precisely stratifies newly diagnosed patients. In 2002, the AJCC further revised the TNM classification system.[15] Both staging systems are shown below, and both are used in this summary to discuss treatment options. A thorough review of the controversies of staging in prostate cancer has been published.[16]

Primary tumor (T)

• TX: Primary tumor cannot be assessed



• T0: No evidence of primary tumor



• T1: Clinically inapparent tumor not palpable nor visible by imaging
  • T1a: Tumor incidental histologic finding in 5% or less of tissue resected
  • T1b: Tumor incidental histologic finding in more than 5% of tissue resected
  • T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)



• T2: Tumor confined within prostate*
  • T2a: Tumor involves 50% or less of one lobe
  • T2b: Tumor involves more than 50% of one lobe but not both lobes
  • T2c: Tumor involves both lobes



• T3: Tumor extends through the prostate capsule**
  • T3a: Extracapsular extension (unilateral or bilateral)
  • T3b: Tumor invades seminal vesicle(s)



• T4: Tumor is fixed or invades adjacent structures other than seminal vesicles: bladder neck, external sphincter, rectum, levator muscles, and/or pelvic wall

* [Note: Tumor that is found in one or both lobes by needle biopsy but is not palpable or reliably visible by imaging is classified as T1c.]

** [Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified as T2 not T3.]

Regional lymph nodes (N)

• Regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. They include the following groups (laterality does not affect the N classification): pelvic (not otherwise specified [NOS]), hypogastric, obturator, iliac (i.e., internal, external, or NOS), and sacral (lateral, presacral, promontory [e.g., Gerota], or NOS). Distant lymph nodes are outside the confines of the true pelvis. They can be imaged using ultrasound, CT, MRI, or lymphangiography and include: aortic (para-aortic, periaortic, or lumbar), common iliac, inguinal (deep), superficial inguinal (femoral), supraclavicular, cervical, scalene, and retroperitoneal (NOS) nodes. Although enlarged lymph nodes can occasionally be visualized, because of a stage migration associated with PSA screening, very few patients will be found to have nodal disease, so false-positive and false-negative results are common when imaging tests are employed. In lieu of imaging, risk tables are generally used to determine individual patient risk of nodal involvement. Involvement of distant lymph nodes is classified as M1a.
  • NX: Regional lymph nodes were not assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in regional lymph node(s)

Distant metastasis (M)*

• MX: Distant metastasis cannot be assessed (not evaluated by any modality)
• M0: No distant metastasis
• M1: Distant metastasis
  • M1a: Nonregional lymph node(s)
  • M1b: Bone(s)
  • M1c: Other site(s) with or without bone disease

* [Note: When more than one site of metastasis is present, the most advanced category (pM1c) is used.]

Histopathologic grade (G)

• GX: Grade cannot be assessed
• G1: Well differentiated (slight anaplasia) (Gleason score of 2–4)
• G2: Moderately differentiated (moderate anaplasia) (Gleason score of 5–6)
• G3-4: Poorly differentiated or undifferentiated (marked anaplasia) (Gleason score of 7–10)

Stage I

• T1a, N0, M0, G1

Stage II

• T1a, N0, M0, G2–4
• T1b, N0, M0, any G
• T1c, N0, M0, any G
• T1, N0, M0, any G
• T2, N0, M0, any G

Stage III

• T3, N0, M0, any G

Stage IV

• T4, N0, M0, any G
• Any T, N1, M0, any G
• Any T, any N, M1, any G

Stage A

Stage A is clinically undetectable tumor confined to the prostate gland and is an incidental finding at prostatic surgery.

• Substage A1: well differentiated with focal involvement and usually left untreated
• Substage A2: moderately or poorly differentiated or involves multiple foci in the gland

Stage B

Stage B is tumor confined to the prostate gland.

• Substage B0: nonpalpable and PSA detected [17]
• Substage B1: single nodule in one lobe of the prostate
• Substage B2: more extensive involvement of one lobe or involvement of both lobes

Stage C

Stage C is tumor clinically localized to the periprostatic area but extending through the prostatic capsule; seminal vesicles may be involved.

• Substage C1: clinical extracapsular extension
• Substage C2: extracapsular tumor producing bladder outlet or ureteral obstruction

Stage D

Stage D is metastatic disease.

• Substage D0: clinically localized disease (prostate only) but persistently elevated enzymatic serum acid phosphatase titers
• Substage D1: regional lymph nodes only
• Substage D2: distant lymph nodes and metastases to bone or visceral organs
• Substage D3: D2 prostate cancer patients who relapsed after adequate endocrine therapy

References

1. Oesterling JE, Martin SK, Bergstralh EJ, et al.: The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer. JAMA 269 (1): 57-60, 1993.  [PUBMED Abstract]
   
   
2. Huncharek M, Muscat J: Serum prostate-specific antigen as a predictor of radiographic staging studies in newly diagnosed prostate cancer. Cancer Invest 13 (1): 31-5, 1995.  [PUBMED Abstract]
   
   
3. Oesterling JE, Brendler CB, Epstein JI, et al.: Correlation of clinical stage, serum prostatic acid phosphatase and preoperative Gleason grade with final pathological stage in 275 patients with clinically localized adenocarcinoma of the prostate. J Urol 138 (1): 92-8, 1987.  [PUBMED Abstract]
   
   
4. Daniels GF Jr, McNeal JE, Stamey TA: Predictive value of contralateral biopsies in unilaterally palpable prostate cancer. J Urol 147 (3 Pt 2): 870-4, 1992.  [PUBMED Abstract]
   
   
5. Schuessler WW, Pharand D, Vancaillie TG: Laparoscopic standard pelvic node dissection for carcinoma of the prostate: is it accurate? J Urol 150 (3): 898-901, 1993.  [PUBMED Abstract]
   
   
6. Stone NN, Stock RG, Unger P: Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in men with localized carcinoma of the prostate. J Urol 154 (4): 1392-6, 1995.  [PUBMED Abstract]
   
   
7. Fournier GR Jr, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. Br J Urol 72 (4): 484-8, 1993.  [PUBMED Abstract]
   
   
8. Smith JA Jr, Scardino PT, Resnick MI, et al.: Transrectal ultrasound versus digital rectal examination for the staging of carcinoma of the prostate: results of a prospective, multi-institutional trial. J Urol 157 (3): 902-6, 1997.  [PUBMED Abstract]
   
   
9. Gerber GS, Goldberg R, Chodak GW: Local staging of prostate cancer by tumor volume, prostate-specific antigen, and transrectal ultrasound. Urology 40 (4): 311-6, 1992.  [PUBMED Abstract]
   
   
10. Hanks GE, Krall JM, Pilepich MV, et al.: Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification. Int J Radiat Oncol Biol Phys 23 (2): 293-8, 1992.  [PUBMED Abstract]
    
    
11. Schiebler ML, Yankaskas BC, Tempany C, et al.: MR imaging in adenocarcinoma of the prostate: interobserver variation and efficacy for determining stage C disease. AJR Am J Roentgenol 158 (3): 559-62; discussion 563-4, 1992.  [PUBMED Abstract]
    
    
12. Consensus conference. The management of clinically localized prostate cancer. JAMA 258 (19): 2727-30, 1987.  [PUBMED Abstract]
    
    
13. Schiebler ML, Schnall MD, Pollack HM, et al.: Current role of MR imaging in the staging of adenocarcinoma of the prostate. Radiology 189 (2): 339-52, 1993.  [PUBMED Abstract]
    
    
14. Jewett HJ: The present status of radical prostatectomy for stages A and B prostatic cancer. Urol Clin North Am 2 (1): 105-24, 1975.  [PUBMED Abstract]
    
    
15. Prostate. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 309-316. 
    
    
16. Montie JE: Staging of prostate cancer: current TNM classification and future prospects for prognostic factors. Cancer 75 (7 Suppl): 1814-1818, 1995. 
    
    
17. Bostwick DG, Myers RP, Oesterling JE: Staging of prostate cancer. Semin Surg Oncol 10 (1): 60-72, 1994 Jan-Feb.  [PUBMED Abstract]
    
    

Back to Top

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or radiation therapy. This development is the result of the high incidence of clinical understaging, even with current diagnostic techniques. Metastatic tumor is currently not curable.

Surgery is usually reserved for patients in good health who elect surgical intervention.[1-3] Tumors in these patients should be confined to the prostate gland (stage I and stage II). Prostatectomy can be performed by the perineal or retropubic approach. The perineal approach requires a separate incision for lymph node dissection. Laparoscopic lymphadenectomy is technically possible and accomplished with much less patient morbidity.[4] For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted.[5] With larger, less differentiated tumors, a pelvic lymph node dissection is more important. The value of pelvic node dissection (i.e., open surgical or laparoscopic) is not therapeutic but spares patients with positive nodes the morbidity of prostatectomy. Radical prostatectomy is not usually performed if frozen section evaluation of pelvic nodes reveals metastases; such patients should be considered for entry into existing clinical trials or receive radiation therapy to control local symptoms. The role of preoperative (neoadjuvant) hormonal therapy is not established.[6,7]

Following radical prostatectomy, pathological evaluation stratifies tumor extent into organ-confined, specimen-confined, and margin-positive disease. The incidence of disease recurrence increases when the tumor is not specimen-confined (extracapsular) and/or the margins are positive.[8-10] Results of the outcome of patients with positive surgical margins have not been reported. Patients with extraprostatic disease are suitable candidates for clinical trials such as RTOG-9601, for example. These trials include evaluation of postoperative radiation delivery, cytotoxic agents, and hormonal treatment using luteinizing hormone-releasing hormone (LHRH) agonists and/or antiandrogens.

Cryosurgery is a surgical technique under development that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes, followed by thawing.[11][Level of evidence: 3iiiC];[12,13][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. Impotence is common. The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[12,13]

Candidates for definitive radiation therapy must have a confirmed pathological diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stage I, stage II, and stage III). Patients should have a computed tomographic scan negative for metastases, but staging laparotomy and lymph node dissection are not required. Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival (OS) or prostate cancer-specific survival as seen in the RTOG-7706trial, for example.[14][Level of evidence: 1iiA] In addition, patients considered poor medical candidates for radical prostatectomy can be treated with an acceptably low complication rate if care is given to the delivery technique.[15] Long-term results with radiation therapy are dependent on stage. A retrospective review of 999 patients treated with megavoltage radiation therapy showed cause-specific survival rates to be significantly different at 10 years by T-stage: T1 (79%), T2 (66%), T3 (55%), and T4 (22%).[16] An initial serum prostate-specific antigen (PSA) level higher than 15 ng/mL is a predictor of probable failure with conventional radiation therapy.[17] Several randomized studies have demonstrated an improvement in freedom from biochemical (PSA-based) recurrence with higher doses of radiation therapy (78 Gy–79 Gy) as compared to conventional doses (68 Gy–70 Gy).[18-20][Level of evidence: 1iiDiii] The higher doses were delivered using conformal techniques. None of the studies demonstrated a cause-specific survival benefit to higher doses; however, an ongoing study through the Radiation Therapy Oncology Group will be powered for OS.

Interstitial brachytherapy has been employed in several centers, generally for patients with T1 and T2 tumors. Patients are selected for favorable characteristics, including low Gleason score, low PSA level, and stage T1 to T2 tumors. Information and further study are required to better define the effects of modern interstitial brachytherapy on disease control and quality of life and to determine the contribution of favorable patient selection to outcomes.[21][Level of evidence: 3iiiDiv] Information about ongoing clinical trials is available from the NCI Web site.

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[22,23] One population-based study with 15 years of follow-up (mean observation time = 12.5 years) has shown excellent survival without any treatment in patients with well-differentiated or moderately well-differentiated tumors clinically confined to the prostate, irrespective of age.[8] None of these men were detected by PSA screening, since PSA was not available at the time. The patient cohort was followed for a mean of 21 years after initial diagnosis.[24] The risk of prostate cancer progression and prostate cancer death persisted throughout the follow-up period. By the end of follow-up, 91% of the cohort had died; 16% had died of prostate cancer. A second, smaller population-based study of 94 patients with clinically localized prostate cancer managed by a watch and wait strategy gave very similar results at 4 to 9 years of follow-up.[25] In a selected series of 50 stage C patients, 48 of whom had well-differentiated or moderately well-differentiated tumors, the prostate cancer-specific survival rates at 5 and 9 years were 88% and 70%, respectively.[9]

Long-term follow-up of a population-based cohort of 767 men with clinically localized prostate cancer diagnosed in the pre-PSA era and managed with either watchful waiting or androgen withdrawal has also been reported in the United States.[26][Level of evidence: 3iiiA] After a follow-up of 20 years, prostate cancer-specific mortality was 6 per 1,000 person-years in men with Gleason scores of 2 to 4. Men with Gleason scores of 8 to 10, however, had a prostate cancer-specific mortality of 121 per 1,000 person years, and men with Gleason scores of 5 to 7 had intermediate prostate cancer mortality (i.e., 12, 30, and 65 deaths per 1,000 person years for Gleason scores 5, 6, and 7, respectively).

Since the early 1980s, a dramatic increase has occurred in the rates of radical prostatectomy in the United States for men aged 65 to 79 years (5.75-fold rise from 1984 to 1990). Wide geographic variation is seen with these rates.[27] A structured literature review of 144 papers has been done in an attempt to compare the 3 primary treatment strategies for clinically localized prostate cancer:[28]

• Radical prostatectomy.
• Definitive radiation therapy.
• Watchful waiting.

The authors concluded that poor reporting and selection factors within all series precluded a valid comparison of efficacy for the three management strategies. In another literature review of a case series of patients with palpable, clinically localized disease, the authors found that 10-year prostate cancer-specific survival rates were best in radical prostatectomy series (about 93%), worst in radiation therapy series (about 75%), and intermediate with deferred treatment (about 85%).[29] Because it is highly unlikely that radiation therapy would worsen disease-specific survival, the most likely explanation is that selection factors affect choice of treatment. Such selection factors make comparisons of therapeutic strategies imprecise.[30] A retrospective analysis of outcomes of men demonstrated a 10-year disease-specific survival rate of 94% for expectant management for Gleason score 2 to 4 tumors and 75% for Gleason score 5 to 7 tumors;[31] this is similar to a previous study using the Surveillance, Epidemiology, and End Results database with survival rates of 93% and 77%, respectively.[32]

A randomized trial comparing radical prostatectomy to watchful waiting in men with early-stage disease in the pre-PSA screening era (clinical stages T1b, T1c, or T2) showed a statistically significant difference in OS at 10 years.[33][Level of evidence: 1iiA] After 10 years, the difference in OS was approximately 73% versus 68%; absolute difference 5.0%; relative risk of death 0.74 (95% confidence interval, 0.56–0.99). This benefit was restricted to men younger than 65 years at the time of surgery (P = .01 in a planned subset analysis of the effect of age on treatment efficacy).[34] Results from the Prostate Intervention Versus Observation Trial (PIVOT) in the United States, an ongoing randomized trial (VA-CSP-407) that compared radical prostatectomy with watchful waiting, have not been reported. The PIVOT uses overall mortality as its primary endpoint. (Refer to the Stage II Prostate Cancer treatment section of this summary for more information.)

Cryotherapy is also under evaluation for the treatment of localized prostate cancer. There is limited evidence on its efficacy and safety compared to the more commonly used local therapies, and the technique is evolving in an attempt to reduce local toxicity and normal tissue damage (see below). The quality of evidence on efficacy is low, currently limited to case series of relatively small size, short follow-up, and surrogate outcomes of efficacy.[35]

Complications of radical prostatectomy can include urinary incontinence, urethral stricture, impotence, and the morbidity associated with general anesthesia and a major surgical procedure. An analysis of Medicare records on 101,604 radical prostatectomies performed from 1991 to 1994 showed a 30-day operative mortality rate of 0.5%, a rehospitalization rate of 4.5%, and a major complication rate of 28.6%; over the study period, these rates decreased by 30%, 8%, and 12%, respectively.[36] Prostatectomies done at hospitals where fewer prostatectomies were performed were associated with higher rates of 30-day postoperative mortality, major acute surgical complications, longer hospital stays, and higher rates of rehospitalization than those done at hospitals where more prostatectomies were performed. Morbidity and mortality rates increase with age.[27,37] Comorbidity, especially underlying cardiovascular disease and a history of stroke, accounts for a portion of the age-related increase in 30-day mortality. In a cohort of all men with prostate cancer who underwent radical prostatectomy from 1990 to 1999 in Ontario, 75-year-old men with no comorbidities had a predicted 30-day mortality of 0.74%.[37] Thirty-day surgical complication rates also depended more on comorbidity than age (i.e., about 5% vs. 40% for 0 vs. 4 or more underlying comorbid conditions).

In one large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy, approximately 6% of the men required the use of pads for urinary incontinence, but an unknown additional proportion of men had occasional urinary dribbling. About 40% to 65% of the men who were sexually potent before surgery retained potency adequate for vaginal penetration and sexual intercourse.[38] Preservation of potency with this technique is dependent on tumor stage and patient age, but the operation probably induces at least a partial deficit in nearly all patients.[38]

A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series.[39] In that survey, more than 30% of the men reported the need for pads or clamps for urinary wetness, and 63% of all patients reported a current problem with wetness. About 60% of the men reported having no erections since surgery; about 90% of the men had no erections sufficient for intercourse during the month before the survey. About 28% of the patients reported follow-up treatment of cancer with radiation therapy and/or hormonal therapy within 4 years after their prostatectomy.

In a population-based longitudinal cohort (Prostate Cancer Outcomes Study) of 901 men aged 55 to 74 years who had recently undergone radical prostatectomy for prostate cancer, 15.4% of the men had either frequent urinary incontinence or no urinary control at 5 years after surgery, and 20.4% of those studied wore pads to stay dry.[40] Inability to have an erection sufficient for intercourse was reported by 79.3% of men. Reasons for the difference in outcomes between the population-based surveys and previous case series could include:

• Age difference among the populations.
• Surgical expertise at the major reporting centers.
• Selection factors.
• Publication bias of favorable series.
• Different methods of collecting information from patients.

Case series of 93, 459, and 89 men who had undergone radical prostatectomy by experienced surgeons showed rates of impotence as high as those in the national Medicare survey when men were carefully questioned about sexual potency, though the men in the case series were on average younger than those in the Medicare survey.[41-43] One of the case series used the same questionnaire as that used in the Medicare survey.[41] The urinary incontinence rate in that series was also similar to that in the Medicare survey.

A cross-sectional survey of prostate cancer patients who were treated in a managed care setting by radical prostatectomy, radiation therapy, or watchful waiting showed substantial sexual and urinary dysfunction in the prostatectomy group.[44] Results reported by the patients were consistent with those from the national Medicare survey. In addition, though statistical power was limited, differences in sexual and urinary dysfunction between men who had undergone either nerve-sparing or standard radical prostatectomy were not statistically significant. This issue requires more study.

Radical prostatectomy may also cause fecal incontinence, and the incidence may vary with surgical method.[45] In a national survey sample of 907 men who had undergone radical prostatectomy at least 1 year before the survey, 32% of the men who had undergone perineal (nerve-sparing) radical prostatectomy and 17% of the men who had undergone retropubic radical prostatectomy reported accidents of fecal leakage. Ten percent and 4% of the respondents reported moderate and large amounts of fecal leakage, respectively. Fewer than 15% of men with fecal incontinence had reported it to a physician or health care provider.

Definitive external-beam radiation therapy (EBRT) can result in acute cystitis, proctitis, and sometimes enteritis.[1,43,46-48] These conditions are generally reversible but may be chronic and rarely require surgical intervention. Potency, in the short term, is preserved with radiation therapy in most cases but may diminish over time.[48] A cross-sectional survey of prostate cancer patients who had been treated in a managed care setting by radical prostatectomy, radiation therapy, or watchful waiting showed substantial sexual and urinary dysfunction in the radiation therapy group.[44]

Morbidity may be reduced with the employment of sophisticated radiation therapy techniques—such as the use of linear accelerators—and careful simulation and treatment planning.[49] Radiation side effects of three-dimensional conformal versus conventional radiation therapy using similar doses (total dose of 60–64 Gy) have been compared in a randomized nonblinded study.[50][Level of evidence: 1iiC] No differences were observed in acute morbidity, and late side effects serious enough to require hospitalization were infrequent with both techniques; however, the cumulative incidence of mild or greater proctitis was lower in the conformal arm than in the standard therapy arm (37% vs. 56%; P = .004). Urinary symptoms were similar in the two groups as were local tumor control and OS rates at 5 years’ follow-up.

Radiation therapy can be delivered after an extraperitoneal lymph node dissection without an increase in complications if careful attention is paid to radiation technique. The treatment field should not include the dissected pelvic nodes. Previous transurethral resection of the prostate (TURP) increases the risk of stricture above that seen with radiation therapy alone, but if radiation therapy is delayed 4 to 6 weeks after the TURP, the risk of stricture can be minimized.[51-53] Pretreatment TURP to relieve obstructive symptoms has been associated with tumor dissemination; however, multivariate analysis in pathologically staged cases indicates that this is the result of a worse underlying prognosis of the cases that require TURP rather than the result of the procedure itself.[54]

A population-based survey of Medicare recipients who had received radiation therapy as primary treatment of prostate cancer (similar in design to the survey of Medicare patients who underwent radical prostatectomy,[39] described above) has been reported, showing substantial differences in posttreatment morbidity profiles between surgery and radiation therapy.[55] Although the men who had undergone radiation therapy were older at the time of initial therapy, they were less likely to report the need for pads or clamps to control urinary wetness (7% vs. more than 30%). A larger proportion of patients treated with radiation therapy before surgery reported the ability to have an erection sufficient for intercourse in the month before the survey (men <70 years, 33% who received radiation therapy vs. 11% who underwent surgery alone; men ≥70 years, 27% who received radiation therapy vs. 12% who underwent surgery alone). Men receiving radiation therapy, however, were more likely to report problems with bowel function, especially frequent bowel movements (10% vs. 3%). As in the results of the surgical patient survey, about 24% of radiation patients reported additional subsequent treatment of known or suspected cancer persistence or recurrence within 3 years of primary therapy.

Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men. In a randomized placebo-controlled crossover design study (RTOG-0215) of 60 men who had undergone radiation therapy for clinically localized prostate cancer, and who reported erectile dysfunction that began after their radiation therapy, 55% reported successful intercourse after sildenafil versus 18% after placebo (P <.001).[56][Level of evidence: 1iC]

A prospective community-based cohort of men aged 55 to 74 years treated with radical prostatectomy (n = 1156) or EBRT (n = 435) attempted to compare acute and chronic complications of the two treatment strategies after adjusting for baseline differences in patient characteristics and underlying health.[57] Regarding acute treatment-related morbidity, radical prostatectomy was associated with higher rates of cardiopulmonary complications (5.5% vs. 1.9%) and the need for treatment of urinary strictures (17.4% vs. 7.2%). Radiation therapy was associated with more acute rectal proctitis (18.7% vs. 1.6%). With regard to chronic treatment-related morbidity, radical prostatectomy was associated with more urinary incontinence (9.6% vs. 3.5%) and impotence (80% vs. 62%). Radiation therapy was associated with slightly greater declines in bowel function.

Impotence is common in the reported case series, ranging from about 47% to 100%. Other major complications include incontinence, urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.[35]

Several different hormonal approaches can benefit men in various stages of prostate cancer. These approaches include bilateral orchiectomy, estrogen therapy, LHRH agonists, antiandrogens, ketoconazole, and aminoglutethimide.

Benefits of bilateral orchiectomy include ease of the procedure, compliance, its immediacy in lowering testosterone levels, and low cost. Disadvantages include psychologic effects, loss of libido, impotence, hot flashes, and osteoporosis.[58]

Estrogens at a dose of 3 mg per day of diethylstilbestrol will achieve castrate levels of testosterone. Like orchiectomy, estrogens may cause loss of libido and impotence. Gynecomastia may be prevented by low-dose radiation therapy to the breasts. Estrogen is seldom used today because of the risk of serious side effects, including myocardial infarction, cerebrovascular accident, and pulmonary embolism.

LHRH agonists such as leuprolide, goserelin, and buserelin will lower testosterone to castrate levels. Like orchiectomy and estrogens, LHRH agonists cause impotence, hot flashes, and loss of libido. Tumor flare reactions may occur transiently but can be prevented by antiandrogens or by short-term estrogens at low dose for several weeks.

The pure antiandrogen flutamide may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.[59] Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[60] The steroidal antiandrogen megestrol acetate suppresses androgen production incompletely and is generally not used as initial therapy.

Long-term use of ketoconazole can result in impotence, pruritus, nail changes, and adrenal insufficiency. Aminoglutethimide commonly causes sedation and skin rashes. A national Medicare survey of men who had undergone radical prostatectomy for prostate cancer showed a decrease in all seven health-related quality-of-life measures (impact of cancer and treatment, concern regarding body image, mental health, general health, activity, worries about cancer and dying, and energy) in men who had received androgen depletion therapy (either medically or surgically induced) versus those who had not.[61][Level of evidence: 3iC] Additional studies that evaluate the effects of various hormone therapies on quality of life are required.[62]

Androgen deprivation therapy also can cause osteoporosis and bone fractures. In a population-based sample of 50,613 Medicare patients aged 66 years or older followed for a median of 5.1 years, men who had been treated with either a gonadotropin-releasing hormone (GnRH) or orchiectomy had a 19.4% bone fracture rate compared to 12.6% in men who had not received hormone deprivation therapy. The effect was similar in men whether or not they had metastatic bone disease.[63] A small nonblinded study with short follow-up suggests that the bisphosphonate pamidronate can prevent bone loss in men receiving a GnRH agonist for prostate cancer.[64] Forty-seven prostate cancer patients (41 evaluable) with locally advanced prostate cancer, but with no known bone metastases, were randomly assigned to receive 3-monthly depot leuprolide with or without pamidronate (60 mg intravenously). No bone fractures were reported in either group. The use of surrogate endpoints and unblinded assessment of endpoints makes it difficult to know with certainty whether pamidronate use would prevent fractures.[64][Level of evidence: 1iiDiii]

References

1. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 143 (3): 538-43; discussion 544, 1990.  [PUBMED Abstract]
   
   
2. Corral DA, Bahnson RR: Survival of men with clinically localized prostate cancer detected in the eighth decade of life. J Urol 151 (5): 1326-9, 1994.  [PUBMED Abstract]
   
   
3. Zincke H, Bergstralh EJ, Blute ML, et al.: Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. J Clin Oncol 12 (11): 2254-63, 1994.  [PUBMED Abstract]
   
   
4. Schuessler WW, Vancaillie TG, Reich H, et al.: Transperitoneal endosurgical lymphadenectomy in patients with localized prostate cancer. J Urol 145 (5): 988-91, 1991.  [PUBMED Abstract]
   
   
5. Fournier GR Jr, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. Br J Urol 72 (4): 484-8, 1993.  [PUBMED Abstract]
   
   
6. Witjes WP, Schulman CC, Debruyne FM: Preliminary results of a prospective randomized study comparing radical prostatectomy versus radical prostatectomy associated with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. The European Study Group on Neoadjuvant Treatment of Prostate Cancer. Urology 49 (3A Suppl): 65-9, 1997.  [PUBMED Abstract]
   
   
7. Fair WR, Cookson MS, Stroumbakis N, et al.: The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer: Memorial Sloan-Kettering Cancer Center results. Urology 49 (3A Suppl): 46-55, 1997.  [PUBMED Abstract]
   
   
8. Johansson JE, Holmberg L, Johansson S, et al.: Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 277 (6): 467-71, 1997.  [PUBMED Abstract]
   
   
9. Adolfsson J, Rönström L, Löwhagen T, et al.: Deferred treatment of clinically localized low grade prostate cancer: the experience from a prospective series at the Karolinska Hospital. J Urol 152 (5 Pt 2): 1757-60, 1994.