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Prostate Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

Prostate Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Prostate Cancer Treatment

General Information About Prostate Cancer

Incidence and Mortality

Estimated new cases and deaths from prostate cancer in the United States in 2012:[1]

  • New cases: 241,740.
  • Deaths: 28,170.

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 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 (US) is controversial.[7,8] Serum PSA and transrectal US 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.[9,10,11,12] 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.[13] In addition, the upper limit of the normal range of PSA, and therefore the threshold at which to biopsy, is not well defined.[14] A multicenter trial (PLCO-1) that was sponsored by the National Cancer Institute was conducted 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.[15,16,17,18,19] 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.[20][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.[21,22,23,24]

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.[25,26] 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 [27,28,29,30] or after [31,32] 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. One independently validated nomogram demonstrated increased accuracy in predicting biochemical recurrence-free survival by including preoperative plasma levels of transforming growth factor B1 and interleukin-6 soluble receptor.[33,34] 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.[35,36] 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.[28]

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.[17,18,37,38,39,40,41,42] After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[39] 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.[43] 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.[44]

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.[45,46] 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.[47,48]

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.[49] 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.[50] 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.[51]

After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status;[17] however, decreases in PSA of less than 80% may not be very predictive.[17] 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.[52]

Related Summaries

Other PDQ summaries containing information related to prostate cancer include the following:

  • Genetics of Prostate Cancer
  • Prostate Cancer Prevention
  • Prostate Cancer Screening

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed September 24, 2012.
2. Garnick MB: Prostate cancer: screening, diagnosis, and management. Ann Intern Med 118 (10): 804-18, 1993.
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.
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.
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.
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.
7. Krahn MD, Mahoney JE, Eckman MH, et al.: Screening for prostate cancer. A decision analytic view. JAMA 272 (10): 773-80, 1994.
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.
9. Hinman F Jr: Screening for prostatic carcinoma. J Urol 145 (1): 126-9; discussion 129-30, 1991.
10. Gerber GS, Chodak GW: Routine screening for cancer of the prostate. J Natl Cancer Inst 83 (5): 329-35, 1991.
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.
12. Welch HG, Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst 101 (19): 1325-9, 2009.
13. 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.
14. 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.
15. Gittes RF: Carcinoma of the prostate. N Engl J Med 324 (4): 236-45, 1991.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. 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.
33. Shariat SF, Walz J, Roehrborn CG, et al.: External validation of a biomarker-based preoperative nomogram predicts biochemical recurrence after radical prostatectomy. J Clin Oncol 26 (9): 1526-31, 2008.
34. Kattan MW, Shariat SF, Andrews B, et al.: The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol 21 (19): 3573-9, 2003.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. 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.
41. 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.
42. Andriole GL: Serum prostate-specific antigen: the most useful tumor marker. J Clin Oncol 10 (8): 1205-7, 1992.
43. 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.
44. Pound CR, Partin AW, Eisenberger MA, et al.: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281 (17): 1591-7, 1999.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. Baker SG: Surrogate endpoints: wishful thinking or reality? J Natl Cancer Inst 98 (8): 502-3, 2006.
52. 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.

Cellular Classification of Prostate Cancer

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 (US) guidance, which is relatively painless. The risk of complications with this technique is low. A transperineal, US-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.
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.
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.
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.
6. Desmond PM, Clark J, Thompson IM, et al.: Morbidity with contemporary prostate biopsy. J Urol 150 (5 Pt 1): 1425-6, 1993.

Stage Information for Prostate Cancer

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 ?g/L had a positive bone scan, and 2 of 114 patients with a PSA of less than 10 ?g/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 (US).[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 US (TRUS) may facilitate diagnosis by directing needle biopsy; however, US 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] US and MRI, however, can reduce clinical understaging and 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. The AJCC further revised the TNM classification system in 2002 and, most recently, in 2010.[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]

Definitions of TNM

The AJCC has designated staging by TNM classification to define prostate cancer.[15]

Table 1. Primary Tumor (T)a

Clinical
a Reprinted with permission from AJCC: Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
b Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c.
c Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2.
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
T1 Clinically inapparent tumor neither palpable nor visible by imaging.
T1a Tumor incidental histologic finding in ?5% of tissue resected.
T1b Tumor incidental histologic finding in >5% of tissue resected.
T1c Tumor identified by needle biopsy (e.g., because of elevated PSA).
T2 Tumor confined within prostate.b
T2a Tumor involves ?one-half of one lobe.
T2b Tumor involves >one-half of one lobe but not both lobes.
T2c Tumor involves both lobes.
T3 Tumor extends through the prostate capsule.c
T3a Extracapsular extension (unilateral or bilateral).
T3b Tumor invades seminal vesicle(s).
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall.

Table 2. Pathologic (pT)a, b

a Reprinted with permission from AJCC: Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
b There is no pathologic T1 classification.
c Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
pT2 Organ confined.
pT2a Unilateral, ?one-half of one side.
pT2b Unilateral, involving >one-half of side but not both sides.
pT2c Bilateral disease.
pT3 Extraprostatic extension.
pT3a Extraprostatic extension or microscopic invasion of bladder neck.c
pT3b Seminal vesicle invasion.
pT4 Invasion of rectum, levator muscles, and/or pelvic wall.

Table 3. Regional Lymph Nodes (N)a

a Reprinted with permission from AJCC: Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
Clinical
NX Regional lymph nodes were not assessed.
N0 No regional lymph node metastasis.
N1 Metastases in regional lymph node(s).
Pathologic
pNX Regional nodes not sampled.
pN0 No positive regional nodes.
pN1 Metastases in regional node(s).

Table 4. Distant Metastasis (M)a, b

a Reprinted with permission from AJCC: Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
b When more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced.
M0 No distant metastasis.
M1 Distant metastasis.
M1a Nonregional lymph node(s).
M1b Bone(s).
M1c Other site(s) with or without bone disease.

Table 5. Anatomic Stage/Prognostic Groupsa b

Group T N M PSA Gleason
PSA = prostate-specific antigen.
a Reprinted with permission from AJCC: Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
b When either PSA or Gleason is not available, grouping should be determined by T stage and/or either PSA or Gleason as available.
I T1a–c N0 M0 PSA <10 Gleason ?6
  T2a N0 M0 PSA <10 Gleason ?6
  T1–2a N0 M0 PSA X Gleason X
IIA T1a–c N0 M0 PSA <20 Gleason 7
  T1a–c N0 M0 PSA ?10 <20 Gleason ?6
  T2a N0 M0 PSA ?10 <20 Gleason ?6
  T2a N0 M0 PSA <20 Gleason 7
  T2b N0 M0 PSA <20 Gleason ?7
  T2b N0 M0 PSA X Gleason X
IIB T2c N0 M0 Any PSA Any Gleason
  T1–2 N0 M0 PSA ?20 Any Gleason
  T1–2 N0 M0 Any PSA Gleason ?8
III T3a–b N0 M0 Any PSA Any Gleason
IV T4 N0 M0 Any PSA Any Gleason
  Any T N1 M0 Any PSA Any Gleason
  Any T Any N M1 Any PSA Any Gleason

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
12. Consensus conference. The management of clinically localized prostate cancer. JAMA 258 (19): 2727-30, 1987.
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.
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.
15. Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
16. Montie JE: Staging of prostate cancer: current TNM classification and future prospects for prognostic factors. Cancer 75 (7 Suppl): 1814-1818, 1995.

Treatment Option Overview

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.[1,2,3] 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.[8,9,10] Results of the outcome of patients with positive surgical margins have not been reported. Patients with extraprostatic disease are suitable candidates for clinical trials. Trials such as RTOG-9601 included the 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.) 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-7706 trial, 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).[18,19,20][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.

There is interest in the use of novel radiation techniques (e.g., intensity-modulated radiation therapy, proton-beam therapy, cyber knife) for the treatment of prostate cancer. Although proton therapy could theoretically improve the therapeutic ratio of prostate radiation, allowing for an increase in dose to the tumor without a substantial increase in side effects, no randomized, controlled trials have been conducted to compare its efficacy and toxicity with those of other forms of radiation therapy.

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[22,23,24] 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.[25] 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.[26] 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]

In the United States, as in other settings with widespread PSA screening, the results of conservative management of localized prostate cancer are particularly favorable. In a population-based Surveillance, Epidemiology and End Results (SEER) Medicare-linked database, 14,516 men with localized prostate cancer (T1 or T2 prostate cancer) who were diagnosed from 1992 to 2002 were followed while undergoing conservative management (i.e., no surgery or radiation for at least 6 months) for a median of 8.3 years.[27] The median age at diagnosis was 78 years. At 10 years, the prostate cancer–specific mortality rates were 8.3%, 9.1%, and 25.6% for men with well-differentiated, moderately differentiated, and poorly differentiated tumors, respectively. Corresponding risks of dying of other causes were 59.8%, 57.2%, and 56.6%.[27][Levels of evidence: 3iA, 3iB]

Another population-based observational study of men with clinically localized prostate cancer diagnosed in the PSA-screening era has also been reported, with a median follow-up of 8.2 years.[28] A nationwide Swedish cohort of 6,849 men aged 70 or younger with T1 or T2 prostate cancer, Gleason scores of 7 or lower, and serum PSA levels of lower than 20 ng/mL was followed after an initial strategy of surveillance (N = 2,021), radical prostatectomy (N = 3,399), or radiation therapy (N = 1,429). The cumulative risk of prostate cancer–specific death at 10 years was 3.6% in the initial surveillance group and 2.7% in the curative intent groups (i.e., 2.4% and 3.3% in the prostatectomy and radiation therapy groups, respectively). The 10-year risk of dying from non–prostate-cancer causes was 19.2% in the surveillance group versus 10.2% in the curative intent group, respectively, showing evidence of selection of less healthy patients for surveillance on average.[28][Levels of evidence: 3iA, 3iB]

Tumor pathological characteristics of 222 men in that cohort who followed an initial strategy of surveillance but underwent deferred prostatectomy at a median of 19.2 months (10th –90th percentile, 9.2–45.5 months) were compared to those who underwent immediate prostatectomy.[29] There were no differences between the groups in extraprostatic extension or tumor margin positivity. Although the Gleason scores at radical prostatectomy were higher in the surveillance groups than in the immediate prostatectomy group, this occurred concurrently with a national training effort in prostate tumor pathology evaluation that led to the upgrading of tumor specimens. Therefore, the investigators concluded that the delay in prostatectomy in the surveillance group artifactually led to assignment of higher tumor grades.

Many men with screen-detected prostate cancer are candidates for active surveillance, with definitive therapy reserved for signs of tumor progression. In a retrospective analysis from four of the centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC), 616 men (mean age 66.3 years) in the screening arm represented between 27% and 38% of the men diagnosed with prostate cancer in the trial. The 616 men met the following criteria for active surveillance:[30]

  • PSA ?10 ng/mL.
  • PSA density <0.2 ng/mL.
  • Tumor stage T1c/T2.
  • Gleason score ?3 + 3 = 6.
  • ?2 positive biopsy cores.

With a median follow-up of 3.91 years, the 10-year prostate cancer–specific survival rate was 100%. By 7.75 years, 50% of men had received active treatment; however, 55.8% of these men received treatment despite continued favorable PSA and PSA–doubling time. The OS rate at 10 years was 77%.[30][Level of evidence: 3iiB]

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.[31] A structured literature review of 144 papers has been done in an attempt to compare the following three primary treatment strategies for clinically localized prostate cancer:[32]

  • 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%).[33] 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.[34] 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;[35] this is similar to a previous study using the Surveillance, Epidemiology, and End Results database with survival rates of 93% and 77%, respectively.[36]

Radical prostatectomy has been compared to watchful waiting in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2) in a randomized clinical trial performed in Sweden in the pre-PSA screening era.[37,38,39] Only about 5% of the men in the trial had been diagnosed by PSA screening. The cumulative overall mortality at 15 years in the radical prostatectomy and watchful waiting study arms was 46.1% and 52.7%, respectively (absolute difference, 6.6%; 95% confidence interval [CI], -1.3–14.5; relative risk [RR]death of 0.75; 95% CI, 0.61–0.92).[39] The cumulative incidence of prostate cancer deaths at 15 years was 14.6% versus 20.7% (absolute difference, 6.1%; 95% CI, 0.2–12.0; RRdeath from prostate cancer, 0.62; 95% CI, 0.44–0.87).[39][Level of evidence: 1iiA]

In a post hoc–subset analysis, the improvement in overall- and prostate-cancer specific mortality associated with radical prostatectomy was restricted to men younger than 65 years.

The Prostate Intervention Versus Observation Trial (PIVOT-1) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/ml) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[40] About 50% of the men had nonpalpable, screen-detected disease. After a median follow-up of 10 years (range up to about 15 years), the all-cause mortality was 47.0% versus 49.9% in the prostatectomy and watchful-waiting study arms, respectively, which was a difference that was not statistically significant (hazard ratio [HR], 0.88; 95% CI, 0.71–1.08; P = .22). Prostate cancer-specific mortality was 5.8% versus 8.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.36–1.09; P = .09].[40][Levels of evidence: 1iiA, 1iiB]

Subgroup analyses showed a statistically significant reduction in overall mortality in the group of men with a baseline PSA greater than 10 ng/ml (61 of 126 men vs. 77 of 125 men; HR, 0.67) but no difference in men with a PSA of 10 or less (110 of 238 men vs. 101/ of 241 men; HR, 1.03; P value for interaction = .04). Because the test for interaction was not adjusted for the numerous subgroup comparisons, it should be interpreted with caution. Although there was a trend favoring prostatectomy, for prostate cancer-specific mortality, in men with a PSA greater than 10, the numbers were very small (7 of 126 men vs. 16 of125 men for a PSA >10; 14 of 238 men vs. 15 of 241 men), and the interaction with the PSA level was not statistically significant (P = .11). There were no statistically significant differences in efficacy associated with prostatectomy by age (<65 years vs. ?65 years), Gleason score, Charlson comorbidity status, race, or performance score.[40]

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.[41]

Surgical Complications

Complications of radical prostatectomy can include urinary incontinence, urethral stricture, impotence,[42] and the morbidity associated with general anesthesia and a major surgical procedure. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.) 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.[43] 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.[31,44] 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%.[44] 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.[45] 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.[45]

A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series.[46] 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on erectile dysfunction.) 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.[47] 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 the following:

  • 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.[48,49,50] One of the case series used the same questionnaire as that used in the Medicare survey.[48] 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.[51] 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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for information on sexual and urinary dysfunction.) This issue requires more study.

Case series in men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[52,53,54] The functional consequence of the shortening is not well studied, but it is noticeable to some men.

Retrospective cohort studies and case series have shown an increased incidence of inguinal hernia, in the range of 7% to 21%, in men undergoing radical prostatectomy, with rates peaking within 2 years of surgery.[55,56,57,58,59] Observational studies suggest that the rates are higher than in comparable men who have undergone prostate biopsy alone, transurethral resections, and simple open prostatectomy for benign disease;[55,56] or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.[55,57,58] Although the observations of increased rates of inguinal hernia after radical prostatectomy are consistent, it is conceivable that men with prostate cancer who are being followed carefully by urologists could have higher detection rates of hernia as a result of frequent examinations or diagnostic imaging (i.e., "detection bias"). Men should be made aware of this potential complication of prostatectomy.

Radical prostatectomy may also cause fecal incontinence, and the incidence may vary with surgical method.[60] 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.

Radiation Therapy Complications

Definitive external-beam radiation therapy (EBRT) can result in acute cystitis, proctitis, and sometimes enteritis.[1,42,50,61,62,63] 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.[63] 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.[51] (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information.)

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.[64] 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.[65][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.[66,67,68] 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.[69]

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,[46] described above) has been reported, showing substantial differences in posttreatment morbidity profiles between surgery and radiation therapy.[70] 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 versus 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; men ?70 years, 27% who received radiation therapy vs. 12% who underwent surgery). 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).[71][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.[72] 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.

Radiation is also known to be carcinogenic.[73,74] EBRT for prostate cancer is associated with an increased risk of both bladder and rectal cancer. Brachytherapy is associated with bladder cancer.

Cryotherapy Complications

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.[41]

Hormone Therapy Complications

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.[42,75] (Refer to the PDQ summary on Sexuality and Reproductive Issues for information on loss of libido and impotence and refer to the PDQ summary on Fever, Sweats, and Hot Flashes.)

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.

In a population-based study within the Veterans Administration system, LHRH agonists were associated with an increased risk of diabetes as well as cardiovascular disease, including coronary heart disease, myocardial infarction, sudden death, and stroke. Bilateral orchiectomy was also associated with an elevated risk of coronary heart disease and myocardial infarction.[76,77,78]

However, a systematic evidence review and meta-analysis of eight trials (4,141 patients) of men with nonmetastatic prostate cancer who were randomly assigned to receive LHRH agonists or not found no difference in cardiovascular death rates (11.0% vs. 11.2%; RR for death, 0.93; 95% CI, 0.79–1.10; P = .41).[79] Median follow-up in those studies was 7.6 to 13.2 years. No excess risk of LHRH agonists was found regardless of treatment duration or patient age (median age, <70 vs. ?70).

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. There is conflicting evidence regarding whether LHRH agonists are associated with increased risk of cardiovascular morbidity or mortality.[80]

The pure antiandrogen flutamide may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.[81] Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[82] (Refer to the PDQ summary on Gastrointestinal Complications; refer to the PDQ summaries on Nausea and Vomiting and Fever, Sweats, and Hot Flashes; and for information on loss of libido and impotence, refer to the Sexuality and Reproductive Issues summary.) 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. (Refer to the PDQ summary on Pruritus for more information.) 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.[83][Level of evidence: 3iC] Additional studies that evaluate the effects of various hormone therapies on quality of life are required.[84]

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.[85] 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.[86] 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.[86][Level of evidence: 1iiDiii]

The use of androgen-deprivation therapy has also been associated with an increased risk of colorectal cancer. Using the SEER Medicare database, investigators assessed the risk of subsequent colorectal cancer in 107,859 men aged 67 years and older after an initial diagnosis of prostate cancer.[87] The rates of colorectal cancer per 1,000 person-years were 6.3 (95% CI, 5.3–7.5) in men who had orchiectomy, 4.4 (95% CI, 4.0–4.9) in men treated with GnRH agonists, and 3.7 (95% CI, 3.5–3.9) in men who had no androgen deprivation. In men treated with GnRH agonists, the risk increased with increasing duration of treatment (P for trend = .01).

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.
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.
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.
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.
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.
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.
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.
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.
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.
10. Grossfeld GD, Chang JJ, Broering JM, et al.: Impact of positive surgical margins on prostate cancer recurrence and the use of secondary cancer treatment: data from the CaPSURE database. J Urol 163 (4): 1171-7; quiz 1295, 2000.
11. Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999.
12. Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002.
13. Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002.
14. Asbell SO, Martz KL, Shin KH, et al.: Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG #77-06, a phase III study for T1BN0M0 (A2) and T2N0M0 (B) prostate carcinoma. Int J Radiat Oncol Biol Phys 40 (4): 769-82, 1998.
15. Forman JD, Order SE, Zinreich ES, et al.: Carcinoma of the prostate in the elderly: the therapeutic ratio of definitive radiotherapy. J Urol 136 (6): 1238-41, 1986.
16. Duncan W, Warde P, Catton CN, et al.: Carcinoma of the prostate: results of radical radiotherapy (1970-1985) Int J Radiat Oncol Biol Phys 26 (2): 203-10, 1993.
17. Zietman AL, Coen JJ, Shipley WU, et al.: Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate specific antigen value as a predictor of treatment outcome. J Urol 151 (3): 640-5, 1994.
18. Peeters ST, Heemsbergen WD, Koper PC, et al.: Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 24 (13): 1990-6, 2006.
19. Zietman AL, DeSilvio ML, Slater JD, et al.: Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 294 (10): 1233-9, 2005.
20. Pollack A, Zagars GK, Starkschall G, et al.: Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53 (5): 1097-105, 2002.
21. Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 80 (3): 442-53, 1997.
22. 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.
23. Whitmore WF Jr: Expectant management of clinically localized prostatic cancer. Semin Oncol 21 (5): 560-8, 1994.
24. Shappley WV 3rd, Kenfield SA, Kasperzyk JL, et al.: Prospective study of determinants and outcomes of deferred treatment or watchful waiting among men with prostate cancer in a nationwide cohort. J Clin Oncol 27 (30): 4980-5, 2009.
25. Johansson JE, Andrén O, Andersson SO, et al.: Natural history of early, localized prostate cancer. JAMA 291 (22): 2713-9, 2004.
26. Waaler G, Stenwig AE: Prognosis of localised prostatic cancer managed by "watch and wait" policy. Br J Urol 72 (2): 214-9, 1993.
27. Lu-Yao GL, Albertsen PC, Moore DF, et al.: Outcomes of localized prostate cancer following conservative management. JAMA 302 (11): 1202-9, 2009.
28. Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010.
29. Holmström B, Holmberg E, Egevad L, et al.: Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden Follow-Up Study. J Urol 184 (4): 1322-7, 2010.
30. van den Bergh RC, Roemeling S, Roobol MJ, et al.: Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 55 (1): 1-8, 2009.
31. Lu-Yao GL, McLerran D, Wasson J, et al.: An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 269 (20): 2633-6, 1993.
32. Wasson JH, Cushman CC, Bruskewitz RC, et al.: A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 2 (5): 487-93, 1993.
33. Adolfsson J, Steineck G, Whitmore WF Jr: Recent results of management of palpable clinically localized prostate cancer. Cancer 72 (2): 310-22, 1993.
34. Austenfeld MS, Thompson IM Jr, Middleton RG: Meta-analysis of the literature: guideline development for prostate cancer treatment. American Urological Association Prostate Cancer Guideline Panel. J Urol 152 (5 Pt 2): 1866-9, 1994.
35. Barry MJ, Albertsen PC, Bagshaw MA, et al.: Outcomes for men with clinically nonmetastatic prostate carcinoma managed with radical prostactectomy, external beam radiotherapy, or expectant management: a retrospective analysis. Cancer 91 (12): 2302-14, 2001.
36. Lu-Yao GL, Yao SL: Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 349 (9056): 906-10, 1997.
37. Holmberg L, Bill-Axelson A, Helgesen F, et al.: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347 (11): 781-9, 2002.
38. Bill-Axelson A, Holmberg L, Ruutu M, et al.: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 352 (19): 1977-84, 2005.
39. Bill-Axelson A, Holmberg L, Ruutu M, et al.: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 364 (18): 1708-17, 2011.
40. Wilt TJ, Brawer MK, Jones KM, et al.: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367 (3): 203-13, 2012.
41. Shelley M, Wilt TJ, Coles B, et al.: Cryotherapy for localised prostate cancer. Cochrane Database Syst Rev (3): CD005010, 2007.
42. Sanda MG, Dunn RL, Michalski J, et al.: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358 (12): 1250-61, 2008.
43. Yao SL, Lu-Yao G: Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst 91 (22): 1950-6, 1999.
44. Alibhai SM, Leach M, Tomlinson G, et al.: 30-day mortality and major complications after radical prostatectomy: influence of age and comorbidity. J Natl Cancer Inst 97 (20): 1525-32, 2005.
45. Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. J Urol 150 (3): 905-7, 1993.
46. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al.: Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988-1990 (updated June 1993). Urology 42 (6): 622-9, 1993.
47. Potosky AL, Davis WW, Hoffman RM, et al.: Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 96 (18): 1358-67, 2004.
48. Jønler M, Messing EM, Rhodes PR, et al.: Sequelae of radical prostatectomy. Br J Urol 74 (3): 352-8, 1994.
49. Geary ES, Dendinger TE, Freiha FS, et al.: Nerve sparing radical prostatectomy: a different view. J Urol 154 (1): 145-9, 1995.
50. Lim AJ, Brandon AH, Fiedler J, et al.: Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. J Urol 154 (4): 1420-5, 1995.
51. Litwin MS, Hays RD, Fink A, et al.: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 273 (2): 129-35, 1995.
52. Savoie M, Kim SS, Soloway MS: A prospective study measuring penile length in men treated with radical prostatectomy for prostate cancer. J Urol 169 (4): 1462-4, 2003.
53. Gontero P, Galzerano M, Bartoletti R, et al.: New insights into the pathogenesis of penile shortening after radical prostatectomy and the role of postoperative sexual function. J Urol 178 (2): 602-7, 2007.
54. McCullough A: Penile change following radical prostatectomy: size, smooth muscle atrophy, and curve. Curr Urol Rep 9 (6): 492-9, 2008.
55. Sun M, Lughezzani G, Alasker A, et al.: Comparative study of inguinal hernia repair after radical prostatectomy, prostate biopsy, transurethral resection of the prostate or pelvic lymph node dissection. J Urol 183 (3): 970-5, 2010.
56. Sekita N, Suzuki H, Kamijima S, et al.: Incidence of inguinal hernia after prostate surgery: open radical retropubic prostatectomy versus open simple prostatectomy versus transurethral resection of the prostate. Int J Urol 16 (1): 110-3, 2009.
57. Lughezzani G, Sun M, Perrotte P, et al.: Comparative study of inguinal hernia repair rates after radical prostatectomy or external beam radiotherapy. Int J Radiat Oncol Biol Phys 78 (5): 1307-13, 2010.
58. Lodding P, Bergdahl C, Nyberg M, et al.: Inguinal hernia after radical retropubic prostatectomy for prostate cancer: a study of incidence and risk factors in comparison to no operation and lymphadenectomy. J Urol 166 (3): 964-7, 2001.
59. Lepor H, Robbins D: Inguinal hernias in men undergoing open radical retropubic prostatectomy. Urology 70 (5): 961-4, 2007.
60. Bishoff JT, Motley G, Optenberg SA, et al.: Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol 160 (2): 454-8, 1998.
61. Schellhammer PF, Jordan GH, el-Mahdi AM: Pelvic complications after interstitial and external beam irradiation of urologic and gynecologic malignancy. World J Surg 10 (2): 259-68, 1986.
62. Hanlon AL, Schultheiss TE, Hunt MA, et al.: Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 38 (1): 59-63, 1997.
63. Hamilton AS, Stanford JL, Gilliland FD, et al.: Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol 19 (9): 2517-26, 2001.
64. Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41 (3): 501-10, 1998.
65. Dearnaley DP, Khoo VS, Norman AR, et al.: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 353 (9149): 267-72, 1999.
66. Greskovich FJ, Zagars GK, Sherman NE, et al.: Complications following external beam radiation therapy for prostate cancer: an analysis of patients treated with and without staging pelvic lymphadenectomy. J Urol 146 (3): 798-802, 1991.
67. Seymore CH, el-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986.
68. Green N, Treible D, Wallack H, et al.: Prostate cancer--the impact of irradiation on urinary outlet obstruction. Br J Urol 70 (3): 310-3, 1992.
69. Zelefsky MJ, Whitmore WF Jr, Leibel SA, et al.: Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma. J Urol 150 (6): 1860-4, 1993.
70. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al.: Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol 14 (8): 2258-65, 1996.
71. Incrocci L, Koper PC, Hop WC, et al.: Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys 51 (5): 1190-5, 2001.
72. Potosky AL, Legler J, Albertsen PC, et al.: Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 92 (19): 1582-92, 2000.
73. Nieder AM, Porter MP, Soloway MS: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180 (5): 2005-9; discussion 2009-10, 2008.
74. Abdel-Wahab M, Reis IM, Wu J, et al.: Second primary cancer risk of radiation therapy after radical prostatectomy for prostate cancer: an analysis of SEER data. Urology 74 (4): 866-71, 2009.
75. Daniell HW: Osteoporosis after orchiectomy for prostate cancer. J Urol 157 (2): 439-44, 1997.
76. Keating NL, O'Malley AJ, Freedland SJ, et al.: Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 102 (1): 39-46, 2010.
77. Keating NL, O'Malley AJ, Smith MR: Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24 (27): 4448-56, 2006.
78. D'Amico AV, Denham JW, Crook J, et al.: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25 (17): 2420-5, 2007.
79. Nguyen PL, Je Y, Schutz FA, et al.: Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 306 (21): 2359-66, 2011.
80. Levine GN, D'Amico AV, Berger P, et al.: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 60 (3): 194-201, 2010 May-Jun.
81. Wysowski DK, Freiman JP, Tourtelot JB, et al.: Fatal and nonfatal hepatotoxicity associated with flutamide. Ann Intern Med 118 (11): 860-4, 1993.
82. Soloway MS, Schellhammer PF, Smith JA, et al.: Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II multicenter trial. Urology 47 (1A Suppl): 33-7; discussion 48-53, 1996.
83. Fowler FJ Jr, McNaughton Collins M, Walker Corkery E, et al.: The impact of androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer 95 (2): 287-95, 2002.
84. Kirschenbaum A: Management of hormonal treatment effects. Cancer 75 (7 Suppl): 1983-1986, 1995.
85. Shahinian VB, Kuo YF, Freeman JL, et al.: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352 (2): 154-64, 2005.
86. Smith MR, McGovern FJ, Zietman AL, et al.: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 345 (13): 948-55, 2001.
87. Gillessen S, Templeton A, Marra G, et al.: Risk of colorectal cancer in men on long-term androgen deprivation therapy for prostate cancer. J Natl Cancer Inst 102 (23): 1760-70, 2010.

Stage I Prostate Cancer

Stage I prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T1a–c, N0, M0, prostate-specific antigen (PSA) <10, Gleason ?6.
  • T2a, N0, M0, PSA <10, Gleason ?6.
  • T1–2a, N0, M0, PSA X, Gleason X.

The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Undoubtedly, the incidental discovery of these occult cancers at prostatic surgery performed for other reasons accounts for the similar survival of men with stage I prostate cancer, compared with the normal male population, adjusted for age. Many stage I cancers are well differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.[2]

In a retrospective, pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormone therapy given at the time of symptomatic disease progression. This study showed that the patients with grade 1 or grade 2 tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival (OS) closely approximated the expected survival among men of similar ages in the general population.[3]

In younger patients (aged 50–60 years) whose expected survival is long, treatment should be considered.[4] Radical prostatectomy, external-beam radiation therapy (EBRT), and interstitial implantation of radioisotopes and watchful waiting yield apparently similar survival rates in noncontrolled selected series. The decision to treat should be made in the context of the patient's age, associated medical illnesses, and personal desires.[4]

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+).[5] Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.91–1.09; P = .89]).[5][Level of evidence: 1iA]

The Prostate Intervention Versus Observation Trial (PIVOT-1) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/ml) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[6] About 50% of the men had nonpalpable, screen-detected disease. After a median follow-up of 10 years (range up to about 15 years), the all-cause mortality was 47.0% versus 49.9% in the prostatectomy and watchful-waiting study arms, respectively, which was a difference that was not statistically significant (HR, 0.88; 95% CI, 0.71–1.08; P = .22). Prostate cancer-specific mortality was 5.8% versus 8.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.36–1.09; P = .09].[6][Levels of evidence: 1iiA, 1iiB]

Subgroup analyses showed a statistically significant reduction in overall mortality in the group of men with a baseline PSA greater than 10 ng/ml (61 of 126 men vs. 77 of 125 men; HR, 0.67) but no difference in men with a PSA of 10 or less (110 of 238 men vs. 101 of 241 men; HR, 1.03; P value for interaction = .04). Because the test for interaction was not adjusted for the numerous subgroup comparisons, it should be interpreted with caution. Although there was a trend favoring prostatectomy, for prostate cancer-specific mortality, in men with a PSA greater than 10, the numbers were very small (7 of 126 men vs. 16 of 125 men for a PSA >10; 14 fo 238menvs. 15 of 241 men), and the interaction with the PSA level was not statistically significant (P = .11). There were no statistically significant differences in efficacy associated with prostatectomy by age (<65 years vs. ?65 years), Gleason score, Charlson comorbidity status, race, or performance score.[6]

Standard treatment options:

1. Careful observation without further immediate treatment in selected patients.[3,4,7,8,9]
2. Radical prostatectomy, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency).[10,11,12] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[13,14,15,16,17,18] Because duration of follow-up in available studies is still relatively short, the value of postoperative radiation therapy is yet to be determined; however, postoperative radiation therapy does reduce local recurrence.[19] Careful treatment planning is necessary to avoid morbidity.[13,14,15,16,17,18] Clinical trials are in progress.
3. EBRT.[20,21,22,23,24] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[25]
4. Interstitial implantation of radioisotopes (i.e., iodine I 125, palladium, and iridium) done through a transperineal technique with either ultrasound (US) or computed tomography guidance is being done in carefully selected patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[26,27,28][Level of evidence: 3iiiDiv] One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%,[26,28] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with EBRT; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. In one series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration were seen. This risk decreased with increased operator experience and modification of implant technique.[26] Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with iodine I 125 has been associated with an increased local failure and complication rate [29,30] and is now rarely done.

Treatment options under clinical evaluation:

1. High-intensity focused US.[31,32,33,34]
2. Other clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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2. Consensus conference. The management of clinically localized prostate cancer. JAMA 258 (19): 2727-30, 1987.
3. 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.
4. Epstein JI, Paull G, Eggleston JC, et al.: Prognosis of untreated stage A1 prostatic carcinoma: a study of 94 cases with extended followup. J Urol 136 (4): 837-9, 1986.
5. McLeod DG, Iversen P, See WA, et al.: Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 97 (2): 247-54, 2006.
6. Wilt TJ, Brawer MK, Jones KM, et al.: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 367 (3): 203-13, 2012.
7. Graversen PH, Nielsen KT, Gasser TC, et al.: Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year follow-up. Urology 36 (6): 493-8, 1990.
8. Cantrell BB, DeKlerk DP, Eggleston JC, et al.: Pathological factors that influence prognosis in stage A prostatic cancer: the influence of extent versus grade. J Urol 125 (4): 516-20, 1981.
9. Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010.
10. 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.
11. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 143 (3): 538-43; discussion 544, 1990.
12. Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. J Urol 150 (3): 905-7, 1993.
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24. Amdur RJ, Parsons JT, Fitzgerald LT, et al.: The effect of overall treatment time on local control in patients with adenocarcinoma of the prostate treated with radiation therapy. Int J Radiat Oncol Biol Phys 19 (6): 1377-82, 1990.
25. Seymore CH, el-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986.
26. Wallner K, Roy J, Harrison L: Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 14 (2): 449-53, 1996.
27. D'Amico AV, Coleman CN: Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. J Clin Oncol 14 (1): 304-15, 1996.
28. Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 80 (3): 442-53, 1997.
29. Kuban DA, el-Mahdi AM, Schellhammer PF: I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 63 (12): 2415-20, 1989.
30. Fuks Z, Leibel SA, Wallner KE, et al.: The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 21 (3): 537-47, 1991.
31. Thüroff S, Chaussy C, Vallancien G, et al.: High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study. J Endourol 17 (8): 673-7, 2003.
32. Blana A, Murat FJ, Walter B, et al.: First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol 53 (6): 1194-201, 2008.
33. Ficarra V, Novara G: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1201-2, 2008.
34. Eastham JA: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1202-3, 2008.

Stage II Prostate Cancer

Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]

Stage IIA

  • T1a–c, N0, M0, prostate-specific antigen (PSA) <20, Gleason 7.
  • T1a–c, N0, M0, PSA ?10 <20, Gleason ?6.
  • T2a, N0, M0, PSA ?10 <20, Gleason ?6.
  • T2a, N0, M0, PSA <20, Gleason 7.
  • T2b, N0, M0, PSA <20, Gleason ?7.
  • T2b, N0, M0, PSA X, Gleason X.

Stage IIB

  • T2c, N0, M0, any PSA, any Gleason.
  • T1–2, N0, M0, PSA ?20, any Gleason.
  • T1–2, N0, M0, any PSA, Gleason ?8.

Radical prostatectomy, external-beam radiation therapy (EBRT), and interstitial implantation of radioisotopes are each employed in the treatment of stage II prostate cancer with apparently similar therapeutic effects. Radical prostatectomy and radiation therapy yield apparently similar survival rates with as many as 10 years of follow-up. For well-selected patients, radical prostatectomy can achieve 15-year survival comparable to an age-matched population without prostate cancer.[2] Unfortunately, randomized comparative trials of these treatment methods with prolonged follow-up are lacking. Patients with a small palpable cancer (T2a, N0, M0) fare better than patients in whom the disease involves both lobes of the gland (T2c, N0, M0). Patients proven free of node metastases by pelvic lymphadenectomy fare better than patients in whom this staging procedure is not performed; however, this is the result of selection of patients who have a more favorable prognosis. Side effects of the various forms of therapy—including impotence, incontinence, and bowel injury—should be considered in determining the type of treatment to employ. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.)

In a retrospective, pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormone therapy given at the time of symptomatic disease progression. This study showed that the patients with well or moderately well differentiated tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival (OS) closely approximated the expected survival among men of similar ages in the general population.[2] The decision to treat should be made in the context of the patient's age, associated medical illnesses, and personal desires.

Radical prostatectomy has been compared to watchful waiting in men with early-stage disease (clinical stages T1b, T1c, or T2) in a randomized clinical trial performed in Sweden in the pre-PSA screening era.[3,4,5] Only about 5% of the men in the trial had been diagnosed by PSA screening. The cumulative overall mortality at 15 years in the radical-prostatectomy and watchful-waiting study arms was 46.1% and 52.7%, respectively (absolute difference, 6.6%; 95% confidence interval [CI], -1.3–14.5; relative risk [RR]death of 0.75; 95% CI, 0.61–0.92).[5] The cumulative incidence of prostate cancer deaths at 15 years was 14.6% versus 20.7% (absolute difference, 6.1%; 95% CI, 0.2–12.0; RRdeath from prostate cancer, 0.62; 95% CI, 0.44–0.87).[5][Level of evidence: 1iiA]

In a post hoc–subset analysis, the improvement in overall and prostate cancer-specific mortality associated with radical prostatectomy was restricted to men younger than 65 years.

The Prostate Intervention Versus Observation Trial (PIVOT) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/ml) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[6] About 50% of the men had palpable tumors. After a median follow-up of 10 years (range up to about 15 years), the all-cause mortality was 47.0% versus 49.9% in the radical-prostatectomy and watchful-waiting study arms, respectively, which was a difference that was not statistically significant (hazard ratio [HR], 0.88; 95% CI, 0.71–1.08; P = .22). Prostate cancer-specific mortality was 5.8% versus 8.4%, and it also was not statistically significant (HR, 0.63; 95% CI, 0.36–1.09; P = .09).[6][Levels of evidence: 1iiA, 1iiB]

Subgroup analyses showed a statistically significant reduction in overall mortality in the group of men with a baseline PSA greater than 10ng/ml (61 of 126 men vs. 77 of 125 men; HR, 0.67) but no difference in men with a PSA of 10 or less (110 of 238 men vs. 101 of 241 men; HR, 1.03; P value for interaction = .04). Because the test for interaction was not adjusted for the numerous subgroup comparisons, it should be interpreted with caution. Although there was a trend favoring prostatectomy, for prostate cancer-specific mortality, in men with a PSA greater than 10, the numbers were very small (7 of 126 men vs. 16 of 125 men for a PSA >10; 14 of 238 men vs. 15 of 241 men), and the interaction with the PSA level was not statistically significant (P = .11). There were no statistically significant differences in efficacy associated with prostatectomy by age (< 65 years vs. ? 65 years), Gleason score, Charlson comorbidity status, race, or performance score.[6]

A quality-of-life substudy was conducted in 326 of the men in the randomized study.[7] Men filled out questionnaires at a median of about 4 years after study entry. The principal differences in symptoms between the two groups were in sexual and urinary function. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on sexual and urinary function.) In the surgery and watchful waiting groups, 80% versus 45% of the men answering the questionnaire said they seldom or never had erections sufficient for sexual intercourse. Forty-nine percent of men in the prostatectomy arm had urinary leakage at least once a week, 43% used protective aids regularly, and 14% used diapers or urine bags compared to 21%, 10%, and 1%, respectively, in the watchful waiting arm; however, the men on the watchful waiting arm had more obstructive symptoms (e.g., severe symptoms on the American Urologic Symptom Index of 7% in the watchful waiting arm vs. 10% in the prostatectomy arm and moderate symptoms of 42% vs. 24%).[7][Level of evidence: 1iiC]

An older, randomized study comparing radical prostatectomy at diagnosis to expectant therapy (careful observation with therapy as needed) in stage I and stage II cancers did not show a statistically significant difference in survival;[8] however, the trial of 95 patients was not large enough to exclude a small but medically significant difference in OS, nor did it include information to measure time to progression, cancer-specific survival, or quality of life.

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.[9,10] 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.

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality). Most patients have more advanced disease, but patients with bulky T2b to T2c tumors were included in the study groups that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease. Randomized clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression (LHRH agonist or orchiectomy) compared to radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).[11][Level of evidence: 1iiA]

Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR, 0.86; 95% CI, 0.82–0.91).[12][Level of evidence: 1iiA]

Short-term neoadjuvant androgen therapy administered before and during radiation therapy has shown benefit in at least some patients with clinically localized prostate cancer. In a completed, open-label, randomized trial (RTOG-9408) [NCT00002597], 1,979 men with nonmetastatic stage T1b–c, T2a, or T2b tumors and a PSA level of 20 ng/ml or less were randomly assigned to receive radiation therapy (66.6 Gy prostate dose in 1.8 Gy daily fractions) with or without 4 months of androgen-deprivation therapy (flutamide 250 mg PO tid plus either monthly goserelin 3.6 mg SQ or leuprolide 7.5 mg IM), beginning 2 months prior to radiation therapy.[13] Median follow-up was about 9 years.

The 10-year OS rate was 57% in the radiation-only group versus 62% in the combined-therapy group (HR for death, 1.17; 95% CI, 1.01–1.35; P = .03). In a post hoc analysis, there was no statistically significant interaction between treatment effect and the baseline risk category of the patients.[13][Level of evidence: 1iiA] However, there appeared to be little, if any, benefit associated with combined therapy in the lowest-risk category of patients (Gleason score ?6, PSA 10 ng/ml, and clinical stage ?T2a). The OS benefit was most apparent in men with intermediate-risk tumors (Gleason score 7, or Gleason score ?6 and PSA >10, or clinical stage T2b).

The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG-9601) [ACTRN12607000237482] of 818 men with locally advanced (T2b, T2c, T3, or T4), nonmetastatic cancer treated with radiation therapy (66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes).[14] In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen-deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation. After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation-alone group and the radiation-plus-3-months-of-NADT group. However, the 6-month-NADT arm showed better prostate cancer-specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83; P = .0008).[14][Level of evidence: 1iiA]

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer (EPC) program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+).[15] Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [HR, 0.99; 95% CI, 0.91–1.09; P = .89]).[15][Level of evidence: 1iA]

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[16][Level of evidence: 1iA]

Standard treatment options:

1. Careful observation without further immediate treatment in selected patients.[2,8,17]
2. Radical prostatectomy, with or without pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency).[18,19,20] If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection may avoid impotence postoperatively in some patients.[20,21] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP). Consideration may be given to postoperative radiation therapy for patients who are found to have capsular penetration or seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[22,23,24,25,26,27,28] Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60 Gy–64 Gy to the prosthetic fossa over 30–32 fractions) was compared to observation.[29] The primary endpoint, metastasis-free survival, was an endpoint that could be affected by serial PSA monitoring and resulting metastatic work-up for PSA increase. This could have biased the primary endpoint in favor of radiation therapy, which was associated with a lower rate of PSA rise. Nevertheless, metastasis-free survival was not statistically different between the two study arms (P = .06). After a median follow-up of 10.6 years, the median survival was 14.7 years in the radiation therapy group versus 13.8 years in the observation group (P = .16).[29][Level of evidence: 1iiA] Although the survival rates were not statistically different, complication rates were substantially higher in the radiation therapy group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%, respectively. After a median follow-up of about 12.5 years, OS was better in the radiation therapy arm; hazard ratio of death equaled 0.72 (95% CI, 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% and 66% in the radiation therapy and control arms, respectively. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[28][Level of evidence: 1iiA] Careful treatment planning is necessary to avoid morbidity.[22,23,24,25,26,27]

3. External-beam radiation therapy (EBRT).[30,31,32,33,34] Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer–specific survival as seen in the Radiation Therapy Oncology Group (RTOG-7706) trial, for example.[35][Level of evidence: 1iiA] Although the RTOG-9413 trial showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement who received whole-pelvic radiation therapy as compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.[36,37][Level of evidence: 1iiDiii] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[38] For patients with bulky T2b to T2c tumors, adjuvant hormonal therapy should be considered.[11]

In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of an LHRH-agonist plus long-term flutamide (250 mg orally tid) with or without EBRT.[39] Nineteen percent of the men had tumor stage T2, and 78% of the men had T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–18.8%) and the prostate cancer–specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.[39][Level of evidence: 1iiA]

While flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3, nonetheless, it is interesting to see that radiation therapy provided a disease-free survival (DFS) or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.

Another trial compared androgen-deprivation therapy (ADT: an LHRH agonist or orchiectomy) to ADT plus radiation therapy (RT: 65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative).[40] This NCIC CGT PR.3/MRC UK PR07 trial randomly assigned 1,205 patients with high-risk (PSA >40 ng/ml or PSA >20 and Gleason score ?8) T2 (12%–13% of the patients), T3 (83%), and T4 (4%–5%) with clinical or pathologic-staged N0, M0 disease. At a median follow-up of 6 years (maximum 13 years), OS was superior in the ADT plus RT group (HR death, 0.77; 95% CI, 0.61–0.98; P = .03). OS at 7 years was 74% for the ADT plus RT group versus 66% for the ADT alone group. Although RT had the expected bowel and urinary side effects, quality of life was the same in each study arm by 24 months and beyond.[40][Level of evidence: 1iiA]

4. EBRT plus androgen-suppression therapy.[13,14,39,41,42,43,44,45]
5. Interstitial implantation of radioisotopes (i.e., iodine I 125, palladium, and iridium) done through a transperineal technique with either ultrasound (US) or computed tomography (CT) guidance is being done in carefully selected patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[46,47,48][Level of evidence: 3iiiDiv] One advantage is that the implant is performed as outpatient surgery. The rate of maintenance of sexual potency with interstitial implants has been reported to be 86% to 92%,[46,48] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with EBRT; however, urinary tract frequency, urgency, and less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. In one series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration were seen. This risk decreased with increased operator experience and modification of implant technique.[46] Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with iodine I 125 has been associated with an increased local failure and complication rate [49,50] and is now rarely done.

6. EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.[51]

Treatment options under clinical evaluation:

1. US-guided percutaneous cryosurgery.

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes and is followed by thawing.[52][Level of evidence: 3iiiC][53,54][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. (Refer to the PDQ summary on Sexuality and Reproductive Issues for more information on impotence.) 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.[53,54]

2. High-intensity focused US.[55,56,57]
3. Proton-beam radiation therapy. Outcome data is awaited.
4. Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.[58,59]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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48. Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 80 (3): 442-53, 1997.
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51. Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 41 (3): 501-10, 1998.
52. Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999.
53. Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002.
54. Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002.
55. Blana A, Murat FJ, Walter B, et al.: First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol 53 (6): 1194-201, 2008.
56. Ficarra V, Novara G: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1201-2, 2008.
57. Eastham JA: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1202-3, 2008.
58. Fair WR, Cookson MS, Stroumbakis N, et al.: Update on neoadjuvant androgen deprivation therapy (ADT) and radical prostatectomy in localized prostate cancer. [Abstract] Proceedings of the American Urological Association 155(Suppl): A-1426, 667A, 1996.
59. Soloway MS, Sharifi R, Wajsman Z, et al.: Randomized prospective study: radical prostatectomy alone vs radical prostatectomy preceded by androgen blockade in cT2b prostate cancer - initial results. [Abstract] Proceedings of the American Urological Association 155(Suppl): A-976, 555A, 1996.

Stage III Prostate Cancer

Stage III prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T3a–b, N0, M0, any prostate-specific antigen (PSA), any Gleason.

Extraprostatic invasion with microscopic bladder neck invasion (T4) is included with T3a.

External-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and radical prostatectomy are used.[2] The results of radical prostatectomy in stage III patients are greatly inferior compared with results in patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors. EBRT using a linear accelerator is the most appropriate treatment for most patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival (DFS).[3,4] Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved. The patient's symptoms related to cancer, age, and coexisting medical illnesses should be taken into account before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.[4]

Hormonal therapy should be considered in conjunction with radiation therapy, especially in men who do not have underlying moderate or severe comorbidities.[5,6] Several studies have investigated its utility in patients with locally advanced disease. The Radiation Therapy Oncology Group (RTOG) performed a prospective, randomized trial (RTOG-8531) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomly assigned to receive immediate adjuvant goserelin or observation with administration of goserelin at time of relapse. In patients assigned to receive adjuvant goserelin, the drug was started during the last week of the radiation therapy course and was continued indefinitely or until signs of progression. The actuarial 10-year OS rate for the entire population of 945 analyzable patients was 49% on the adjuvant arm versus 39% on the observation arm P = .002. There was also an improved actuarial 10-year local failure rate (23% vs. 38%, P < .001).[7][Level of evidence: 1iiA]

A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (World Health Organization grade 3), N0–NX or T3, T4, N0 disease were randomly assigned to receive either pelvic/prostate radiation therapy, or identical radiation therapy and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation therapy and continuing for 3 years. The 401 patients available for analysis were followed for a median of 9.1 years. The Kaplan-Meier estimates of OS at 10 years were 58.1% on the adjuvant arm and 39.8% on the radiation alone arm (P = .0004). Similarly, 10-year DFS (47.7% vs. 22.7%, P < .0001) and local control (94.0% vs. 76.5%, P < .001) favored the adjuvant arm.[8,9][Levels of evidence: 1iiA,1iiDii] Two smaller studies, with 78 and 91 patients each, have also shown similar results.[10,11]

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality). Most patients had more advanced disease, but patients with bulky T2b tumors were included in the study. Randomized clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression (with a luteinizing hormone-releasing hormone [LHRH] agonist or orchiectomy) was evaluated. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression compared with radiation therapy alone (hazard ratio [HR], 0.631; 95% confidence interval [CI], 0.479–0.831).[12][Level of evidence: 1iiA]

Additionally, the RTOG did a study (RTOG-8610) in patients with bulky local disease (T2b, T2c, T3, or T4), with or without nodal involvement below the common iliac chain: 456 men were evaluable and were randomly assigned to receive either radiation therapy alone or radiation therapy with androgen ablation started 8 weeks before radiation therapy and continued for 16 weeks.[13] At 10 years, OS was not statistically significantly different; however, disease-specific mortality (23% vs. 36%) and DFS (11% vs. 3%) favored the combined arm.[14][Level of evidence: 1iiA] This trial assessed only short-term hormonal therapy, not long-term therapy, as the studies analyzed by the AHCPR did. A subset analysis of this trial and the RTOG-8531 trial with 575 patients with T3, N0, M0 disease concluded that long-term hormones compared with short-term hormones resulted in improved biochemical DFS and cause-specific survival.[15] This finding was confirmed by RTOG-9202, which reported that radiation therapy plus 28 months of androgen deprivation resulted in longer 10-year disease-specific survival (23% vs. 13%; P < .0001) but not OS (53.9% vs. 51.6%; P = 0.36).[16] An unplanned post hoc–subgroup analysis reported increased OS with longer androgen deprivation (28 months vs. 4 months) (45% vs. 32%; P = .0061) in men with high-grade cancers and Gleason scores of 8 through 10.

Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR, 0.86; 95% CI, 0.82–0.91).[17][Level of evidence: 1iiA]

The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG-9601) [ACTRN12607000237482] of 818 men with locally advanced (T2b, T2c, T3, or T4), nonmetastatic cancer treated with radiation therapy (66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes).[18] In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen-deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation. After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation-alone group and the radiation-plus-3-months-of-NADT group. However, the 6-month-NADT arm showed better prostate cancer–specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83; P = .0008).[18][Level of evidence: 1iiA]

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer (EPC) program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+).[19] Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms (HR, 0.99; 95% CI, 0.91–1.09; P = .89).[19][Level of evidence: 1iA]

In patients who are not candidates for or who are unwilling to undergo radical prostatectomy or radiation therapy, immediate hormonal therapy has been compared with deferred treatment (i.e., watchful waiting with hormonal therapy at progression). Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analog) versus deferred treatment in men with locally advanced or asymptomatic metastatic prostate cancer showed better OS and prostate cancer–specific survival with the immediate treatment. This subsequently lost statistical significance as was recorded in abstract form.[20] The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[21][Level of evidence: 1iiA] In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms). No statistically significant difference in OS was seen over a 12-year period of follow-up.[22][Level of evidence: 1iiA]

In the EORTC-30891 trial, 985 patients newly diagnosed with prostate cancer, stage T0–4, N0–2 M0, and a median age of 73 years were randomly assigned to receive androgen deprivation, either immediately or on symptomatic disease progression.[23] The study was designed to demonstrate the noninferiority of deferred treatment compared with immediate treatment in relation to OS. At a median follow-up of 7.8 years, approximately 50% of the patients in the deferred treatment group had been started on androgen deprivation. The median OS in the immediate treatment group was 7.4 years and in the deferred treatment group was 6.5 years, corresponding to a mortality HR of 1.25 (95% CI, 1.05–1.48), which failed to meet the criteria for noninferiority.[23][Level of evidence: 1iiA]

Antiandrogen monotherapy has also been evaluated in men with locally advanced prostate cancer as an alternative to castration. In a randomized, equivalence study involving 480 men with locally advanced (T3 and T4) disease, those who were treated with castration had a median OS of 70 months, while those treated with bicalutamide (150 mg/day) had a median OS of 63.5 months (HR, 1.05; 95% CI, 0.81–1.36); these results failed to meet the prespecified criteria for equivalence.[24][Level of evidence: 1iiA]

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled, randomized trial (MRC-PR04) of a 5-year regimen of the first generation bisphosphonate clodronate in high oral doses (2,080 mg per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[25][Level of evidence: 1iA]

Standard treatment options:

1. EBRT.[3,4,26,27,28] Hormonal therapy (LHRH agonist or orchiectomy) should be considered in addition to EBRT.[5,5,6,9,12,14,16,18,29,30] Although the RTOG-9413 trial showed an increased progression-free survival at 4 years for patients with a 15% estimated risk of lymph node involvement who received whole-pelvic radiation therapy as compared with prostate-only radiation therapy, OS and PSA failure rates were not significantly different.[31,32][Level of evidence: 1iiDiii] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[33] Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography (CT)-based 3-D conformal treatment planning is under clinical evaluation.[34]

In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of an LHRH-agonist plus long-term flutamide (250 mg PO tid) with or without EBRT.[35] Nineteen percent of the men had tumor stage T2 and 78% had T3. At 10 years, both overall mortality (29.6% vs. 39.4%; 95% CI for the difference, 0.8%–8.8%) and the prostate cancer–specific mortality (11.9% vs. 23.9%; 95% CI for the difference, 4.9%–19.1%) favored combined hormonal and radiation therapy.[35][Level of evidence: 1iiA]

While flutamide might not be considered a standard hormonal monotherapy in the setting of T2 or T3, nonetheless, it is interesting to see that radiation therapy provided a DFS or tumor-specific survival advantage even though this monotherapy was applied. This analysis rests on the assumption that flutamide does not shorten life expectancy and cancer-specific survival. Radiation therapy was not delivered by current standards of dose and technique.

Another trial compared androgen-deprivation therapy (ADT: an LHRH agonist or orchiectomy) to ADT plus radiation therapy (RT: 65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative).[36] This NCIC CGT PR.3/MRC UK PR07 trial randomly assigned 1,205 patients with high-risk (PSA >40 ng/ml or PSA >20 and Gleason score ?8) T2 (12%–13% of the patients), T3 (83%), and T4 (4%–5%) with clinical or pathologic-staged N0, M0 disease. At a median follow-up of 6 years (maximum 13 years), OS was superior in the ADT plus RT group (HR death, 0.77; 95% CI, 0.61–0.98; P = .03). Overall survival at 7 years was 74% for the ADT plus RT group versus 66% for the ADT alone group. Although RT had the expected bowel and urinary side effects, quality of life was the same in each study arm by 24 months and beyond.[36][Level of evidence: 1iiA]

2. Hormonal manipulations (orchiectomy or LHRH agonist).[21][Level of evidence: 1iiA]
3. Radical prostatectomy, with or without pelvic lymphadenectomy (in highly selected patients).[37] Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied. In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60 Gy–64 Gy to the prosthetic fossa over 30–32 fractions) was compared to observation.[38,39] After a median follow-up of about 12.5 years, OS was better in the radiation therapy arm; hazard ratio of death equaled 0.72 (95% CI, 0.55–0.96; P = .023). The 10-year estimated survival rates were 74% and 66% in the radiation therapy and control arms, respectively. The 10-year estimated metastasis-free survivals were 73% and 65% (P = .016).[39][Level of evidence: 1iiA] Short-term complication rates were substantially higher in the radiation therapy group: overall complications were 23.8% versus 11.9%, rectal complications were 3.3% versus 0%, and urethral stricture was 17.8% versus 9.5%, respectively. The role of preoperative (neoadjuvant) hormonal therapy is not established.[40,41] Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.[42]
4. Careful observation without further immediate treatment.[43,44]

Symptomatic treatment:

Since many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. This may often be accomplished by radiation therapy, radical surgery, transurethral resection of the prostate, or hormonal manipulation.

1. Radiation therapy.[3,4,26,27] EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
2. Hormonal manipulations effectively used as initial therapy for prostate cancer:
1. Orchiectomy.
2. Leuprolide or other LHRH agonists (goserelin) in daily or depot preparations. (These agents may be associated with tumor flare.)
3. Estrogen (diethylstilbestrol [DES] is no longer available in the United States).
4. Nonsteroidal antiandrogen (e.g., flutamide, nilutamide, and bicalutamide) or steroidal antiandrogen (cyproterone acetate).

A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[45][Level of evidence: 1iiA]

  • OS at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR, 1.26; 95% CI, 0.92–1.39).
  • Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared to orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
  • Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).

When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, the strategy might provide tumor hormone responsiveness for a longer period of time. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.[46] A systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression for OS, prostate cancer–specific survival, disease progression, or quality of life.[47][Level of evidence: 1iiA] All five trials were small and had short follow-up. Intermittent therapy remains under evaluation. In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3–T4, M0–M1, PSA ?4) that responded to an initial 3-month induction course of cyproterone acetate plus an LHRH analogue were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression.[48] After 100 months of follow-up (median 51 months), there was no difference in OS (HR, 0.99; 95% CI, 0.80–1.23; P = .84) for continuous androgen deprivation versus IAD. Quality of life between the two treatment strategies was similar, but IAD was associated with lower rates of hot flushes and gynecomastia. Replication of these findings would be important, and there are ongoing trials such as SWOG-9346 to address this further.[46][Level of evidence: 1iiA]

3. Palliative surgery (transurethral resection).
4. Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.[49]
5. Clinical trials employing alternative forms of radiation therapy. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy compared with standard photon radiation therapy.[50] A subsequent, randomized study from the same group compared fast-neutron radiation therapy with standard photon radiation therapy. Local-regional control was improved with neutron treatment, but no difference in OS was seen, though follow-up was shorter in this trial. Fewer complications were seen with the use of a multileaf collimator.[51] Proton-beam radiation therapy is also under investigation.[52]
6. Other clinical trials.
7. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation. 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.[53][Level of evidence: 3iiiC];[54,55][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. The technique of cryosurgery is under development. 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.[54,55]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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48. Tombal B: Intermittent androgen deprivation therapy: conventional wisdom versus evidence. Eur Urol 55 (6): 1278-80, 2009.
49. Blasko JC, Grimm PD, Ragde H: Brachytherapy and Organ Preservation in the Management of Carcinoma of the Prostate. Semin Radiat Oncol 3 (4): 240-249, 1993.
50. Laramore GE, Krall JM, Thomas FJ, et al.: Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial. Am J Clin Oncol 16 (2): 164-7, 1993.
51. Russell KJ, Caplan RJ, Laramore GE, et al.: Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys 28 (1): 47-54, 1994.
52. Shipley WU, Verhey LJ, Munzenrider JE, et al.: Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 32 (1): 3-12, 1995.
53. Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999.
54. Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002.
55. Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002.

Stage IV Prostate Cancer

Stage IV prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • T4, N0, M0, any prostate-specific antigen (PSA), any Gleason.
  • Any T, N1, M0, any PSA, any Gleason.
  • Any T, any N, M1, any PSA, any Gleason.

Extraprostatic invasion with microscopic bladder neck invasion (T4) is included with T3a.

Treatment selection depends on age, coexisting medical illnesses, symptoms, and the presence of distant metastases (most often bone) or regional lymph node involvement only. The most common symptoms originate from the urinary tract or from bone metastases. Palliation of symptoms from the urinary tract with transurethral resection of the prostate (TURP) or radiation therapy and palliation of symptoms from bone metastases with radiation therapy or hormonal therapy are an important part of the management of these patients. Bisphosphonates are also under clinical evaluation for the management of bone metastases.[2]

The Agency for Health Care Policy and Research (AHCPR) (now the Agency for Healthcare Research and Quality) performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association.[3][Level of evidence: 1iiA] Some patients with bulky T2b tumors were included in the studied groups. The meta-analysis found a difference in 5-year overall survival (OS) in favor of radiation therapy plus continued androgen suppression using a luteinizing hormone-releasing hormone (LHRH) agonist or orchiectomy, compared with radiation therapy alone (hazard ratio [HR], 0.631; 95% confidence interval [CI], 0.479–0.831). This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation therapy and continued for several years. The optimal duration of therapy and the issue of utility of neoadjuvant hormonal therapy have not been determined.

Likewise, a meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) to deferred hormonal treatment (LHRH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting, showed improved overall mortality (RR, 0.86; 95% CI, 0.82–0.91).[4][Level of evidence: 1iiA]

The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG-9601) [ACTRN12607000237482] of 818 men with locally advanced (T2b, T2c, T3, T4) nonmetastatic cancer treated with radiation therapy (66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes).[5] In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen-deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months prior to and during radiation, or 6 months of NADT for 5 months prior to and during radiation. After a median follow-up of 10.6 years, there were no statistically significant differences between the radiation-alone group and the radiation-plus-3-months-of-NADT group. However, the 6-month-NADT arm showed better prostate cancer–specific mortality and overall mortality than radiation alone; 10-year all-cause mortality 29.2% versus 42.5% (HR, 0.63; 95% CI, 0.48–0.83; P = .0008).[5][Level of evidence: 1iiA]

In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2 N1, M0), immediate continuous hormonal therapy with the LHRH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[6][Level of evidence: 1iA];[7] After a median follow-up of 11.9 years, both OS and prostate cancer–specific survival were superior in the immediate adjuvant therapy arm (P = .04 and P = .004, respectively). At 10 years, the survival rate in the immediate therapy arm was about 80% versus about 60% for the deferred therapy arm.[8] Another trial (RTOG-8531), with twice as many patients in a randomization, showed no difference in OS with early versus late hormonal manipulation.[9]

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer. The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg orally per day) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, NX; T3–4, any N; or any T, N+).[10] Less than 2% of the 8,113 men had known node disease. At a median follow-up of 7.4 years, there was no difference in OS between the bicalutamide and placebo groups (about 76% in both arms [HR, 0.99; 95% CI, 0.91–1.09; P = .89]).[10][Level of evidence: 1iA]

Immediate hormone therapy with goserelin or orchiectomy has also been compared with deferred hormone therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical metastases (any T, N+, M0).[11] None of the 234 men received prostatectomy or prostatic radiation therapy. After a median follow-up of 8.7 years, the HR for OS in the deferred versus immediate hormone therapy arms was 1.23 (95% CI, 0.88–1.71). No statistically significant difference in OS between deferred and immediate hormone therapy was found, but the trial was underpowered to detect small or modest differences.[11][Level of evidence: 1iiA]

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg per day) had no favorable impact on either time to symptomatic bone metastasis or survival.[12][Level of evidence: 1iA]

Hormonal treatment is the mainstay of therapy for distant metastatic (stage D2) prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. Initial results from a randomized study of immediate hormonal treatment (e.g., orchiectomy or LHRH analog) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better OS and prostate cancer–specific survival with the immediate treatment. The incidence of pathologic fractures, spinal cord compression, and ureteric obstruction were also lower in the immediate treatment arm.[13][Level of evidence: 1iiA] In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms). Over a 12-year period of follow-up, no statistically significant difference was observed in OS.[14][Level of evidence: 1iiA]

In some series, pretreatment levels of PSA are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is instituted, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive.[15] Orchiectomy and estrogens yield similar results, and selection of one or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. Diethylstilbestrol (DES) in a dose of 1 mg per day is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects, and DES is no longer commercially available in the United States. The psychological implications of orchiectomy are objectionable to many patients, and many will choose alternative therapy if effective.[16] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[17]

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[18,19] In a randomized trial, the LHRH analog leuprolide (1 mg subcutaneously every day) was found to be as effective as DES (3 mg orally every day) in any T, any N, M1 patients but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[20] In other randomized studies, the depot LHRH analog goserelin was found to be as effective as orchiectomy [21,22,23] or DES at a dose of 3 mg per day.[19] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide.[24] A small, randomized study comparing 1 mg of DES orally 3 times per day to 250 mg of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with the DES treatment.[25][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from such case series led to widespread use of the strategy, known as maximal androgen blockage (MAB) or complete androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration. In a large, randomized controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[26][Level of evidence: 1iA] Although it has been suggested that MAB may improve the more subjective end point of response rate, prospectively assessed quality of life was worse in the flutamide arm than in the placebo arm, primarily because of more diarrhea and worse emotional function in the flutamide-treated group.[27][Level of evidence: 1iC] A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration to MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[28][Level of evidence: 1iA]

When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined therapy group (2.9% better, 95% CI, 0.3–5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined therapy group (2.8% worse, 95% CI, -7.6 to +2.0).[28]

The AHCPR has performed a systematic review of the available randomized clinical trial evidence of single hormonal therapies and combined androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:

1. OS at 2 years using any of the LHRH agonists is similar to treatment with orchiectomy or 3 mg per day of DES (HR, 1.26; 95% CI, 0.92–1.39).
2. Survival rates at 2 years are similar or worse with nonsteroidal antiandrogens compared with orchiectomy (HR, 1.22; 95% CI, 0.99–1.50).
3. Treatment withdrawals, used as a surrogate for adverse effects, occurred less with LHRH agonists (0%–4%) than with nonsteroidal antiandrogens (4%–10%).[29][Level of evidence: 1iiA]

Combined androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen-suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[3]

When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, the strategy might provide tumor hormone responsiveness for a longer period of time. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.[30] A systematic review of all five randomized trials addressing this issue found no reliable data on the relative effectiveness of intermittent versus continuous androgen suppression for OS, prostate cancer–specific survival, disease progression, or quality of life.[31][Level of evidence: 1iiA] All five trials were small and had short follow-up. Intermittent therapy therefore remains under evaluation. In a subsequent randomized trial, 626 men with clinically advanced prostate cancer (T3–T4, M0–M1, PSA ?4 ng/mL) who responded to an initial 3-month induction course of cyproterone acetate plus an LHRH analogue were randomly assigned to either continue the regimen or cease treatment until there was evidence of progression.[32] After 100 months of follow-up (median 51 months), there was no difference in OS (HR, 0.99; 95% CI, 0.80–1.23; P = 0.84) for continuous androgen deprivation (CAD) versus IAD. Quality of life between the two treatment strategies was similar, but IAD was associated with lower rates of hot flushes and gynecomastia. Replication of these findings would be important, and there are ongoing trials such as SWOG-9346 to address this further.[30][Level of evidence: 1iiA]

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years.[33] Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate.

In addition to hormonal therapy, adjuvant treatment has been tested using bisphosphonates.[34] In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg per day) or a matching placebo for up to 3 years. At a median follow-up of 11.5 years, OS was better in the clodronate arm: HR of death was 0.77 (95% CI, 0.60–0.98; P = .032). Five- and 10-year survival rates were 30% and 17% in the clodronate arm versus 21% and 9% in the placebo arm.[34][Level of evidence: 1iA] A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate. Confirmatory trials about the effect of bisphosphonates on OS, such as CALGB-90202 and CALGB-70604, are ongoing.

After tumor progression on one form of hormonal manipulation develops, an objective tumor response to any other form is uncommon.[35] Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA values and that one may need to monitor for this response before initiating new therapy.[36,37,38] Low-dose prednisone may palliate symptoms in about 33% of cases.[39] (Refer to the Recurrent Prostate Cancer section of this summary for more information.)

Treatment options:

1. Hormonal manipulations effectively used as initial therapy for prostate cancer: [40]
1. Orchiectomy alone or with an androgen blocker as seen in the SWOG-8894 trial, for example.
2. LHRH agonists such as leuprolide in daily or depot preparations. (These agents may be associated with tumor flare when used alone; therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)[18,20,21,41][Level of evidence: 1iiA]
3. Leuprolide plus flutamide;[42] however, the addition of an antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival.[28]
4. Estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens USP, and DES-diphosphate). (DES is no longer commercially available in the United States.)
2. External-beam radiation therapy (EBRT) for attempted cure (highly selected stage M0 patients).[43,44] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[45]

Hormonal therapy should be considered in addition to EBRT.[3,5]

3. Palliative radiation therapy. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy × 10) as evidenced in the RTOG-9714 trial.[46,47][Level of evidence: 1iiC] (Refer to the PDQ summary on Pain for more information.)
4. Palliative surgery (TURP).
5. Careful observation without further immediate treatment (in selected patients).[48]
6. Radical prostatectomy with immediate orchiectomy is under clinical evaluation.[49] An uncontrolled, retrospective review of a large series of patients with any T, N1–3, M0 disease treated at the Mayo Clinic by concurrent radical prostatectomy and orchiectomy showed prolongation of intervals to local and distant progression; however, a significant increase in survival has not been demonstrated.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Prostate. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 457-68.
2. Dearnaley DP, Sydes MR, Mason MD, et al.: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95 (17): 1300-11, 2003.
3. Seidenfeld J, Samson DJ, Aronson N, et al.: Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) (4): i-x, 1-246, I1-36, passim, 1999.
4. Boustead G, Edwards SJ: Systematic review of early vs deferred hormonal treatment of locally advanced prostate cancer: a meta-analysis of randomized controlled trials. BJU Int 99 (6): 1383-9, 2007.
5. Denham JW, Steigler A, Lamb DS, et al.: Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 12 (5): 451-9, 2011.
6. Messing EM, Manola J, Sarosdy M, et al.: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341 (24): 1781-8, 1999.
7. Eisenberger MA, Walsh PC: Early androgen deprivation for prostate cancer? N Engl J Med 341 (24): 1837-8, 1999.
8. Messing EM, Manola J, Yao J, et al.: Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7 (6): 472-9, 2006.
9. Lawton CA, Winter K, Grignon D, et al.: Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31. J Clin Oncol 23 (4): 800-7, 2005.
10. McLeod DG, Iversen P, See WA, et al.: Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 97 (2): 247-54, 2006.
11. Schröder FH, Kurth KH, Fosså SD, et al.: Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol 172 (3): 923-7, 2004.
12. Mason MD, Sydes MR, Glaholm J, et al.: Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 99 (10): 765-76, 2007.
13. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 79 (2): 235-46, 1997.
14. Studer UE, Hauri D, Hanselmann S, et al.: Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88. J Clin Oncol 22 (20): 4109-18, 2004.
15. 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.
16. Cassileth BR, Soloway MS, Vogelzang NJ, et al.: Patients' choice of treatment in stage D prostate cancer. Urology 33 (5 Suppl): 57-62, 1989.
17. Byar DP: Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32 (5): 1126-30, 1973.
18. Parmar H, Edwards L, Phillips RH, et al.: Orchiectomy versus long-acting D-Trp-6-LHRH in advanced prostatic cancer. Br J Urol 59 (3): 248-54, 1987.
19. Waymont B, Lynch TH, Dunn JA, et al.: Phase III randomised study of zoladex versus stilboestrol in the treatment of advanced prostate cancer. Br J Urol 69 (6): 614-20, 1992.
20. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. The Leuprolide Study Group. N Engl J Med 311 (20): 1281-6, 1984.
21. Peeling WB: Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology 33 (5 Suppl): 45-52, 1989.
22. Vogelzang NJ, Chodak GW, Soloway MS, et al.: Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. Urology 46 (2): 220-6, 1995.
23. Kaisary AV, Tyrrell CJ, Peeling WB, et al.: Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 67 (5): 502-8, 1991.
24. Bales GT, Chodak GW: A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 47 (1A Suppl): 38-43; discussion 48-53, 1996.
25. Chang A, Yeap B, Davis T, et al.: Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. J Clin Oncol 14 (8): 2250-7, 1996.
26. Eisenberger MA, Blumenstein BA, Crawford ED, et al.: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 339 (15): 1036-42, 1998.
27. Moinpour CM, Savage MJ, Troxel A, et al.: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst 90 (20): 1537-44, 1998.
28. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 355 (9214): 1491-8, 2000.
29. Seidenfeld J, Samson DJ, Hasselblad V, et al.: Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132 (7): 566-77, 2000.
30. Calais da Silva FE, Bono AV, Whelan P, et al.: Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 55 (6): 1269-77, 2009.
31. Conti PD, Atallah AN, Arruda H, et al.: Intermittent versus continuous androgen suppression for prostatic cancer. Cochrane Database Syst Rev (4): CD005009, 2007.
32. Tombal B: Intermittent androgen deprivation therapy: conventional wisdom versus evidence. Eur Urol 55 (6): 1278-80, 2009.
33. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J Urol 152 (4): 1170-3, 1994.
34. Dearnaley DP, Mason MD, Parmar MK, et al.: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10 (9): 872-6, 2009.
35. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 15 (1): 382-8, 1997.
36. Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 11 (8): 1566-72, 1993.
37. Sartor O, Cooper M, Weinberger M, et al.: Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer. J Natl Cancer Inst 86 (3): 222-7, 1994.
38. Small EJ, Srinivas S: The antiandrogen withdrawal syndrome. Experience in a large cohort of unselected patients with advanced prostate cancer. Cancer 76 (8): 1428-34, 1995.
39. Tannock I, Gospodarowicz M, Meakin W, et al.: Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7 (5): 590-7, 1989.
40. Scott WW, Menon M, Walsh PC: Hormonal therapy of prostatic cancer. Cancer 45 (7 Suppl): 1929-36, 1980.
41. Sharifi R, Soloway M: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer.The Leuprolide Study Group. J Urol 143 (1): 68-71, 1990.
42. Crawford ED, Eisenberger MA, McLeod DG, et al.: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 321 (7): 419-24, 1989.
43. Bagshaw MA: External radiation therapy of carcinoma of the prostate. Cancer 45 (7 Suppl): 1912-21, 1980.
44. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27 (1): 10-6, 1986.
45. Seymore CH, el-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986.
46. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006.
47. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007.
48. Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010.
49. Zincke H: Extended experience with surgical treatment of stage D1 adenocarcinoma of prostate. Significant influences of immediate adjuvant hormonal treatment (orchiectomy) on outcome. Urology 33 (5 Suppl): 27-36, 1989.

Recurrent Prostate Cancer

Overview

In prostate cancer, the selection of further treatment depends on many factors, including previous treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy.[1,2,3,4] An occasional patient can be salvaged with prostatectomy after a local recurrence following definitive radiation therapy;[5] however, only about 10% of patients treated initially with radiation therapy will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure.[6] Cryosurgical ablation of recurrence following radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.[7]

Most relapsing patients who initially received locoregional therapy with surgery or radiation therapy will fail with disseminated disease and are managed with hormonal therapy. The management of these patients with stage IV disease is discussed in the preceding section.

Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation therapy, corticosteroids, bone-seeking radionuclides, gallium nitrate, bisphosphonates, and denosumab (a monoclonal antibody that inhibits osteoclast function).[8,9,10,11,12] (Refer to the PDQ summary on Pain for more information.)

A placebo-controlled, randomized trial (NCT00321620) comparing denosumab to zoledronic acid for the prevention of skeletal events (i.e., pathologic fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy–resistant prostate cancer with at least one bone metastasis showed that denosumab was more effective than zoledronic acid; median time to first on-study skeletal event 20.7 versus 17.1 months (HR, 0.82; 95% confidence interval [CI], 0.71–0.95).[12] Serious adverse events were reported in 63% of denosumab patients versus 60% in patients on zoledronic acid. The cumulative incidence of osteonecrosis of the jaw was low in both study arms: 2% in the denosumab arm versus 1% in the zoledronic acid arm. There was Grade 3 to 4 toxocity. There was no difference in survival. The incidence of hypocalcemia was higher in the denosumab arm: 13% versus 6%.

External-beam radiation therapy (EBRT) for palliation of bone pain can be very useful. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and quality of life as multiple fractions (3 Gy × 10) as seen in the RTOG-9714 trial, for example.[13,14][Level of evidence: 1iiC] Also, the use of radioisotopes such as strontium chloride Sr 89 has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. As a single agent, strontium chloride Sr 89 has been reported to decrease bone pain in 80% of patients treated [15] and is similar to responses with local or hemibody radiation therapy.[16]

A multicenter, randomized trial of a single intravenous dose of strontium chloride Sr 89 (150 MBq: 4 mCi) versus palliative EBRT in men with painful bone metastases from prostate cancer despite hormone treatment showed similar subjective pain response rates: 34.7% versus 33.3%, respectively. Overall survival (OS) was better in the EBRT group than in the strontium chloride Sr 89 group (P = .046; median survival 11.0 vs. 7.2 months). No statistically significant differences in time-to-subjective progression or in progression-free survival were seen.[17][Level of evidence: 1iiA] When used as an adjunct to EBRT, strontium chloride Sr 89 was shown to slow disease progression and to reduce analgesic requirements, compared with EBRT alone.[18]

Chemotherapy for Hormone-Refractory Prostate Cancer

A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[19] Differences in OS or measured global quality of life between the two treatments were not statistically significant.

In randomized trials of men with hormone-refractory prostate cancer, regimens of docetaxel given every 3 weeks have produced better OS (at 21–33 months) than mitoxantrone.[20,21][Level of evidence: 1iiA]

1. In a randomized trial of patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks).[20] All patients received oral prednisone (5 mg twice per day). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg were given at 12 hours, 3 hours, and 1 hour prior to the 3-week regimen; 8 mg were given at 1 hour prior to the 5 out-of-every-6 weeks' regimen). OS at 3 years was statistically significantly better in the 3-weekly docetaxel arm (18.6%) than in the mitoxantrone arm (13.5%, hazard ratio [HR]death, 0.79; 95% CI, 0.67–0.93). However, the OS rate for the 5 out-of-every-6 weeks' docetaxel regimen was 16.8%, which was not statistically significantly better than mitoxantrone. Quality of life was also superior in the docetaxel arms compared with mitoxantrone (P = .009).[22][Levels of evidence: 1iiA; 1iiC]
2. In another randomized trial of patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg orally 3 times a day for days 1 to 5, plus daily warfarin and 325 mg of aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 intravenously on day 2, preceded by dexamethasone [20 mg times 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 intravenously every 3 weeks) plus prednisone (5 mg daily).[21] After a median follow-up of 32 months, median OS was 17.5 months in the estramustine/docetaxel arm versus 15.6 months in the mitoxantrone arm (P = .02; HRdeath, 0.80; 95% CI, 0.67–0.97).[21][Level of evidence: 1iiA] Global quality of life and pain palliation measures were similar in the two treatment arms.[23][Level of evidence: 1iiC]

In hormone-resistant patients whose disease progresses during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared to mitoxantrone in a randomized trial (NCT00417079).[24] In the trial, 755 such men were treated with daily oral prednisone (10 mg) and randomly assigned to receive either cabazitaxel (25 mg/m2 I.V.) or mitoxantrone (12 mg/m2 I.V.) every 3 weeks. Median OS in the cabazitaxel and mitoxantrone study arms was 15.1 and 12.7 months, respectively (HRdeath, 0.70; 95% CI, 0.59–0.83; P < .0001).[24][Level of evidence: 1iiA]

Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[25][Level of evidence: 3iiiDiii];[26]

  • Paclitaxel.
  • Estramustine/etoposide.
  • Estramustine/vinblastine.
  • Estramustine/paclitaxel.

One study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[27]

Immunotherapy

Sipuleucel-T, an active cellular immunotherapy has been shown to increase OS in patients with hormone-refractory metastatic prostate cancer. Sipuleucel-T consists of autologous peripheral blood mononuclear cells that have been exposed ex vivo to a recombinant fusion protein (PA2024) composed of prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor (gmCSF).

1. In the largest trial (the Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT [NCT00065442] trial), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (341 patients) versus placebo (171 patients) intravenously by 60-minute infusion every 2 weeks for a total of 3 times.[28] Patients with visceral metastases, pathologic bone fractures, or Eastern Cooperative Oncology Group (ECOG) performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician's discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary endpoints, but the primary endpoint was changed prior to study unblinding based upon survival differences in two prior trials of similar design (described below).

After a median follow-up of 34.1 months, the overall mortality was 61.6% in the sipuleucel-T group versus 70.8% in the placebo group (HRdeath, 0.78; 95% CI, 0.61–0.98; P = .03).[28][Level of evidence: 1iA] However, the improved survival was not accompanied by measurable antitumor effects. There was no difference between the study groups in rate of disease progression. In 2011, the estimated price of sipuleucel-T is $93,000 for a 1-month course of therapy. This translates into an estimated cost of about $276,000 per year of life saved.[29]

2. The same investigators performed two prior smaller trials (NCT00005947 ) of nearly identical design to the IMPACT trial.[30,31] The combined results of the two smaller trials, conducted on a total of 225 patients randomly assigned in a 2:1 ratio of sipuleucel-T to placebo were similar to those in the IMPACT trial. The HRdeath, 0.67; (95% CI, 0.49–0.91), but the time-to-progression rates were not statistically significantly different.

Hormonal Approaches

As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, a hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Abiraterone inhibits androgen biosynthesis by blocking cytochrome P450 c17 (CYP17). Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (n = 1195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1000 mg) (n = 797) or placebo (n = 398) orally once a day (COU-AA-301 [NCT00638690]).[32] Both groups received prednisone (5 mg) orally twice a day. After a median follow-up of 12.8 months, the trial was stopped when an interim analysis showed an OS advantage in the abiraterone group. Median OS was 14.8 months in the abiraterone group versus 10.9 months in the placebo group (HRdeath, 0.65; 95% CI, 0.54–0.77; P < .001).[32][Level of evidence: 1iA] Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, and hypertension.

Enzalutamide, an androgen receptor signaling inhibitor, has been shown to increase survival in patients with progressive prostate cancer who received prior androgen deprivation therapy as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg orally per day) versus placebo.[33] After a median follow-up of 14.4 months, the study was stopped at the single-planned interim analysis because improved OS, the primary endpoint, was found in the enzalutamide study group: median OS, 18.4 months (95% CI, 17.3 to not yet reached) versus 13.6 months (95% CI, 11.3–15.8); HR death of 0.63 (95% CI, 0.53–0.75; P < .001). In addition, quality of life, measured by the FACT-P questionnaire, was superior in the enzalutamide arm.[33][Level of evidence: 1iA, 1iC] A seizure was reported in five of the 800 men in the enzalutamide study group, versus none in the placebo group; however, the relationship to enzalutamide is not clear. Of the reported seizures, two patients had brain metastases, one patient had just received intravenous lidocaine, and one seizure was not witnessed.

Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormone therapy.[34] The absolute level of PSA at the initiation of therapy in relapsed or hormone-refractory patients has not been shown to be of prognostic significance.[35] Some patients whose disease has progressed on combined androgen blockade can respond to a variety of second-line hormonal therapies. Aminoglutethimide, hydrocortisone, flutamide withdrawal, progesterone, ketoconazole, and combinations of these therapies have produced PSA responses in 14% to 60% of patients treated and have also produced clinical responses of 0% to 25% when assessed. The duration of these PSA responses has been in the range of 2 to 4 months.[36] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as anti-androgen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of anti-androgen withdrawal as seen in the CLB-9583 trial, for example.[37][Level of evidence: 1iiA] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[35,38]

Patients treated with either luteinizing-hormone agonists or estrogens as primary therapy are generally maintained with castrate levels of testosterone. One study from the Eastern Cooperative Oncology Group showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[39] however, another study from the Southwest Oncology Group did not show an advantage to continued androgen blockade.[40]

Low-dose prednisone may palliate symptoms in some patients.[41] In a randomized comparison of prednisone (5 mg 4 times per day) with flutamide (250 mg 3 times per day) in patients with disease progression after androgen-ablative therapy (castration or luteinizing hormone-releasing hormone [LHRH] agonist), prednisone and flutamide produced similar survival, symptomatic response, PSA response, and time to progression;[42] however, there were statistically significant differences in pain, nausea and vomiting, and diarrhea in patients who received prednisone. (Refer to the PDQ summaries on Pain and Nausea and Vomiting; for information on diarrhea, refer to the PDQ summary on Gastrointestinal Complications.) Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[19,25,26,27,43,44,45,46]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent prostate cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Trock BJ, Han M, Freedland SJ, et al.: Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 299 (23): 2760-9, 2008.
2. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. J Urol 132 (5): 926-30, 1984.
3. Carter GE, Lieskovsky G, Skinner DG, et al.: Results of local and/or systemic adjuvant therapy in the management of pathological stage C or D1 prostate cancer following radical prostatectomy. J Urol 142 (5): 1266-70; discussion 1270-1, 1989.
4. Freeman JA, Lieskovsky G, Cook DW, et al.: Radical retropubic prostatectomy and postoperative adjuvant radiation for pathological stage C (PcN0) prostate cancer from 1976 to 1989: intermediate findings. J Urol 149 (5): 1029-34, 1993.
5. Moul JW, Paulson DF: The role of radical surgery in the management of radiation recurrent and large volume prostate cancer. Cancer 68 (6): 1265-71, 1991.
6. Schellhammer PF, Kuban DA, el-Mahdi AM: Treatment of clinical local failure after radiation therapy for prostate carcinoma. J Urol 150 (6): 1851-5, 1993.
7. Bales GT, Williams MJ, Sinner M, et al.: Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology 46 (5): 676-80, 1995.
8. Scher HI, Chung LW: Bone metastases: improving the therapeutic index. Semin Oncol 21 (5): 630-56, 1994.
9. Dearnaley DP, Sydes MR, Mason MD, et al.: A double-blind, placebo-controlled, randomized trial of oral sodium clodronate for metastatic prostate cancer (MRC PR05 Trial). J Natl Cancer Inst 95 (17): 1300-11, 2003.
10. Ernst DS, Tannock IF, Winquist EW, et al.: Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 21 (17): 3335-42, 2003.
11. Saad F, Gleason DM, Murray R, et al.: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96 (11): 879-82, 2004.
12. Fizazi K, Carducci M, Smith M, et al.: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377 (9768): 813-22, 2011.
13. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006.
14. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007.
15. Robinson RG: Strontium-89--precursor targeted therapy for pain relief of blastic metastatic disease. Cancer 72 (11 Suppl): 3433-5, 1993.
16. Bolger JJ, Dearnaley DP, Kirk D, et al.: Strontium-89 (Metastron) versus external beam radiotherapy in patients with painful bone metastases secondary to prostatic cancer: preliminary report of a multicenter trial. UK Metastron Investigators Group. Semin Oncol 20 (3 Suppl 2): 32-3, 1993.
17. Oosterhof GO, Roberts JT, de Reijke TM, et al.: Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 44 (5): 519-26, 2003.
18. Porter AT, McEwan AJ, Powe JE, et al.: Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 25 (5): 805-13, 1993.
19. Tannock IF, Osoba D, Stockler MR, et al.: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 14 (6): 1756-64, 1996.
20. Tannock IF, de Wit R, Berry WR, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351 (15): 1502-12, 2004.
21. Petrylak DP, Tangen CM, Hussain MH, et al.: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351 (15): 1513-20, 2004.
22. Berthold DR, Pond GR, Soban F, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26 (2): 242-5, 2008.
23. Berry DL, Moinpour CM, Jiang CS, et al.: Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 24 (18): 2828-35, 2006.
24. de Bono JS, Oudard S, Ozguroglu M, et al.: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376 (9747): 1147-54, 2010.
25. Petrylak DP, Macarthur RB, O'Connor J, et al.: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 17 (3): 958-67, 1999.
26. Millikan RE: Chemotherapy of advanced prostatic carcinoma. Semin Oncol 26 (2): 185-91, 1999.
27. Amato RJ, Logothetis CJ, Hallinan R, et al.: Chemotherapy for small cell carcinoma of prostatic origin. J Urol 147 (3 Pt 2): 935-7, 1992.
28. Kantoff PW, Higano CS, Shore ND, et al.: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363 (5): 411-22, 2010.
29. Longo DL: New therapies for castration-resistant prostate cancer. N Engl J Med 363 (5): 479-81, 2010.
30. Higano CS, Schellhammer PF, Small EJ, et al.: Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115 (16): 3670-9, 2009.
31. Small EJ, Schellhammer PF, Higano CS, et al.: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24 (19): 3089-94, 2006.
32. de Bono JS, Logothetis CJ, Molina A, et al.: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364 (21): 1995-2005, 2011.
33. Scher HI, Fizazi K, Saad F, et al.: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367 (13): 1187-97, 2012.
34. Fosså SD, Dearnaley DP, Law M, et al.: Prognostic factors in hormone-resistant progressing cancer of the prostate. Ann Oncol 3 (5): 361-6, 1992.
35. Kelly WK, Scher HI, Mazumdar M, et al.: Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. J Clin Oncol 11 (4): 607-15, 1993.
36. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 15 (1): 382-8, 1997.
37. Small EJ, Halabi S, Dawson NA, et al.: Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 22 (6): 1025-33, 2004.
38. Sridhara R, Eisenberger MA, Sinibaldi VJ, et al.: Evaluation of prostate-specific antigen as a surrogate marker for response of hormone-refractory prostate cancer to suramin therapy. J Clin Oncol 13 (12): 2944-53, 1995.
39. Taylor CD, Elson P, Trump DL: Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 11 (11): 2167-72, 1993.
40. Hussain M, Wolf M, Marshall E, et al.: Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 12 (9): 1868-75, 1994.
41. Tannock I, Gospodarowicz M, Meakin W, et al.: Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response. J Clin Oncol 7 (5): 590-7, 1989.
42. Fosså SD, Slee PH, Brausi M, et al.: Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 19 (1): 62-71, 2001.
43. Debruyne FJ, Murray R, Fradet Y, et al.: Liarozole--a novel treatment approach for advanced prostate cancer: results of a large randomized trial versus cyproterone acetate. Liarozole Study Group. Urology 52 (1): 72-81, 1998.
44. Eisenberger MA: Chemotherapy for prostate carcinoma. NCI Monogr (7): 151-63, 1988.
45. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. J Clin Oncol 12 (10): 2005-12, 1994.
46. Hudes GR, Greenberg R, Krigel RL, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 10 (11): 1754-61, 1992.

Changes to This Summary (09 / 21 / 2012)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview

Revised text on the results of a Swedish trial to state that the cumulative overall mortality at 15 years in the radical-prostatectomy and watchful-waiting study arms was 46.1% and 52.7%, respectively, and that the cumulative incidence of prostate cancer deaths at 15 years was 14.6% versus 20.7% (cited Bill-Axelson et al. as reference 39 and level of evidence 1iiA).

Added text to state that the Prostate Intervention Versus Observation Trial (PIVOT-1) is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting, and in it, men aged 75 years or younger with localized prostate cancer and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting. After a median follow-up of 10 years, the all-cause mortality was 47.0% versus 49.9% in the prostatectomy and watchful-waiting study arms, respectively, and prostate cancer-specific mortality was 5.8% versus 8.4% (cited Wilt et al. as reference 40 and levels of evidence 1iiA and 1iiB).

Stage I Prostate Cancer

Added text to state that the PIVOT-1 is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting, and in it, men aged 75 years or younger with localized prostate cancer and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting. After a median follow-up of 10 years, the all-cause mortality was 47.0% versus 49.9% in the prostatectomy and watchful-waiting study arms, respectively, and prostate cancer-specific mortality was 5.8% versus 8.4% (cited Wilt et al. as reference 6 and levels of evidence 1iiA and 1iiB).

Stage II Prostate Cancer

Added text on the results of a Swedish trial to state that the cumulative overall mortality at 15 years in the radical-prostatectomy and watchful-waiting study arms was 46.1% and 52.7%, respectively. The cumulative incidence of prostate cancer deaths at 15 years was 14.6% versus 20.7% (cited Bill-Axelson et al. as reference 5 and level of evidence 1iiA.)

Added text to state that the PIVOT-1 is the only published randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting, and in it, men aged 75 years or younger with localized prostate cancer and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting. After a median follow-up of 10 years, the all-cause mortality was 47.0% versus 49.9% in the radical-prostatectomy and watchful-waiting study arms, respectively, and prostate cancer-specific mortality was 5.8% versus 8.4% (cited Wilt et al. as reference 6 and levels of evidence 1iiA and 1iiB).

Recurrent Prostate Cancer

Added text on the results of a study that showed that enzalutamide increased survival in patients with progressive prostate cancer who received prior androgen deprivation therapy as well as docetaxel (cited Scher et al. as reference 33 and level of evidence 1iA and 1iC).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. It 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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Prostate Cancer Treatment are:

  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)
  • Barnett S. Kramer, MD (National Institutes of Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this 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.

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National Cancer Institute: PDQ® Prostate Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/prostate/HealthProfessional. Accessed <MM/DD/YYYY>.

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The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

Last Revised: 2012-09-21

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