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Important: This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Prostate cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
AJCC stage groupings
Stage I
Stage II
Stage III
Stage IV
Stage A
Stage B
Stage C
Stage D
TREATMENT OPTION OVERVIEW
Surgical complications
Radiation complications
Hormone therapy complications
STAGE I PROSTATE CANCER
T1a, N0, M0, well-differentiated (stage A1)
STAGE II PROSTATE CANCER
T1a, N0, M0, moderately differentiated, poorly differentiated, or undifferentiated or T1b, N0, M0 or T1c, N0, M0 or T1, N0, M0 or T2, N0, M0
T2, N0, M0 (stage A2 or B1 or B2)
STAGE III PROSTATE CANCER
T3, N0, M0 (stage C)
STAGE IV PROSTATE CANCER
T4, N0, M0, or any T, N1-3, M0, or any T, any N, M1 (stage D1 or D2)
RECURRENT PROSTATE CANCER

GENERAL INFORMATION

(Separate summaries containing information on prevention of prostate cancer and screening for prostate cancer are also available in PDQ.)

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

Carcinoma of the prostate is predominantly a tumor of older men, which frequently responds to treatment when widespread and may be cured when localized. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites, such as to bone. Since the median age at diagnosis is 72 years, many patients, especially those with localized tumor, may die of other illnesses without ever having suffered significant disability from their 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.[1] A complicating feature of any analysis of survival after treatment of prostate cancer and comparison of the various treatment strategies is that there is evidence of increasing diagnosis of nonlethal tumors as diagnostic methods have changed over time. Nonrandomized comparisons of treatments may therefore be confounded not only by patient-selection factors but also by time trends. For example, a population- based study in Sweden showed that during the period from 1960 to the late 1980s, prior to 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 fact that watchful waiting or palliative hormonal treatment were the most common treatment strategies for localized prostate cancer during the entire era (fewer than 150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that if all cancers diagnosed in 1960 to 1964 were of the lethal variety, then at least one-third of cancers diagnosed in 1980 to 1984 were of the nonlethal variety.[2][Level of evidence: 3iB] With the advent of PSA screening, the ability to diagnose nonlethal prostate cancers may increase further.

The issue of screening asymptomatic men for prostate cancer with digital rectal examination (DRE), PSA, and/or ultrasound is controversial.[3,4] Serum PSA and transrectal ultrasound are more sensitive and will increase the diagnostic yield of prostate cancer when used in combination with rectal examination. (Refer to the PDQ summary on screening for prostate cancer for a discussion of this issue.) However, they are also associated with high false positive rates and may identify some tumors that will not threaten the patient's health.[5-7] Morbidity associated with work-up and treatment of such tumors, as well as considerable cost beyond a routine DRE complicate the issue. 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 there is no uniform standard, so that if a laboratory changes to a different assay kit, serial assays may yield nonequivalent PSA values.[8] A multicenter trial sponsored by the National Cancer Institute is underway to test the value of early detection on reducing mortality.[9]

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 their tumor, although 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 the majority of 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.[10-14] 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 (T) stage, Gleason score, and pretreatment PSA level can be used to more accurately estimate the risk of relapse.[15][Level of evidence: 3iDi] In the majority of 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 C and D1. Diploid tumors have a more favorable outcome than either tetraploid or aneuploid tumors. The use of flow cytometry techniques, histogram analysis, and computer-assisted cell morphology as tools to determine prognosis will require standardization.[16-20]

Definitive treatment is usually considered for younger men with prostate cancer and no major comorbid medical illnesses since they 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.[12,13,21-26] After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease.[23] However, a significant proportion of patients with elevated or rising PSA levels after surgery may remain clinically free of symptoms for extended periods of time.[27] Therefore, biochemical evidence of failure on the basis of elevated or slowly rising PSA alone 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 greater than or equal to 0.2 ng/ml, felt to be 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. Once the men developed metastatic disease, the median time to death was an additional 5 years.[28][Level of evidence: 3iiiA,B,D]

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." No definition has been shown to be an accurate surrogate for either clinical progression or survival.[29] Therefore, 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 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.[30]

After hormonal therapy, reduction of PSA to undetectable levels provides information regarding the duration of progression-free status.[12] However, decreases in PSA of less than 80% may not be very predictive.[12] Yet, because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Therefore, clinicians cannot rely solely on the serum PSA level to monitor a patient's response to hormone therapy; they must also follow clinical criteria.[31]

References:

  1. Garnick MB: Prostate cancer: screening, diagnosis, and management. Annals of Internal Medicine 118(10): 804-818, 1993.

  2. 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. Journal of the National Cancer Institute 88(17): 1216-1221, 1996.

  3. Krahn MD, Mahoney JE, Eckman MH, et al.: Screening for prostate cancer: a decision analytic view. Journal of the American Medical Association 272(10): 773-780, 1994.

  4. Kramer BS, Brown ML, Prorok PC, et al.: Prostate cancer screening: what we know and what we need to know. Annals of Internal Medicine 119(9): 914-923, 1993.

  5. Hinman F: Screening for prostatic carcinoma. Journal of Urology 145(1): 126-130, 1991.

  6. Gerber GS, Chodak GH: Routine screening for cancer of the prostate. Journal of the National Cancer Institute 83(5): 329-335, 1991.

  7. Catalona WJ, Smith DS, Ratliff TL, et al.: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. New England Journal of Medicine 324(17): 1156-1161, 1991.

  8. Takayama TK, Vessella RL, Lange PH: Newer applications of serum prostate-specific antigen in the management of prostate cancer. Seminars in Oncology 21(5): 542-553, 1994.

  9. Gohagan JK, Early Detection Branch, DCP, NCI, NIH: A 16-Year Randomized Screening Study for Prostate, Lung, Colorectal, and Ovarian Cancer - PLCO Trial (Summary Last Modified 09/1999), PLCO-1, clinical trial, active, 11/16/1993.

  10. Gittes RF: Carcinoma of the prostate. New England Journal of Medicine 324(4): 236-245, 1991.

  11. Paulson DF, Moul JW, Walther PJ: Radical prostatectomy for clinical stage T1-2N0M0 prostatic adenocarcinoma: long-term results. Journal of Urology 144: 1180-1184, 1990.

  12. 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): 2302-2309, 1992.

  13. 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. Journal of Clinical Oncology 11(11): 2158-2166, 1993.

  14. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. New England Journal of Medicine 330(4): 242-248, 1994.

  15. 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): 337-344, 1997.

  16. Nativ O, Winkler HZ, Raz Y, et al.: Stage C prostatic adenocarcinoma: flow cytometric nuclear DNA ploidy analysis. Mayo Clinic Proceedings 64(8): 911-919, 1989.

  17. 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. Journal of Urology 140(4): 769-774, 1988.

  18. Ritchie AW, Dorey F, Layfield LJ, et al.: Relationship of DNA content to conventional prognostic factors in clinically localised carcinoma of the prostate. British Journal of Urology 62(3): 254-260, 1988.

  19. Lieber MM: Pathological stage C (pT3) prostate cancer treated by radical prostatectomy: clinical implications of DNA ploidy analysis. Seminars in Urology 8(4): 219-224, 1990.

  20. Partin AW, Steinberg GD, Pitcock RV, et al.: Use of nuclear morphometry, Gleason histologic scoring, clinical stage, and age to predict disease-free survival among patients with prostate cancer. Cancer 70(1): 161-168, 1992.

  21. Carlton JC, Zagars GK, Oswald MJ: The role of serum prostatic acid phosphatase in the management of adenocarcinoma of the prostate with radiotherapy. International Journal of Radiation Oncology, Biology, Physics 19(6): 1383-1388, 1990.

  22. Stamey TA, Yang N, Hay AR, et al.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New England Journal of Medicine 317(15): 909-916, 1987.

  23. Stamey TA, Kabalin JN: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. I. Untreated patients. Journal of Urology 141(5): 1070-1075, 1989.

  24. 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. Journal of Urology 141(5): 1076-1083, 1989.

  25. Stamey TA, Kabalin JN, Ferrari M: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. III. Radiation treated patients. Journal of Urology 141(5): 1084-1087, 1989.

  26. Andriole GL: Serum prostate-specific antigen: the most useful tumor marker. Journal of Clinical Oncology 10(8): 1205-1207, 1992.

  27. Frazier HA, Robertson JE, Humphrey PA, et al.: Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy. Journal of Urology 149(3): 516-518, 1993.

  28. Pound CR, Partin AW, Eisenberger MA, et al.: Natural history of progression after PSA elevation following radical prostatectomy. Journal of the American Medical Association 281(17): 1591-1597, 1999.

  29. American Society for Therapeutic Radiology and Oncology Consensus Panel: Consensus statement: guidelines for PSA following radiation therapy. International Journal of Radiation Oncology, Biology, Physics 37(5): 1035-1041, 1997.

  30. Kuban DA, El-Mahdi AM, Schellhammer PF: Prostate-specific antigen for pretreatment prediction and posttreatment evaluation of outcome after definitive irradiation for prostate cancer. International Journal of Radiation Oncology, Biology, Physics 32(2): 307-316, 1995.

  31. Ruckle HC, Klee GG, Oesterling JE: Prostate-specific antigen: concepts for staging prostate cancer and monitoring response to therapy. Mayo Clinic Proceedings 69(1): 69-79, 1994.


CELLULAR CLASSIFICATION

Over 95% of primary prostate cancers are adenocarcinomas, and this discussion is confined to patients with this diagnosis. In general, degree of tumor differentiation and abnormality of histologic growth pattern directly correlate with 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 which are present in a biopsy (Gleason grade).[1,2] When the cytopathologist is experienced in the technique and the specimen is adequate for analysis, fine needle aspiration of the prostate (usually performed transrectally) has been shown to have an accuracy of diagnosis equal to that of traditional core needle biopsy.[3] Fine needle aspiration is less painful than core biopsy and therefore can be performed as an outpatient procedure and at periodic intervals for serial follow-up. Controversy exists as to whether it is as reliable for grading purposes, particularly with grade range apparent in different fields.[4] Many urologists now use a bioptic gun with ultrasound guidance, which is relatively painless. The risk of complications with this technique is low. A transperineal, ultrasound-guided approach can be used in those patients who may be at increased risk of complications through a transrectal approach.[5] In a series of 670 men undergoing biopsy with an 18-gauge needle, the complication rate was 2%, with only 4 patients requiring hospitalization.[6]

References:

  1. Gleason DF, Mellinger GT: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. Journal of Urology 111(1): 58-64, 1974.

  2. Gleason DF: Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M: Urologic Pathology: The Prostate. Philadelphia: 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 follow-up. Journal of Urology 135(5): 955-958, 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): 376-381, 1996.

  5. Webb JA, Shanmuganathan K, McLean A: Complications of ultrasound-guided transperineal prostate biopsy: a prospective study. British Journal of Urology 72(5[11]): 775-777, 1993.

  6. Desmond PM, Clark J, Thompson IM, et al.: Morbidity with contemporary prostate biopsy. Journal of Urology 150(5, Part 1): 1425-1426, 1993.


STAGE INFORMATION

Detection of asymptomatic metastatic disease in prostate cancer is greatly affected by the staging tests performed. Radionuclide bone scans are currently the most widely used tests for metastases to the bone, 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 may be able to predict the results of radionuclide bone scan in newly diagnosed patients. In 1 series, only 2 of 852 patients (0.23%) with a PSA of less than 20 micrograms per liter had a positive bone scan in the absence of bone pain.[1] In another series of 265 prostate cancer patients, 0/23 with a PSA less than 4 had a positive bone scan, and 2/114 with a PSA less than 10 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. However, in patients who are undergoing a radical perineal prostatectomy in whom the PSA value is less than 20 and the Gleason sum is low, evidence is mounting that a PLND is probably unnecessary, especially in patients whose malignancy was not palpable but detected on ultrasound.[3,4] A PLND remains the most accurate method to assess metastases to pelvic nodes, and laparoscopic PLND has been shown to accurately assess pelvic nodes as effectively as an open procedure.[5] Its exact role in diagnosis and subsequent treatment is being evaluated, although 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), since seminal vesicle involvement could affect choice of primary therapy and predicts for pelvic lymph node metastasis.[6]

In patients with clinically localized (stage A, B) 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 A and B prostate cancer undergoing radical prostatectomy revealed a correlation 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 5, 6, and 8, respectively.[7]

Transrectal ultrasound (TRUS) may facilitate diagnosis by directing needle biopsy. However, ultrasound is operator dependent and does not assess lymph node size. Moreover, a prospective multi-institutional study of preoperative TRUS in men with clinically localized prostate cancer felt to be eligible for radical prostatectomy showed that TRUS was no better than digital rectal examination in predicting extracapsular tumor extension or seminal vesicle involvement.[8] Computed tomography can detect grossly enlarged nodes but poorly defines intraprostatic features;[9] therefore, it is not reliable for 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] However, ultrasound and MRI can reduce clinical understaging and thereby improve patient selection for local therapy. Preliminary data with the endorectal MRI coil for prostate imaging report the highest sensitivity and specificity for identification of organ-confined and extracapsular disease.[3,12,13] MRI is a poor tool for evaluating nodal disease.

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


TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Clinically inapparent tumor not palpable nor visible by imaging
T1a: Tumor incidental histologic finding in 5% or less of tissue
resected
T1b: Tumor incidental histologic finding in more than 5% of tissue
resected
T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2: Tumor confined within prostate*
T2a: Tumor involves 1 lobe
T2b: Tumor involves both lobes
T3: Tumor extends through the prostatic capsule**
T3a: Extracapsular extension (unilateral or bilateral)
T3b: Tumor invades seminal vesicle(s)
T4: Tumor is fixed or invades adjacent structures other than seminal
vesicles: bladder neck, external sphincter, rectum, levator muscles,
and/or pelvic wall

*Note: Tumor found in 1 or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c.

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

Regional lymph nodes (N)

Regional lymph nodes are the nodes of the true pelvis, which essentially are
the pelvic nodes below the bifurcation of the common iliac arteries. They
include the following groups (laterality does not affect the N
classification): pelvic (NOS), hypogastric, obturator, iliac (internal,
external, NOS), periprostatic, and sacral (lateral, presacral, promontory
(Gerota's), or NOS). Distant lymph nodes are outside the confines of the
true pelvis and their involvement constitutes distant metastasis. They can
be imaged using ultrasound, computed tomography, magnetic resonance imaging,
or lymphangiography, and include: aortic (para-aortic, periaortic, lumbar),
common iliac, inguinal, superficial inguinal (femoral), supraclavicular,
cervical, scalene, and retroperitoneal (NOS) nodes.
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis in regional lymph node or nodes

Abbreviation: NOS, not otherwise specified.

Distant metastasis*** (M)

MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis
M1a: Nonregional lymph node(s)
M1b: Bone(s)
M1c: Other site(s)

***Note: When more than 1 site of metastasis is present, the most advanced category (pM1c) is used.

Histopathologic grade (G)

GX: Grade cannot be assessed
G1: Well differentiated (slight anaplasia)
G2: Moderately differentiated (moderate anaplasia)
G3-4: Poorly differentiated or undifferentiated (marked anaplasia)


AJCC stage groupings


Stage I

T1a, N0, M0, G1


Stage II

T1a, N0, M0, G2, 3-4
T1b, N0, M0, Any G
T1c, N0, M0, Any G
T1, N0, M0, Any G
T2, N0, M0, Any G


Stage III

T3, N0, M0, Any G


Stage IV

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

The Jewett staging system is as described below.


Stage A

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

Substage A1: well-differentiated with focal involvement, usually left
untreated

Substage A2: moderately or poorly differentiated or involves multiple foci
in the gland


Stage B

Stage B is tumor confined to the prostate gland.

Substage B0: nonpalpable, PSA-detected [17]

Substage B1: single nodule in 1 lobe of the prostate

Substage B2: more extensive involvement of 1 lobe or involvement of both

lobes


Stage C

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

Substage C1: clinical extracapsular extension

Substage C2: extracapsular tumor producing bladder outlet or ureteral

obstruction


Stage D

Stage D is metastatic disease.

Substage D0: clinically localized disease (prostate only) but persistently
elevated enzymatic serum acid phosphatase titers

Substage D1: regional lymph nodes only

Substage D2: distant lymph nodes, metastases to bone or visceral organs

Substage D3: D2 prostate cancer patients who relapsed after adequate

endocrine therapy

References:

  1. Oesterling JE, Martin SK, Bergstralh EJ, et al.: The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer. Journal of the American Medical Association 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 Investigation 13(1): 31-35, 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. Journal of Urology 138(1): 92-98, 1987.

  4. Daniels GF, McNeal JE, Stamey TA: Predictive value of contralateral biopsies in unilaterally palpable prostate cancer. Journal of Urology 147(3, Part 2): 870-874, 1992.

  5. Schuessler WW, Pharand D, Vancaillie TG: Laparoscopic standard pelvic node dissection for carcinoma of the prostate: is it accurate? Journal of Urology 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. Journal of Urology 154(4): 1392-1396, 1995.

  7. Fournier GR, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. British Journal of Urology 72(4): 484-488, 1993.

  8. Smith JA, 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. Journal of Urology 157(3): 902-906, 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): 311-316, 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. International Journal of Radiation Oncology, Biology, Physics 23(2): 293-298, 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. American Journal of Radiology 158(3): 559-562, 1992.

  12. National Institutes of Health: National Institute of Health Consensus Development Conference statement: the management of clinically localized prostate cancer. Journal of the American Medical Association 258(19): 2727-2730, 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): 339-352, 1993.

  14. Jewett HJ: The present status of radical prostatectomy for stages A and B prostatic cancer. Urologic Clinics of North America 2(1): 105-124, 1975.

  15. Prostate. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 219-224.

  16. Montie JE: Staging of prostate cancer: current TNM classification and future prospects for prognostic factors. Cancer 75(7, Suppl): 1814-1818, 1995.

  17. Bostwick DG, Myers RP, Oesterling JE, et al.: Staging of prostate cancer. Seminars in Surgical Oncology 10(1): 60-72, 1994.


TREATMENT OPTION OVERVIEW

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

State-of-the-art treatment in prostate cancer provides prolonged disease-free survival for many patients with localized disease, but is rarely curative in patients with locally extensive tumor. Even when the cancer appears clinically localized to the prostate gland, a substantial fraction of patients will develop disseminated tumor after local therapy with surgery or irradiation. This is due to 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 are under the age of 70 and who elect surgical intervention.[1-3] These patients should have a negative bone scan and tumors confined to the prostate gland (stages I and 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 (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, and 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 at the present time.[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] Patients with extraprostatic disease are suitable candidates for clinical trials. These trials include evaluation of postoperative radiation delivery, cytotoxic agents, and hormonal treatment using luteinizing hormone-releasing hormone (LHRH) agonists and/or antiandrogens.

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes followed by thawing.[10][Level of evidence: 3iiiDiii] It is less well established than standard prostatectomy and long-term outcomes are not known. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development.

Candidates for definitive radiation therapy must have a confirmed pathological diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stages I, II, and III). Patients should have a bone scan and computed tomographic scan negative for metastases, but staging laparotomy and lymph node dissection are not required. Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival.[11][Level of evidence: 1iiA] In addition, patients considered poor medical candidates for radical prostatectomy can be treated with acceptably low complications if care is given to delivery technique.[12] Long-term results with radiation therapy are dependent on stage. A retrospective review of 999 patients treated with megavoltage irradiation showed cause-specific survival rates to be significantly different at 10 years by T-stage: T1 (79%), T2 (66%), T3 (55%), and T4 (22%).[13] An initial serum prostate-specific antigen (PSA) level of greater than 15 nanograms per milliliter is a predictor of probable failure with conventional radiation therapy.[14]

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.[15][Level of evidence: 3iiiDiii]

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment, especially those patients with low-grade and early-stage tumors.[16,17] The variable history of carcinoma of the prostate emphasizes the need for randomized studies to identify the statistical benefit of any definitive treatment. 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- or moderately well-differentiated tumors clinically confined to the prostate, irrespective of age.[8] 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.[18] In fact, in a selected series of 50 stage C patients, 48 of whom had well- and moderately well-differentiated tumors, the prostate cancer-specific survival rates at 5 and 9 years were 88% and 70%.[9] Since the early 1980s, there has been a dramatic increase in rates of radical prostatectomy in the United States for men ages 65 to 79 (5.75-fold rise from 1984-1990). There is wide geographic variation in these rates, probably a reflection of uncertainty about the indications for and efficacy of radical prostatectomy.[19] In fact, a structured literature review of 144 papers has been done in an attempt to compare the 3 primary treatment strategies for clinically localized prostate cancer: 1) radical prostatectomy, 2) definitive radiation therapy, and 3) watchful waiting.[20] The authors concluded that poor reporting and selection factors within all series precluded a valid comparison of efficacy for the 3 management strategies, and proponents of any of the 3 strategies cannot look to the current literature for convincing support. 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%).[21] Since it is highly unlikely that radiation 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.[22] Unfortunately, these series constitute the same data on which opinions regarding management of clinically localized cancer are based.


Surgical complications

Complications of radical prostatectomy can include urinary incontinence, urethral stricture, impotence, and the morbidity associated with general anesthesia and a major surgical procedure. A national review of 10,600 radical prostatectomies determined that 30-day mortality and cardiovascular morbidity rates were 2% and 8%, respectively.[19] Morbidity and mortality rates increase with age and were appreciably greater in those patients older than 75 years.[19] In 1 large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy, only about 6% of 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 men who were sexually potent before surgery retained potency adequate for vaginal penetration and sexual intercourse.[23] 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.[23] A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series.[24] In that survey, over 30% of men reported the need for pads or clamps for urinary wetness and 63% of all patients reported a current problem with wetness. About 60% reported having no erections since surgery; about 90% had no erections sufficient for intercourse during the month prior to the survey. About 28% reported follow-up treatment of cancer with radiation and/or hormonal therapy within 4 years after their prostatectomy. Reasons for the difference in outcomes between the national survey and previous case series could include: 1) the older Medicare population in the former, 2) surgical expertise at the major reporting centers, 3) selection factors, 4) publication bias of favorable series, or 5) different methods of collecting information from patients. Case series of 93, 459, and 89 men who had undergone radical prostatectomy by experienced surgeons showed similarly high rates of impotence as in the national Medicare survey when men were carefully questioned about sexual potency, although the men in the case series were on average younger than those in the Medicare survey.[25-27] In 1 of the case series the same questionnaire was used as in the Medicare survey.[25] 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 had been treated in a managed care setting by either radical prostatectomy, radiation, or watchful waiting showed substantial sexual and urinary dysfunction in the prostatectomy group.[28] 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 anatomic (nerve-sparing) or standard radical prostatectomy were not statistically significant. This issue, therefore, requires more study.

Radical prostatectomy may also cause fecal incontinence, and the incidence may vary with surgical method.[29] In a national survey sample of 907 men who had undergone radical prostatectomy at least 1 year prior to the survey, 32% of the men who had undergone perineal (anatomic "nerve-sparing") radical prostatectomy and 17% of the men who had undergone retropubic radical prostatectomy reported accidents of fecal leakage. Ten percent and 4%, respectively, reported moderate to large amounts of fecal leakage. Less than 15% of men with fecal incontinence had reported it to a physician or health care provider.


Radiation complications

Definitive external-beam radiation therapy can result in acute cystitis, proctitis, and sometimes enteritis.[1,27,30,31] These are generally reversible but may be chronic and rarely require surgical intervention. Potency, in the short term, is preserved with irradiation in the majority of cases, but may diminish over time. A cross-sectional survey of prostate cancer patients who had been treated in a managed care setting by either radical prostatectomy, radiation, or watchful waiting showed substantial sexual and urinary dysfunction in the radiation therapy group.[28] Morbidity may be reduced with the employment of sophisticated radiation techniques, such as the use of linear accelerators, and careful simulation and treatment planning.[32] 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 non-blinded study.[33][Level of evidence: 1iiC] There were no differences 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% versus 56%, p=0.004). Urinary symptoms were similar in the 2 groups, as were local tumor control and overall survival rates at 5 years' follow-up. Radiation therapy can be delivered after an extra-peritoneal 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. Prior transurethral resection of the prostate (TURP) increases the risk of stricture above that seen with radiation alone, but if radiation is delayed 4 to 6 weeks after the TURP, the risk of stricture can be minimized.[34-36] Although pretreatment TURP to relieve obstructive symptoms has been associated with tumor dissemination, multivariate analysis in pathologically staged cases indicates that this is due to a worse underlying prognosis of the cases that require transurethral resection rather than to the procedure itself.[37]

A population-based survey of Medicare recipients who had received radiation therapy as primary treatment of prostate cancer, similar in design to the survey described above of Medicare patients who underwent radical prostatectomy [24], has been reported, showing substantial differences in post-treatment morbidity profiles between surgery and radiation.[38] Although the men who had undergone radiation 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% versus more than 30%). A larger proportion of patients treated with radiation before surgery reported the ability to have an erection sufficient for intercourse in the month prior to the survey (men <70 years of age, 33% who received radiation versus 11% who underwent surgery alone; men >/=70 years of age, 27% who received radiation versus 12% who underwent surgery alone). However, men receiving radiation were more likely to report problems with bowel function, especially frequent bowel movements (10% versus 3%). Similar to 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.


Hormone therapy complications

Several different hormonal approaches can benefit men with various stages of prostate cancer. These 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.[39] Estrogens at a dose of 3 milligrams per day of diethylstilbestrol will achieve castrate levels of testosterone. Similar to orchiectomy, estrogens may cause loss of libido and impotence. Gynecomastia may be prevented by low-dose radiation to the breasts. However, estrogen is seldom used today because of the risk of serious side effects including myocardial infarction, cerebrovascular accident, and pulmonary embolism. LHRH agonists such as leuprolide, goserelin, and buserelin will lower testosterone to castrate levels. Similar to orchiectomy and estrogens, LHRH agonists cause impotence, hot flashes, and loss of libido. Tumor flare reactions may occur transiently but can be prevented by antiandrogens or by short-term estrogens at low dose for several weeks. The pure antiandrogen flutamide may cause diarrhea, breast tenderness, and nausea. There have been case reports of fatal and nonfatal liver toxic effects.[40] Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[41] The steroidal antiandrogen megestrol acetate suppresses androgen production incompletely and is generally not used as initial therapy. Long-term use of ketoconazole can result in impotence, pruritus, nail changes, and adrenal insufficiency. Aminoglutethimide commonly causes sedation and skin rashes. Additional studies that evaluate the effects of various hormone therapies on quality of life are required.[42]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. Journal of Urology 143(3): 538-544, 1990.

  2. Corral DA, Bahnson RR: Survival of men with clinically localized prostate cancer detected in the eighth decade of life. Journal of Urology 151(5): 1326-1329, 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. Journal of Clinical Oncology 12(11): 2254-2263, 1994.

  4. Schuessler WW, Vancaillie TG, Reich H, et al.: Transperitoneal endosurgical lymphadenectomy in patients with localized prostate cancer. Journal of Urology 145(5): 988-991, 1991.

  5. Fournier GR, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. British Journal of Urology 72(4): 484-488, 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. Urology 49(Suppl 3A): 65-69, 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(Suppl 3A): 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. Journal of the American Medical Association 277(6): 467-471, 1997.

  9. Adolfsson J, Ronstrom L, Lowhagen T, et al.: Deferred treatment of clinically localized low grade prostate cancer: the experience from a prospective series at the Karolinska hospital. Journal of Urology 152(5, Part 2): 1757-1760, 1994.

  10. Shinohara K, Connolly JA, Presti JC, et al.: Cryosurgical treatment of localized prostate cancer (stages T1 to T4): preliminary results. Journal of Urology 156(1): 115-121, 1996.

  11. 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. International Journal of Radiation Oncology, Biology, Physics 40(4): 769-782, 1998.

  12. Forman JD, Order SE, Zinreich ES, et al.: Carcinoma of the prostate in the elderly: the therapeutic ratio of definitive radiotherapy. Journal of Urology 136(6): 1238-1241, 1986.

  13. Duncan W, Warde P, Catton CN, et al.: Carcinoma of the prostate: results of radical radiotherapy (1970-1985). International Journal of Radiation Oncology, Biology, Physics 26(2): 203-210, 1993.

  14. 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. Journal of Urology 151(3): 640-645, 1994.

  15. 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): 442-453, 1997.

  16. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. New England Journal of Medicine 330(4): 242-248, 1994.

  17. Whitmore WF: Expectant management of clinically localized prostatic cancer. Seminars in Oncology 21(5): 560-568, 1994.

  18. Waaler G, Stenwig AE: Prognosis of localised prostatic cancer managed by "watch and wait" policy. British Journal of Urology 72(2): 214-219, 1993.

  19. Lu-Yao GL, McLerran D, Wasson J, et al.: An assessment of radical prostatectomy: time trends, geographic variation, and outcomes. Journal of the American Medical Association 269(20): 2633-2636, 1993.

  20. Wasson JH, Cushman CC, Bruskewitz RC, et al.: A structured literature review of treatment for localized prostate cancer. Archives of Family Medicine 2: 487-493, 1993.

  21. Adolfsson J, Steineck G, Whitmore WF: Recent results of management of palpable clinically localized prostate cancer. Cancer 72(2): 310-322, 1993.

  22. Austenfeld MS, Thompson IM, Middleton RG, et al.: Meta-analysis of the literature: guideline development for prostate cancer treatment. Journal of Urology 152(5, Part 2): 1866-1869, 1994.

  23. Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. Journal of Urology 150(3): 905-907, 1993.

  24. Fowler FJ, 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): 622-629, 1993.

  25. Jonler M, Messing EM, Rhodes PR, et al.: Sequelae of radical prostatectomy. British Journal of Urology 74(3): 352-358, 1994.

  26. Geary ES, Dendinger TE, Freiha FS, et al.: Nerve sparing radical prostatectomy: a different view. Journal of Urology 154(1): 145-149, 1995.

  27. Lim AJ, Brandon AH, Fiedler J, et al.: Quality of life: radical prostatectomy versus radiation therapy for prostate cancer. Journal of Urology 154(4): 1420-1425, 1995.

  28. Litwin MS, Hays RD, Fink A, et al.: Quality-of-life outcomes in men treated for localized prostate cancer. Journal of the American Medical Association 273(2): 129-135, 1995.

  29. Bishoff JT, Motley G, Optenberg SA, et al.: Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. Journal of Urology 160(2): 454-458, 1998.

  30. Schellhammer PF, Jordan GH, El-Mahdi AM: Pelvic complications after interstitial and external beam irradiation of urologic and gynecologic malignancy. World Journal of Surgery 10(2): 259-268, 1986.

  31. 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. International Journal of Radiation Oncology, Biology, Physics 38(1): 59-63, 1997.

  32. Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. International Journal of Radiation Oncology, Biology, Physics 41(3): 501-510, 1998.

  33. 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): 267-272, 1999.

  34. 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. Journal of Urology 146(3): 798-802, 1991.

  35. 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. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.

  36. Green N, Treible D, Wallack H, et al.: Prostate cancer - the impact of irradiation on urinary outlet obstruction. British Journal of Urology 70(3): 310-313, 1992.

  37. Zelefsky MJ, Whitmore WF, Leibel SA, et al.: Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma. Journal of Urology 150(6), 1860-1864, 1993.

  38. Fowler FJ, 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. Journal of Clinical Oncology 14(8): 2258-2265, 1996.

  39. Daniell HW: Osteoporosis after orchiectomy for prostate cancer. Journal of Urology 157(2): 439-444, 1997.

  40. Wysowski DK, Freiman JP, Tourtelot JB, et al.: Fatal and nonfatal hepatotoxicity associated with flutamide. Annals of Internal Medicine 118(11): 860-864, 1993.

  41. Soloway MS, Schellhammer PF, Smith JA, et al.: Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II multicenter trial. Urology 47(Suppl 1A): 33-37, 1996.

  42. Kirschenbaum A: Management of hormonal treatment effects. Cancer 75(7, Suppl): 1983-1986, 1995.


STAGE I PROSTATE CANCER

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


T1a, N0, M0, well-differentiated (stage A1)

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 and over. 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 to the normal male population, adjusted for age. Many stage I cancers are well-differentiated and only focally involve the gland (T1a, N0, M0), and the majority require no treatment other than careful follow-up.[1] 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 2 tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival closely approximated the expected survival among men of similar ages in the general population.[2] However, in younger patients (age 50-60) whose expected survival is long, treatment should be considered.[3] Less differentiated cancers that involve more than a few pieces of resected tissue (T1b, N0, M0) are biologically more aggressive. However, the trial of 95 patients was not large enough to exclude a small but medically significant difference in overall survival, nor did it include information to measure time to progression, cancer-specific survival, or quality of life. Radical prostatectomy, external-beam radiation therapy, 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 the patient's personal desires.[3]

Treatment options:

1. Careful observation without further immediate treatment in selected patients.[2-5]

2. External-beam radiation therapy.[6-10] Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[11]

3. Radical prostatectomy usually with pelvic lymphadenectomy (with or without the nerve sparing technique designed to preserve potency).[12-14] Radical prostatectomy may be difficult after a transurethral resection of the prostate. 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 have a detectable level of prostate-specific antigen more than 3 weeks after surgery.[15-20] 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.[21] Careful treatment planning is necessary to avoid morbidity.[15-20] Clinical trials are in progress.

4. Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or 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 external-beam radiation therapy.[22-24][Level of evidence: 3iiiDiii] 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%, [22,24] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external-beam radiation therapy. 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 1 series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration was seen. This risk decreased with increased operator experience and modification of implant technique.[22] Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with I-125 has been associated with an increased local failure and complication rate [25,26] and is now rarely done.

5. External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.[27]

6. Other clinical trials. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with early stage prostate cancer

References:

  1. National Institutes of Health: National Institute of Health Consensus Development Conference statement: the management of clinically localized prostate cancer. Journal of the American Medical Association 258(19): 2727-2730, 1987.

  2. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. New England Journal of Medicine 330(4): 242-248, 1994.

  3. Epstein JI, Paull G, Eggleston JC, et al.: Prognosis of untreated stage A1 prostatic carcinoma: a study of 94 cases with extended follow-up. Journal of Urology 136(4): 837-839, 1986.

  4. 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): 493-498, 1990.

  5. Cantrell BB, DeKlerk DP, Eggleston JC, et al.: Pathological factors that influence prognosis in stage A prostatic cancer: the influence of extent versus grade. Journal of Urology 125(4): 516-520, 1981.

  6. Bagshaw MA: External radiation therapy of carcinoma of prostate. Cancer 45(7): 1912-1921, 1980.

  7. Forman JD, Zinreich E, Lee DJ, et al.: Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. International Journal of Radiation Oncology, Biology, Physics 11(12): 2073-2080, 1985.

  8. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27(1): 10-16, 1986.

  9. Pilepich MV, Bagshaw MA, Asbell SO, et al.: Definitive radiotherapy in resectable (stage A2 and B) carcinoma of the prostate: results of a nationwide overview. International Journal of Radiation Oncology, Biology, Physics 13(5): 659-663, 1987.

  10. 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. International Journal of Radiation Oncology, Biology, Physics 19(6): 1377-1382, 1990.

  11. 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. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.

  12. 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. Journal of Clinical Oncology 12(11): 2254-2263, 1994.

  13. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. Journal of Urology 143(3): 538-544, 1990.

  14. Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. Journal of Urology 150(3): 905-907, 1993.

  15. Lange PH, Reddy PK, Medini E, et al.: Radiation therapy as adjuvant treatment after radical prostatectomy. Journal of the National Cancer Institute Monographs 7: 141-149, 1988.

  16. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. Journal of Urology 132(5): 926-930, 1984.

  17. 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. Journal of Urology 142(5): 1266-1271, 1989.

  18. 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. Journal of Urology 149(5): 1029-1034, 1993.

  19. Stamey TA, Yang N, Hay AR, et al.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New England Journal of Medicine 317(15): 909-916, 1987.

  20. Hudson MA, Bahnson RR, Catalona WJ: Clinical use of prostate specific antigen in patients with prostate cancer. Journal of Urology 142(4): 1011-1017, 1989.

  21. Paulson DF, Moul JW, Walther PJ: Radical prostatectomy for clinical stage T1-2N0M0 prostatic adenocarcinoma: long-term results. Journal of Urology 144: 1180-1184, 1990.

  22. Wallner K, Roy J, Harrison L: Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. Journal of Clinical Oncology 14(2): 449-453, 1996.

  23. D'Amico AV, Coleman CN: Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. Journal of Clinical Oncology 14(1): 304-315, 1996.

  24. 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): 442-453, 1997.

  25. Kuban DA, El-Mahdi AM, Schellhammer PF: I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 63(12): 2415-2420, 1989.

  26. 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. International Journal of Radiation Oncology, Biology, Physics 21(3): 537-547, 1991.

  27. Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. International Journal of Radiation Oncology, Biology, Physics 41(3): 501-510, 1998.


STAGE II PROSTATE CANCER

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


T1a, N0, M0, moderately differentiated, poorly differentiated, or undifferentiated or T1b, N0, M0 or T1c, N0, M0 or T1, N0, M0 or T2, N0, M0

Treatment options:

For T1b, N0, M0 or T1c, N0, M0 patients:

1. Careful observation without further immediate treatment in selected patients.[1,2]

2. External-beam radiation therapy.[3-7] Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival.[8][Level of evidence: 1iiA] Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[9]

3. Radical prostatectomy usually with pelvic lymphadenectomy (with or without the nerve sparing technique designed to preserve potency).[10-12] Radical prostatectomy may be difficult after a transurethral resection of the prostate. 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 have a detectable level of prostate-specific antigen more than 3 weeks after surgery.[13-18] 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.[13-18] Clinical trials are in progress.

4. Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or 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 external-beam radiation therapy.[20-22][Level of evidence: 3iiiDiii] 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%, [20,22] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external-beam radiation therapy. 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 1 series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration was seen. This risk decreased with increased operator experience and modification of implant technique.[20] Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with I-125 has been associated with an increased local failure and complication rate [23,24] and is now rarely done.

5. External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.[25]

6. Other clinical trials. Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with early stage prostate cancer.


T2, N0, M0 (stage A2 or B1 or B2)

Radical prostatectomy, external-beam irradiation, 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 up to 10 years follow-up. For well-selected patients, radical prostatectomy can achieve 15-year survival comparable to an age-matched population without prostate cancer.[1] 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 (T2b, 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 due to 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 which type of treatment to employ. The only randomized study performed to date comparing radical prostatectomy at diagnosis to expectant therapy (careful observation with therapy as needed) in stages I and II cancers did not show a significant difference in survival.[2] However, the trial of 95 patients was not large enough to exclude a small but medically significant difference in overall survival, nor did it include information to measure time to progression, cancer-specific survival, or quality of life. 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 2 tumors experienced a disease-specific survival of 87% at 10 years and that their overall survival closely approximated the expected survival among men of similar ages in the general population.[1] The decision to treat should be made in the context of the patient's age, associated medical illnesses, and the patient's personal desires.

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research. A majority of patients have more advanced disease, but patients with bulky T2b tumors were included in the study groups re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease. Randomized clinical trial evidence comparing radiation therapy to radiation with prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year overall survival in favor of radiation therapy plus continued androgen suppression compared to radiation therapy alone (hazard ratio=0.631, 95% confidence interval=0.479-0.831).[26][Level of evidence: 1iiA]

Treatment options:

1. Radical prostatectomy usually with pelvic lymphadenectomy.[10,11,27,28] If allowed by the extent of tumor, anatomical dissection that preserves nerves necessary for erection avoids impotence postoperatively in some patients.[12,27] 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 a detectable level of prostate-specific antigen more than 3 weeks after surgery. The value of postoperative radiation therapy is yet to be determined. Postoperative radiation therapy does reduce local recurrence; however, it has not been proven to extend survival.[19] Clinical trials are in progress to test these questions. Careful treatment planning is necessary to avoid morbidity.[13-18] The role of preoperative ("neoadjuvant") hormonal therapy is not established at the present time.[29,30] Also, the morphologic changes induced by neoadjuvant androgen ablation may complicate assessment of surgical margins and capsular involvement.[31]

2. External-beam irradiation.[3-7,32] Prophylactic irradiation of clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve overall survival or prostate cancer-specific survival.[8][Level of evidence: 1iiA] Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[9] For patients with bulky T2b tumors, adjuvant hormonal therapy should be considered.[26]

3. Careful observation without further immediate treatment (in selected patients).[1,2]

4. Interstitial implantation of radioisotopes (i.e., I-125, palladium, iridium) done through a transperineal technique with either ultrasound or CT guidance is being done in carefully selected patients with T1 or T2A tumors. Short term results in these carefully selected patients are similar to those for radical prostatectomy or external-beam radiation therapy.[20-22][Level of evidence: 3iiiDiii] 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%,[20,33] which compares with rates of 10% to 40% with radical prostatectomy and 40% to 60% with external beam-radiation therapy. However, urinary tract frequency, urgency, or less commonly, urinary retention are seen in most patients but subside with time. Rectal ulceration may also be seen. In 1 series, a 10% 2-year actuarial genitourinary grade 2 complication rate and a 12% risk of rectal ulceration was seen. This risk decreased with increased operator experience and modification of implant technique.[20] Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with I-125 has been associated with an increased local failure and complication rate [23,24] and is now rarely done.

5. External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.[25]

6. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation.

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes followed by thawing.[34][Level of evidence: 3iiiDiii] It is less well established than standard prostatectomy and long-term outcomes are not known. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development.

7. Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy.[35,36]

References:

  1. Chodak GW, Thisted RA, Gerber GS, et al.: Results of conservative management of clinically localized prostate cancer. New England Journal of Medicine 330(4): 242-248, 1994.

  2. 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): 493-498, 1990.

  3. Bagshaw MA: External radiation therapy of carcinoma of prostate. Cancer 45(7): 1912-1921, 1980.

  4. Forman JD, Zinreich E, Lee DJ, et al.: Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. International Journal of Radiation Oncology, Biology, Physics 11(12): 2073-2080, 1985.

  5. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27(1): 10-16, 1986.

  6. Pilepich MV, Bagshaw MA, Asbell SO, et al.: Definitive radiotherapy in resectable (stage A2 and B) carcinoma of the prostate: results of a nationwide overview. International Journal of Radiation Oncology, Biology, Physics 13(5): 659-663, 1987.

  7. 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. International Journal of Radiation Oncology, Biology, Physics 19(6): 1377-1382, 1990.

  8. 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. International Journal of Radiation Oncology, Biology, Physics 40(4): 769-782, 1998.

  9. 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. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.

  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. Journal of Clinical Oncology 12(11): 2254-2263, 1994.

  11. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. Journal of Urology 143(3): 538-544, 1990.

  12. Catalona WJ, Basler JW: Return of erections and urinary continence following nerve sparing radical retropubic prostatectomy. Journal of Urology 150(3): 905-907, 1993.

  13. Lange PH, Reddy PK, Medini E, et al.: Radiation therapy as adjuvant treatment after radical prostatectomy. Journal of the National Cancer Institute Monographs 7: 141-149, 1988.

  14. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. Journal of Urology 132(5): 926-930, 1984.

  15. 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. Journal of Urology 142(5): 1266-1271, 1989.

  16. 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. Journal of Urology 149(5): 1029-1034, 1993.

  17. Stamey TA, Yang N, Hay AR, et al.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New England Journal of Medicine 317(15): 909-916, 1987.

  18. Hudson MA, Bahnson RR, Catalona WJ: Clinical use of prostate specific antigen in patients with prostate cancer. Journal of Urology 142(4): 1011-1017, 1989.

  19. Paulson DF, Moul JW, Walther PJ: Radical prostatectomy for clinical stage T1-2N0M0 prostatic adenocarcinoma: long-term results. Journal of Urology 144: 1180-1184, 1990.

  20. Wallner K, Roy J, Harrison L: Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. Journal of Clinical Oncology 14(2): 449-453, 1996.

  21. D'Amico AV, Coleman CN: Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. Journal of Clinical Oncology 14(1): 304-315, 1996.

  22. 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): 442-453, 1997.

  23. Kuban DA, El-Mahdi AM, Schellhammer PF: I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 63(12): 2415-2420, 1989.

  24. 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. International Journal of Radiation Oncology, Biology, Physics 21(3): 537-547, 1991.

  25. Hanks GE, Hanlon AL, Schultheiss TE, et al.: Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. International Journal of Radiation Oncology, Biology, Physics 41(3): 501-510, 1998.

  26. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment: Number 4, January 1999. Agency for Health Care Policy and Research, Rockville, MD. Available at: http://www.ahcpr.gov/clinic/prossumm.htm. Accessed 6/14/99.

  27. Walsh PC: Radical prostatectomy. In: Walsh PC, Gittes RF, Perlmutter AD, et al., Eds.: Campbell's Urology. Philadelphia: W.B. Saunders, 5th ed., 1986, pp 2754-2775.

  28. Paulson DF, Lin GH, Hinshaw W, et al.: Radical surgery versus radiotherapy for adenocarcinoma of the prostate. Journal of Urology 128(3): 502-504, 1982.

  29. 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. Urology 49(Suppl 3A): 65-69, 1997.

  30. 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(Suppl 3A): 46-55, 1997.

  31. Bazinet M, Zheng W, Begin LR, et al.: Morphologic changes induced by neoadjuvant androgen ablation may result in underdetection of positive surgical margins and capsular involvement by prostatic adenocarcinoma. Urology 49(5): 721-725, 1997.

  32. Perez CA, Garcia D, Simpson JR, et al.: Factors influencing outcome of definitive radiotherapy for localized carcinoma of the prostate. Radiotherapy and Oncology 16(1): 1-21, 1989.

  33. Blasko JC, Wallner K, Grimm PD, et al.: Prostate specific antigen based disease control following ultrasound guided iodine-125 implantation for stage T1/T2 prostatic carcinoma. Journal of Urology 154(3): 1096-1099, 1995.

  34. Shinohara K, Connolly JA, Presti JC, et al.: Cryosurgical treatment of localized prostate cancer (stages T1 to T4): preliminary results. Journal of Urology 156(1): 115-121, 1996.

  35. Fair WR, Cookson MS, Stroumbakis N, et al.: Update on neoadjuvant androgen deprivation therapy (ADT) and radical prostatectomy in localized prostate cancer. Proceedings of the American Urological Association 155(Suppl): A-1426, 667A, 1996.

  36. 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. Proceedings of the American Urological Association 155(Suppl): A-976, 555A, 1996.


STAGE III PROSTATE CANCER

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


T3, N0, M0 (stage C)

External-beam irradiation, interstitial implantation of radioisotopes, and radical prostatectomy are used.[1] The results of radical prostatectomy in stage III patients are greatly inferior compared to patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors. External-beam irradiation using a linear accelerator is the most appropriate treatment for the majority of patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival.[2,3] 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.[3]

Hormonal therapy should be considered in conjunction with radiation. Several studies have investigated its utility in patients with locally advanced disease. A prospective, randomized trial was performed by the Radiation Therapy Oncology Group (RTOG) (RTOG 85-31) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomized 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 overall 5-year survival rate for the entire population of 945 analyzable patients was not statistically significantly different (75% on the adjuvant arm versus 71% on the observation arm, p=0.52). The authors report an improved actuarial 5-year local control rate (84% versus 71%, p<.0001), freedom from distant metastasis (83% versus 70%, p<.001), and disease-free survival (60% versus 44%, p<.0001).[4][Level of evidence: 1iiA]

A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (WHO grade 3), N0-NX or T3, T4, N0 disease were randomized to receive either pelvic/prostate radiation, or identical radiation and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation and continuing for 3 years. The 401 patients available for analysis were followed for a median of 45 months. The Kaplan- Meier estimates of overall survival at 5 years were 79% on the adjuvant arm and 52% on the radiation arm alone (p=0.001). Similarly, 5-year disease-free survival (85% versus 48%, p<0.001) and local control (97% versus 77%, p<0.001) favored the adjuvant arm.[5][Levels of evidence: 1iiA,1iiDi] Two smaller studies, with 78 and 91 patients each, have also shown similar results.[6,7]

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). A majority of patients have more advanced disease, but patients with bulky T2b tumors were included in the study groups are-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease. Randomized clinical trial evidence comparing radiation therapy to radiation with prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year overall survival in favor of radiation therapy plus continued androgen suppression compared to radiation therapy alone (hazard ratio=0.631, 95% confidence interval=0.479-0.831).[8][Level of evidence: 1iiA]

Additionally, the RTOG did a study on 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 randomized to receive either radiation alone or radiation with androgen ablation started 8 weeks prior to radiation and continued for 16 weeks. At 5 years, overall survival was identical, and local control (54% versus 29%) and disease-free survival (36% versus 15%) favored the combined arm.[9][Level of evidence: 1iiA] This trial only assessed short-term hormonal therapy, not long-term therapy as the studies analyzed by the AHCPR did.

Initial results from a randomized study of immediate hormonal treatment (orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogue) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better overall survival 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.[10][Level of evidence: 1iiA]

Treatment options:

1. External-beam radiation.[2,3,11-13] Hormonal therapy should be considered in addition to external-beam radiation.[4,5,9,8] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[14] Radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography-based 3-D conformal treatment planning is under clinical evaluation.[15]

2. Hormonal manipulations (orchiectomy or LHRH agonist).[10][Level of evidence: 1iiA]

3. Radical prostatectomy usually with pelvic lymphadenectomy (highly selected patients).[16] 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 a detectable level of prostate-specific antigen more than 3 weeks after surgery.[13,17,18] However, because the duration of follow-up in available studies is still relatively short, the value of postoperative irradiation in reducing the incidence of local failure has yet to be determined. Clinical trials are in progress. Careful treatment planning is necessary to avoid morbidity. The role of preoperative ("neoadjuvant") hormonal therapy is not established at the present time.[19,20] Also, the morphologic changes induced by neoadjuvant androgen ablation may even complicate assessment of surgical margins and capsular involvement.[21]

4. Careful observation without further immediate treatment.[22]

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.[2,3,11,12] External-beam radiation therapy designed to decrease exposure of normal tissues using methods such as computed tomography based 3-D conformal treatment planning is under clinical evaluation.

2. Hormonal manipulations effectively used as initial therapy for prostate cancer:

a) orchiectomy

b) leuprolide or other LHRH agonists (Zoladex) in daily or depot preparations (these agents may be associated with tumor flare)

c) estrogen

3. Palliative surgery (transurethral resection).

4. Interstitial implantation combined with external-beam radiation therapy is being used in selected T3 patients, but little information is available.[23]

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 to standard photon radiation therapy.[24] A subsequent randomized study from the same group compared fast neutron radiation therapy to standard photon radiation therapy. Local-regional control was improved with neutron treatment but no difference in overall survival was seen, although follow-up was shorter in this trial. Decreased complications were seen with the use of a multileaf collimator.[25] Proton-beam radiation therapy is also under investigation.[26]

6. Other clinical trials.[27] Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information on clinical trials for patients with prostate cancer.

7. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation.

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate tissue with cryoprobes followed by thawing.[28][Level of evidence: 3iiiDiii] It is less well established than standard prostatectomy and long-term outcomes are not known. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development.

References:

  1. Paulson DF: Management of prostate malignancy. In: deKernion JB, Paulson DF, Eds.: Genitourinary Cancer Management. Philadelphia: Lea and Febiger, 1987, pp 107-160, 1987.

  2. Babaian RJ, Zagars GK, Ayala AG: Radiation therapy of stage C prostate cancer: significance of Gleason grade to survival. Seminars in Urology 8(4): 225-231, 1990.

  3. del Regato JA, Trailins AH, Pittman DD: Twenty years follow-up of patients with inoperable cancer of the prostate (stage C) treated by radiotherapy: report of a national cooperative study. International Journal of Radiation Oncology, Biology, Physics 26(2): 197-201, 1993.

  4. Pilepich MV, Caplan R, Byhardt RW, et al.: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. Journal of Clinical Oncology 15(3): 1013-1021, 1997.

  5. Bolla M, Gonzalez D, Warde P, et al.: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. New England Journal of Medicine 337(5): 295-300, 1997.

  6. Zagars GK, Johnson DE, von Eschenbach AC, et al.: Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. International Journal of Radiation Oncology, Biology, Physics 14(6): 1085-1091, 1988.

  7. Granfors T, Modig H, Damber JE, et al.: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. Journal of Urology 159(6): 2030-2034, 1998.

  8. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment: Number 4, January 1999. Agency for Health Care Policy and Research, Rockville, MD. Available at: http://www.ahcpr.gov/clinic/prossumm.htm. Accessed 6/14/99.

  9. Pilepich MV, Krall JM, Al-Sarraf M, et al.: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45(4): 616-623, 1995.

  10. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. British Journal of Urology 79(2): 235-246, 1997.

  11. Pilepich MV, Johnson RJ, Perez CA, et al.: Prognostic significance of nodal involvement in locally advanced (stage C) carcinoma of prostate: RTOG experience. Urology 30(6): 535-540, 1987.

  12. Perez CA, Garcia D, Simpson JR, et al.: Factors influencing outcome of definitive radiotherapy for localized carcinoma of the prostate. Radiotherapy and Oncology 16(1): 1-21, 1989.

  13. 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. Journal of Urology 149(5): 1029-1034, 1993.

  14. 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. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.

  15. 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): 267-272, 1999.

  16. Walsh PC, Jewett HJ: Radical surgery for prostatic cancer. Cancer 45(7 Suppl):1906-1911, 1980.

  17. Lange PH, Reddy PK, Medini E, et al.: Radiation therapy as adjuvant treatment after radical prostatectomy. Journal of the National Cancer Institute Monographs 7: 141-149, 1988.

  18. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. Journal of Urology 132(5): 926-930, 1984.

  19. 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. Urology 49(Suppl 3A): 65-69, 1997.

  20. 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(Suppl 3A): 46-55, 1997.

  21. Bazinet M, Zheng W, Begin LR, et al.: Morphologic changes induced by neoadjuvant androgen ablation may result in underdetection of positive surgical margins and capsular involvement by prostatic adenocarcinoma. Urology 49(5): 721-725, 1997.

  22. Adolfsson J: Deferred treatment of low grade stage T3 prostate cancer without distant metastases. Journal of Urology 149(2): 326-329, 1993.

  23. Blasko JC, Grimm PD, Ragde H: Brachytherapy and organ preservation in the management of carcinoma of the prostate. Seminars in Radiation Oncology 3(4): 240-249, 1993.

  24. Laramore GE, Krall JM, Thomas FJ, et al.: Fast neutron radiotherapy for locally advanced prostate cancer: final report of a Radiation Therapy Oncology Group randomized clinical trial. American Journal of Clinical Oncology 16(2): 164-167, 1993.

  25. 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. International Journal of Radiation Oncology, Biology, Physics 28(1): 47-54, 1993.

  26. 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. International Journal of Radiation Oncology, Biology, Physics 32(1): 3-12, 1995.

  27. Thompson IM, Southwest Oncology Group: Phase III Randomized Evaluation of Adjuvant Radiotherapy vs No Adjuvant Therapy Following Radical Prostatectomy and Pelvic Lymphadenectomy in Surgical Stage C Adenocarcinoma of the Prostate (Summary Last Modified 05/98), SWOG-8794, clinical trial, closed, 01/01/1997.

  28. Shinohara K, Connolly JA, Presti JC, et al.: Cryosurgical treatment of localized prostate cancer (stages T1 to T4): preliminary results. Journal of Urology 156(1): 115-121, 1996.


STAGE IV PROSTATE CANCER

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


T4, N0, M0, or any T, N1-3, M0, or any T, any N, M1 (stage D1 or D2)

Treatment selection depends on age, coexisting medical illnesses, symptoms, and whether distant metastases (most often bone) or only regional lymph node involvement is present. The most common symptoms originate from the urinary tract or from bone metastases. Palliation of the former with transurethral resection or radiation therapy and of the latter with radiation therapy or hormonal therapy is an important part of the management of these patients.

T4, N0, M0, or any T, N1-3, M0 patients:

The Agency for Health Care Policy and Research (AHCPR) has had a systematic review of the available randomized, clinical trial evidence comparing radiation therapy to radiation therapy with prolonged androgen suppression performed by its Technology Evaluation Center, and evidence-based Practice Center of the Blue Cross and Blue Shield Association. Some patients with bulky T2b tumors were included in the studied groups. The meta-analysis found a difference in 5-year overall survival in favor of radiation therapy plus continued androgen suppression compared to radiation therapy alone (hazard ratio=0.631, 95% confidence interval=0.479-0.831).[1][Level of evidence: 1iiA] This reduction in overall mortality indicates that adjuvant androgen suppression should be initiated at the time of radiation and continued for several years. The optimal duration of therapy remains to be determined. The issue of utility of neoadjuvant hormonal therapy remains to be determined.

Any T, any N, M1 patients:
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 the majority of patients. Initial results from a randomized study of immediate hormonal treatment (orchiectomy or LHRH analogue) versus deferred treatment (watchful waiting with hormonal therapy at progression) in men with locally advanced or asymptomatic metastatic prostate cancer showed better overall survival 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.[2][Level of evidence: 1iiA]

In some series, pre-treatment levels of prostate-specific antigen (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.[3] Orchiectomy and estrogens yield similar results, and selection of 1 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 milligram per day is not associated with as frequent cardiovascular complications as are higher doses; however, the use of DES has decreased due to cardiovascular toxic effects. The psychologic implications of orchiectomy are objectionable to many patients and many will choose alternative therapy if effective.[4] There is no indication that combined orchiectomy and estrogens are superior to either treatment administered alone.[5]

Approaches using LHRH agonists and/or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to standard hormonal treatments.[6,7] In a randomized trial, the LHRH analogue leuprolide (1 milligram subcutaneously every day) was found to be as effective as DES (3 milligrams orally every day) in any T, any N, M1 patients, but caused less gynecomastia, nausea/vomiting, and thromboembolisms.[8] In other randomized studies, the depot LHRH analogue goserelin (Zoladex) was found to be as effective as orchiectomy [9-11] or DES at a dose of 3 milligrams per day.[7] A depot preparation of leuprolide (Depo Lupron), which is therapeutically equivalent to leuprolide, is available as a monthly or 3-monthly depot. Castration has been shown to be superior to monotherapy with bicalutamide.[12] A small randomized study comparing 1 milligram of DES orally 3 times per day to 250 milligrams of flutamide 3 times per day in patients with metastatic prostate cancer showed similar response rates with both regimens, but superior survival with DES. There was more cardiovascular and/or thromboembolic toxic effects, of borderline statistical significance, associated with the DES treatment.[13][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

Based on the fact 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." However, subsequent randomized controlled trials 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, there was no difference in overall survival.[14][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 due to more diarrhea and worse emotional function in the flutamide-treated group.[15][Level of evidence: 1iC] A meta-analysis of 22 randomized trials of 5,710 patients comparing conventional surgical or medical castration to MAB - castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide - showed no significant improvement in survival associated with MAB.[16][Levels of evidence: 1i,1iiA]

The AHCPR has had 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. Equivalence was shown between orchiectomy and the available LHRH agonists. Additionally, combined androgen blockade was of no greater benefit than single hormonal therapy 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.[1]

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LHRH agonists. These hot flushes can persist for years.[17] Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate (Megace).

After tumor progression on 1 form of hormonal manipulation develops, an objective tumor response to any other form is uncommon.[18] However, some studies suggest that withdrawal of flutamide (with or without aminoglutethimide administration) may be associated with a decline in PSA values and that 1 may need to monitor for this response before initiating new therapy.[19-21] Chemotherapy may be appropriate in selected patients, but remains under evaluation. To date, no evidence exists that indicates chemotherapy prolongs survival.[22] Low-dose prednisone may palliate symptoms in about a third of the cases.[23] Refer to PDQ or to CancerNet (http://cancernet.nci.nih.gov) for information about clinical trials for patients with stage IV prostate cancer.

Treatment options:

1. Hormonal manipulations effectively used as initial therapy for prostate cancer: [24]
a) orchiectomy alone or with an androgen blocker.[25] Orchiectomy plus nilutamide produces superior objective response rates, bone pain relief, and freedom from progression rates compared to orchiectomy alone. However, the addition of an antiandrogen to surgical castration has not been shown to improve survival in a meta-analysis.[1,16][Level of evidence: 1iiA]

b) LHRH agonists such as leuprolide in daily or depot preparations.[6,8,9,26] (These agents may be associated with tumor flare when used alone and therefore, the initial concomitant use of antiandrogens should be considered in the presence of liver pain, ureteral obstruction, or impending spinal cord compression.)[Level of evidence: 1iiA]

c) leuprolide plus flutamide.[27] However, the addition of an antiandrogen to leuprolide has not been shown to improve survival in a meta-analysis.[16]

d) estrogens (DES, chlorotrianisene, ethinyl estradiol, conjugated estrogens U.S.P., DES-diphosphate).

2. External-beam irradiation for attempted cure (highly selected stage M0 patients).[28,29] Definitive radiation therapy should be delayed 4 to 6 weeks after transurethral resection to reduce incidence of stricture.[30]

Hormonal therapy should be considered in addition to external-beam irradiation.[1]

3. Palliative radiation therapy.

4. Palliative surgery (transurethral resection).

5. Careful observation without further immediate treatment (in selected patients).

6. Radical prostatectomy with immediate orchiectomy is under clinical evaluation.[31] 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.

7. Systemic chemotherapy for hormone-refractory disease is under clinical evaluation.[22,32,33]

References:

  1. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Summary, Evidence Report/Technology Assessment: Number 4, January 1999. Agency for Health Care Policy and Research, Rockville, MD. Available at: http://www.ahcpr.gov/clinic/prossumm.htm. Accessed 6/14/99.

  2. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. British Journal of Urology 79(2): 235-246, 1997.

  3. 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): 2302-2309, 1992.

  4. Cassileth BR, Seidmon ED, Soloway MS, et al.: Patients' choice of treatment in stage D prostate cancer. Urology 33(5, Suppl): 57-62, 1989.

  5. Byar DP: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 32(5): 1126-1130, 1973.

  6. Parmar H, Edwards L, Phillips RH, et al.: Orchiectomy versus long-acting D-Trp-6-LHRH in advanced prostatic cancer. British Journal of Urology 59(3): 248-254, 1987.

  7. Waymont B, Lynch TH, Dunn JA, et al.: Phase III randomised study of Zoladex versus stilboestrol in the treatment of advanced prostate cancer. British Journal of Urology 69(6): 614-620, 1992.

  8. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. New England Journal of Medicine 311(20): 1281-1286, 1984.

  9. 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.

  10. Vogelzang NJ, Chodak GW, Soloway MS, et al.: Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Urology 46(2): 220-226, 1995.

  11. Kaisary AV, Tyrrell CJ, Peeling WB, et al.: Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. British Journal of Urology 67(5): 502-508, 1991.

  12. Bales GT, Chodak GW: A controlled trial of bicalutamide versus castration in patients with advanced prostate cancer. Urology 47(Suppl 1A): 38-43, 1996.

  13. Chang A, Yeap B, Davis T, et al.: Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: flutamide versus diethylstilbestrol. Journal of Clinical Oncology 14(8): 2250-2257, 1996.

  14. Eisenberger MA, Blumenstein BA, Crawford ED, et al.: Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. New England Journal of Medicine 339(15): 1036-1042, 1998.

  15. Moinpour CM, Savage MJ, Troxel A, et al.: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. Journal of the National Cancer Institute 90(20): 1537-1544, 1998.

  16. Prostate Cancer Trialists' Collaborative Group: Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 346(8970): 265-269, 1995.

  17. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. Journal of Urology 152(4): 1170-1173, 1994.

  18. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. Journal of Clinical Oncology 15(1): 382-388, 1997.

  19. Scher HI, Kelly WK: Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. Journal of Clinical Oncology 11(8): 1566-1572, 1993.

  20. Sartor O, Cooper M, Weinberger M, et al.: Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer. Journal of the National Cancer Institute 86(3): 222-227, 1994.

  21. Small EJ, Srinivas S: The antiandrogen withdrawal syndrome: experience in a large cohort of unselected patients with advanced prostate cancer. Cancer 76(8): 1428-1434, 1995.

  22. Eisenberger MA: Chemotherapy for prostate carcinoma. Journal of the National Cancer Institute Monographs 7: 151-163, 1988.

  23. 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. Journal of Clinical Oncology 7(5): 590-597, 1989.

  24. Scott WW, Menon M, Walsh PC: Hormonal therapy of prostatic cancer. Cancer 45(7): 1929-1936, 1980.

  25. Eisenberger MA, Southwest Oncology Group: Phase III Comparison of Flutamide vs Placebo Following Bilateral Orchiectomy in Patients with Stage D2 Adenocarcinoma of the Prostate (Summary Last Modified 12/92), SWOG-8894, clinical trial, closed, 09/15/1994.

  26. Sharifi R, Soloway M: Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. Journal of Urology 143(1): 68-71, 1990.

  27. Crawford ED, Eisenberger MA, McLeod DG, et al.: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. New England Journal of Medicine 321(7): 419-424, 1989.

  28. Bagshaw MA: External radiation therapy of carcinoma of prostate. Cancer 45(7): 1912-1921, 1980.

  29. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27(1): 10-16, 1986.

  30. 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. International Journal of Radiation Oncology, Biology, Physics 12(9): 1597-1600, 1986.

  31. Zincke H: Extended experience with surgical treatment of stage D1 adenocarcinoma of prostate: significant influences of immediate adjuvant hormonal treatment (orchiectomy) on outcome. Journal of Urology 33(5, Suppl): 27-36, 1989.

  32. Hudes GR, Greenberg R, Krigel RL, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. Journal of Clinical Oncology 10(11): 1754-1761, 1992.

  33. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. Journal of Clinical Oncology 12(10): 2005-2012, 1994.


RECURRENT PROSTATE CANCER

In prostate cancer, the selection of further treatment depends on many factors, including prior treatment, site of recurrence, coexistent illnesses, and individual patient considerations. Definitive radiation therapy can be given to patients who fail only locally following prostatectomy.[1-4] 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 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 is associated frequently with elevated prostate-specific antigen (PSA) and a high complication rate. This technique is still undergoing clinical evaluation.[7] Most relapsing patients who initially received locoregional therapy with surgery or irradiation 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. Palliative radiation therapy for bone pain can be very useful. Because of the poor prognosis in prostate cancer patients with relapsing or progressive disease after hormonal therapy, clinical trials are appropriate. These include phase I and II trials of new chemotherapeutic or biologic agents.[8]

Even among patients with metastatic "hormone-refractory prostate cancer," there is some heterogeneity 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) prior response to hormone therapy.[9] 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.[10] 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.[11] Data on whether PSA changes while on chemotherapy are predictive of survival are conflicting.[10,12]

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.[13] However, another study from the Southwest Oncology Group did not show an advantage to continued androgen blockade.[14]

Painful bone metastases can be a major problem in prostate cancer. Many strategies have been studied for palliation, including pain medication, radiation, corticosteroids, bone-seeking radionuclides, gallium nitrate, and bisphosphonates.[15] External-beam radiation therapy for palliation of bone pain can be very useful. Also, the use of radioisotopes, such as strontium-89, has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. When this isotope is given alone, it has been reported to decrease bone pain in 80% of patients treated,[16] and is similar to responses with local or hemibody radiation.[17] When used as an adjunct to external-beam radiation therapy, strontium-89 was shown to slow disease progression and to reduce analgesic requirements, compared to external-beam radiation therapy alone.[18]

Because chemotherapy has limited value in the treatment of patients with refractory disease following hormonal therapy, clinical trials are appropriate. These include trials of new chemotherapeutic or biologic agents.[8,19] Clinical trials exploring the value of chemotherapy for hormone-refractory patients are ongoing.[20-22] Low-dose prednisone may palliate symptoms in some patients treated.[23] A randomized trial showed improved pain control in hormone-resistant patients treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[24] However, there were no statistically significant differences in overall survival, well-being, or measured global quality of life between the 2 treatments.

References:

  1. Lange PH, Reddy PK, Medini E, et al.: Radiation therapy as adjuvant treatment after radical prostatectomy. Journal of the National Cancer Institute Monographs 7: 141-149, 1988.

  2. Ray GR, Bagshaw MA, Freiha F: External beam radiation salvage for residual or recurrent local tumor following radical prostatectomy. Journal of Urology 132(5): 926-930, 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. Journal of Urology 142(5): 1266-1271, 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. Journal of Urology 149(5): 1029-1034, 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): 1265-1271, 1991.

  6. Schellhammer PF, Kuban DA, El-Mahdi AM: Treatment of clinical local failure after radiation therapy for prostate carcinoma. Journal of Urology 150(6): 1851-1855, 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): 676-680, 1995.

  8. Myers C, Cooper M, Stein C, et al.: Suramin: a novel growth factor antagonist with activity in hormone-refractory metastatic prostate cancer. Journal of Clinical Oncology 10(6): 881-889, 1992.

  9. Fossa SD, Dearnaley DP, Law M, et al.: Prognostic factors in hormone-resistant progressing cancer of the prostate. Annals of Oncology 3(5): 361-366, 1992.

  10. Kelly WK, Scher HI, Mazumdar M, et al.: Prostate-specific antigen as a measure of disease outcome in metastatic hormone-refractory prostate cancer. Journal of Clinical Oncology 11(4): 607-615, 1993.

  11. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. Journal of Clinical Oncology 15(1): 382-388, 1997.

  12. 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. Journal of Clinical Oncology 13(12): 2944-2953, 1995.

  13. Taylor CD, Elson P, Trump DL: Importance of continued testicular suppression in hormone-refractory prostate cancer. Journal of Clinical Oncology 11(11): 2167-2172, 1993.

  14. 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. Journal of Clinical Oncology 12(9): 1868-1875, 1994.

  15. Scher HI, Chung LW: Bone metastases: improving the therapeutic index. Seminars in Oncology 21(5): 630-656, 1994.

  16. Robinson RG: Strontium-89: precursor targeted therapy for pain relief of blastic metastatic disease. Cancer 72(11, Suppl): 3433-3435, 1993.

  17. 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. Seminars in Oncology 20(3, Suppl 2): 32-33, 1993.

  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. International Journal of Radiation Oncology, Biology, Physics 25(5): 805-813, 1993.

  19. 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. Urology 52(1): 72-81, 1998.

  20. Eisenberger MA: Chemotherapy for prostate carcinoma. Journal of the National Cancer Institute Monographs 7: 151-163, 1988.

  21. Pienta KJ, Redman B, Hussain M, et al.: Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate. Journal of Clinical Oncology 12(10): 2005-2012, 1994.

  22. Hudes GR, Greenberg R, Krigel RL, et al.: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. Journal of Clinical Oncology 10(11): 1754-1761, 1992.

  23. 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. Journal of Clinical Oncology 7(5): 590-597, 1989.

  24. 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. Journal of Clinical Oncology 14(6): 1756-1764, 1996.

Date Last Modified: 11/1999



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