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医療専門家向け Prostate Cancer Treatment (PDQ®)

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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

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General Information About Prostate Cancer

The median age at diagnosis of carcinoma of the prostate is 66 years.[ 1 ] Prostate cancer may be cured when localized, and it frequently responds to treatment when widespread. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites, such as bone. The 5-year relative survival rate for men diagnosed in the United States from 2001 to 2007 with local or regional disease was 100%, and the rate for distant disease was 28.7%; a 99% survival rate was observed for all stages combined.[ 2 ] 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.

Many patients—especially those with localized tumors—may die of other illnesses without ever having suffered disability from the cancer, even if managed conservatively without an attempt at curative therapy.[ 3 ][ 4 ] In part, these favorable outcomes are likely the result of widespread screening with the prostate-specific antigen (PSA) test, which can identify patients with asymptomatic tumors that have little or no lethal potential.[ 5 ] There is a large number of these clinically indolent tumors, estimated from autopsy series of men dying of causes unrelated to prostate cancer to range from 30% to 70% of men older than 60 years.[ 6 ][ 7 ]

Because diagnostic methods have changed over time, any analysis of survival after treatment of prostate cancer and comparison of the various treatment strategies is complicated by the evidence of increasing diagnosis of nonlethal tumors. Nonrandomized comparisons of treatments may be confounded not only by patient selection factors but also by time trends.

For example, a population-based study in Sweden showed that, from 1960 to the late 1980s, before the use of PSA for screening purposes, long-term relative survival rates after the diagnosis of prostate cancer improved substantially as more sensitive methods of diagnosis were introduced. This occurred despite the use of watchful waiting or active surveillance or palliative hormonal treatment as the most common treatment strategies for localized prostate cancer during the entire era (<150 radical prostatectomies per year were performed in Sweden during the late 1980s). The investigators estimated that, if all prostate cancers diagnosed between 1960 and 1964 were of the lethal variety, then at least 33% of cancers diagnosed between 1980 and 1984 were of the nonlethal variety.[ 8 ][Level of evidence: 3iB] With the advent of PSA screening as the most common method of detection in the United States, the ability to diagnose nonlethal prostate cancers has further increased.

Another issue complicating comparisons of outcomes among nonconcurrent series of patients is the possibility of changes in criteria for the histologic diagnosis of prostate cancer.[ 9 ] This phenomenon creates a statistical artifact that can produce a false sense of therapeutic accomplishment and may also lead to more aggressive therapy.

Controversy exists regarding the value of screening, the most appropriate staging evaluation, and the optimal treatment of each stage of the disease.[ 10 ][ 11 ][ 12 ][ 13 ][ 14 ]

Incidence and Mortality

Estimated new cases and deaths from prostate cancer in the United States in 2020:[ 15 ][A Snapshot of Prostate Cancer]

Anatomy

Anatomy of the male reproductive and urinary systems; drawing shows front and side views of ureters, lymph nodes, rectum, bladder, prostate gland, vas deferens, penis, testicles, urethra, seminal vesicle, and ejaculatory duct.

画像を拡大する

Figure 1. Anatomy of the male reproductive and urinary systems.

Screening

The issue of prostate cancer screening is controversial. In the United States, most prostate cancers are diagnosed because of screening, either with a PSA blood test or, less frequently, with a digital rectal examination. Randomized trials have yielded conflicting results.[ 16 ][ 17 ][ 18 ] Systematic literature reviews and meta-analyses have reported no clear evidence that screening for prostate cancer decreases the risk of death from prostate cancer, or that the benefits outweigh the harms of screening.[ 19 ][ 20 ]

(Refer to the PDQ summary on Prostate Cancer Screening for a detailed summary of evidence regarding the benefits and harms of screening for prostate cancer.)

Pathology

More than 95% of primary prostate cancers are adenocarcinomas. Prostate adenocarcinomas are frequently multifocal and heterogeneous in patterns of differentiation. Prostatic intraepithelial neoplasia ([PIN] noninvasive atypical epithelial cells within benign appearing acini) is often present in association with prostatic adenocarcinoma. PIN is subdivided into low grade and high grade. The high-grade form may be a precursor for adenocarcinoma.[ 21 ]

Several rare tumors account for the remaining few percentages of cases. These include the following:

Gleason score

The histologic grade of prostate adenocarcinomas is usually reported according to one of the variations of the Gleason scoring system, which provides a useful, albeit crude, adjunct to tumor staging in determining prognosis.[ 22 ] The Gleason score is calculated based on the dominant histologic grades, from grade 1 (well differentiated) to grade 5 (very poorly differentiated). The classical score is derived by adding the two most prevalent pattern grades, yielding a score ranging from 2 to 10. Because there is some evidence that the least-differentiated component of the specimen may provide independent prognostic information, the score is often provided by its separate components (e.g., Gleason score 3 + 4 = 7; or 4 + 3 = 7).[ 23 ]

There is evidence that, over time, pathologists have tended to award higher Gleason scores to the same histologic patterns, a phenomenon sometimes termed grade inflation.[ 24 ][ 25 ] This phenomenon complicates comparisons of outcomes in current versus historical patient series. For example, prostate biopsies from a population-based cohort of 1,858 men diagnosed with prostate cancer from 1990 through 1992 were re-read in 2002 to 2004.[ 24 ][ 25 ] The contemporary Gleason score readings were an average of 0.85 points higher (95% confidence interval, 0.79–0.91; P < .001) than the same slides read a decade earlier. As a result, Gleason-score standardized prostate cancer mortality rates for these men were artifactually improved from 2.08 to 1.50 deaths per 100-person years—a 28% decrease even though overall outcomes were unchanged.

Molecular markers

A number of tumor markers have been reported to be associated with the outcome of prostate cancer patients, including the following:[ 21 ][ 22 ]

However, none of these has been prospectively validated, and they are not a part of the routine management of patients.

Clinical Presentation

In the United States, most prostate cancers are diagnosed as a result of screening; therefore, symptoms of cancer are infrequent at the time of diagnosis.[ 22 ] Nevertheless, local growth of the tumor may produce symptoms of urinary obstruction such as:

These symptoms are nonspecific and more indicative of benign prostatic hyperplasia than cancer.

Although rare in the current era of widespread screening, prostate cancer may also present with symptoms of metastases, including bone pain, pathologic fractures, or symptoms caused by bone marrow involvement.

Diagnostic Evaluation

Needle biopsy is the most common method used to diagnose prostate cancer. Most urologists now perform a transrectal biopsy using a bioptic gun with ultrasound guidance. Less frequently, a transperineal ultrasound-guided approach can be used in patients who may be at increased risk of complications from a transrectal approach.[ 26 ] Over the years, there has been a trend toward taking eight to ten or more biopsy samples from several areas of the prostate with a consequent increased yield of cancer detection after an elevated PSA blood test.[ 22 ] However, a randomized trial has shown that, in experienced hands, a multiparametric magnetic resonance imaging (MRI)-directed biopsy is more accurate than a transrectal-guided biopsy to detect what are thought to be clinically significant cancers. In that multicenter study, MRI led to the detection of more Gleason score (≥7) lesions and fewer Gleason score (<7) lesions, with fewer biopsies overall.[ 27 ]

Prophylactic antibiotics, especially fluoroquinolones, are often used before transrectal needle biopsies. There are reports of increasing rates of sepsis, particularly with fluoroquinolone-resistant E. coli, and hospitalization after the procedure.[ 28 ][ 29 ] Therefore, men undergoing transrectal biopsy should be told to seek medical attention immediately if they experience fever after biopsy.

Prognostic Factors

The survival of patients with prostate cancer is related to several factors, including the following:[ 30 ][ 31 ][ 32 ][ 33 ][ 34 ]

(Refer to the Surveillance, Epidemiology, and End Results' 5-year and 10-year survival rates.)

Extent of tumor

When the cancer is confined to the prostate gland, long-term prognosis is excellent. Patients with locally advanced cancer are not usually curable, but 5-year survival is still very good. If prostate cancer has spread to distant organs, current therapy will not cure it. Median survival is usually 1 to 3 years, and most of these patients will die of prostate cancer. Even in this group of patients, indolent clinical courses lasting for many years may be observed.

Histologic grade of tumor

Poorly differentiated tumors are more likely to have metastasized before diagnosis and are associated with a poorer prognosis. The most commonly used method to report tumor differentiation is the Gleason score. (Refer to the Pathology section of the General Information About Prostate Cancer section of this summary for more information.)

Patient's age and health

Any benefits of definitive local therapy with curative intent may take years to emerge. Therefore, therapy with curative intent is usually reserved for men with a sufficiently long-life expectancy. For example, radical prostatectomy is often reserved for men with an estimated life expectancy of at least 10 years.

Prostate-specific antigen (PSA) level

PSA, an organ-specific marker, is often used as a tumor marker.[ 32 ][ 33 ][ 35 ][ 36 ][ 37 ][ 38 ][ 39 ][ 40 ] The higher the level of PSA at baseline, the higher is the risk for metastatic disease or subsequent disease progression. However, it is an imprecise marker of risk.

For example, baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting or active surveillance in the control arm of a randomized trial comparing radical prostatectomy with watchful waiting or active surveillance.[ 41 ][ 42 ] Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.

Serum acid phosphatase levels

Elevations of serum acid phosphatase are associated with poor prognosis in both localized and disseminated disease. However, serum acid phosphatase levels are not incorporated into the American Joint Committee on Cancer 's (AJCC) staging system for prostate cancer.[ 35 ]

Use of nomograms as a prognostic tool

Several nomograms have been developed to predict outcomes either before radical prostatectomy [ 43 ][ 44 ][ 45 ][ 46 ] or after radical prostatectomy [ 47 ][ 48 ] with intent to cure. Preoperative nomograms are based on clinical stage, PSA level, Gleason score, and the number of positive and negative prostate biopsy cores. One independently validated nomogram demonstrated increased accuracy in predicting biochemical recurrence-free survival by including preoperative plasma levels of transforming growth factor B1 and interleukin-6 soluble receptor.[ 49 ][ 50 ]

Postoperative nomograms add pathologic findings, such as capsular invasion, surgical margins, seminal vesicle invasion, and lymph node involvement. The nomograms, however, were developed at academic centers and may not be as accurate when generalized to nonacademic hospitals, where the majority of patients are treated.[ 51 ][ 52 ] In addition, the nomograms use nonhealth (intermediate) outcomes, such as PSA rise or pathologic surgical findings, and subjective endpoints, such as the physician's perceived need for additional therapy. In addition, the nomograms may be affected by changing methods of diagnosis or neoadjuvant therapy.[ 44 ]

Follow-up After Treatment

The optimal follow-up strategy for men treated for prostate cancer is uncertain. Men should be interviewed and examined for symptoms or signs of recurrent or progressing disease, as well as side effects of therapy that can be managed by changes in therapy. However, using surrogate endpoints for clinical decision making is controversial, and the evidence that changing therapy based on such endpoints translates into clinical benefit is weak. Often, rates of PSA change are thought to be markers of tumor progression. However, even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor and of very limited utility in making therapeutic decisions.

Although the PSA test is nearly universally used to follow patients, the diversity of recommendations on the provision of follow-up care reflects the current lack of research evidence on which to base firm conclusions. A systematic review of international guidelines highlights the need for robust primary research to inform future evidence-based models of follow-up care for men with prostate cancer.[ 53 ]

Preliminary data from a retrospective cohort of 8,669 patients with clinically localized prostate cancer treated with either radical prostatectomy or radiation therapy suggested that short post-treatment PSA doubling time (<3 months in this study) fulfills some criteria as a surrogate endpoint for all-cause mortality and prostate cancer-specific mortality after surgery or radiation therapy.[ 54 ]

Likewise, a retrospective analysis (SWOG-S9916 [NCT00004001]) showed PSA declines of 20% to 40% (but not 50%) at 3 months and 30% or more at 2 months after initiation of chemotherapy for hormone-independent prostate cancer, and fulfilled several criteria of surrogacy for overall survival (OS).[ 55 ]

These observations should be independently confirmed in prospective study designs and may not apply to patients treated with hormonal therapy. In addition, there are no standardized criteria of surrogacy or standardized cutpoints for adequacy of surrogate endpoints, even in prospective trials.[ 56 ]

Follow-up after radical prostatectomy

After radical prostatectomy, a detectable PSA level identifies patients at elevated risk of local treatment failure or metastatic disease;[ 37 ] however, a substantial proportion of patients with an elevated or rising PSA level after surgery remain clinically free of symptoms for extended periods.[ 57 ] Biochemical evidence of failure on the basis of elevated or slowly rising PSA alone, therefore, may not be sufficient to initiate additional treatment.

For example, in a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is considered evidence of biochemical recurrence. Among these 315 men, 103 (34%) developed clinical evidence of recurrence. The median time to the development of clinical metastasis after biochemical recurrence was 8 years. After the men developed metastatic disease, the median time to death was an additional 5 years.[ 58 ]

Follow-up after radiation therapy

For patients treated with radiation therapy, the combination of clinical tumor stage, Gleason score, and pretreatment PSA level is often used to estimate the risk of relapse.[ 59 ][Level of evidence: 3iDii] As is the case after prostatectomy, PSA is often followed for signs of tumor recurrence after radiation therapy. After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence; however, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[ 60 ][ 61 ] It is difficult to base decisions about initiating additional therapy on biochemical failure alone. The implication of the various definitions of PSA failure for OS is not known, and, as in the surgical series, many biochemical relapses (rising PSA only) may not be clinically manifested in patients treated with radiation therapy.[ 62 ][ 63 ]

Follow-up after hormonal therapy

After hormonal therapy, 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.[ 32 ] Because PSA expression itself is under hormonal control, androgen deprivation therapy can decrease the serum level of PSA independent of tumor response. Clinicians, therefore, cannot rely solely on the serum PSA level to monitor a patient’s response to hormonal therapy; they must also follow clinical criteria.[ 64 ]

Related Summaries

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

参考文献
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  55. Petrylak DP, Ankerst DP, Jiang CS, et al.: Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16. J Natl Cancer Inst 98 (8): 516-21, 2006.[PUBMED Abstract]
  56. Baker SG: Surrogate endpoints: wishful thinking or reality? J Natl Cancer Inst 98 (8): 502-3, 2006.[PUBMED Abstract]
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Stage Information for Prostate Cancer

Staging Tests

Most men are diagnosed with prostate cancer at an early clinical stage and do not have detectable metastases. Therefore, they generally do not have to undergo staging tests, such as a bone scan, computed tomography (CT), or magnetic resonance imaging (MRI). However, staging studies are done if there is clinical suspicion of metastasis, such as bone pain; local tumor spread beyond the prostate capsule; or a substantial risk of metastasis (prostate-specific antigen [PSA] >20 ng/mL and Gleason score >7).[ 1 ]

Tests used to determine stage include the following:

  1. Radionuclide bone scans.
  2. Serum PSA level.
  3. MRI.
  4. Pelvic lymph node dissection (PLND).
  5. Transrectal or transperineal biopsy.
  6. Transrectal ultrasound (TRUS).
  7. CT scans.

Radionuclide bone scans

A radionuclide bone scan is the most widely used test for metastasis to the bone, which is the most common site of distant tumor spread.

Serum prostate-specific antigen (PSA) level

Serum PSA can predict the results of radionuclide bone scans in newly diagnosed patients.

Magnetic resonance imaging (MRI)

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.[ 4 ] Ultrasound and MRI, however, can reduce clinical understaging and thereby improve patient selection for local therapy. MRI with an endorectal coil appears to be more accurate for identification of organ-confined and extracapsular disease, especially when combined with spectroscopy.[ 1 ] MRI is a poor tool for evaluating nodal disease.

MRI is more sensitive than radionuclide bone scans in the detection of bone metastases, but it is impractical for evaluating the entire skeletal system.

Pelvic lymph node dissection (PLND)

PLND remains the most accurate method to assess metastasis to the pelvic nodes, and laparoscopic PLND has been shown to accurately assess pelvic nodes as effectively as an open procedure.[ 5 ]

The determining factor in deciding whether any type of PLND is indicated is when definitive therapy may be altered. For example, radical prostatectomy is generally reserved for men without lymph node metastasis. Likewise, preoperative seminal vesicle biopsy may be useful in patients with palpable nodules who are being considered for radical prostatectomy (unless they have a low Gleason score) because seminal vesicle involvement could affect the choice of primary therapy and predicts for pelvic lymph node metastasis.[ 6 ]

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

Whether to subject all patients to a PLND is debatable, but in patients undergoing a radical retropubic prostatectomy, nodal status is usually ascertained as a matter of course. In patients who are undergoing a radical perineal prostatectomy in whom the PSA value is less than 20 ng/mL and the Gleason sum is low, however, evidence is mounting that a PLND is probably unnecessary, especially in patients whose malignancy was not palpable but detected on ultrasound.[ 7 ][ 9 ]

Transrectal or transperineal biopsy

The most common means to establish a diagnosis and determine the Gleason score in cases of suspected prostate cancer is by needle biopsy. Most urologists now perform a transrectal biopsy using a bioptic gun with ultrasound guidance. Less frequently, a transperineal ultrasound-guided approach can be used for those patients who may be at increased risk of complications from a transrectal approach.[ 10 ] Over the years, there has been a trend toward taking eight to ten or more biopsy samples from several areas of the prostate with a consequent increased yield of cancer detection after an elevated PSA blood test.[ 1 ]

Transrectal ultrasound (TRUS)

TRUS may facilitate diagnosis by directing needle biopsy; however, ultrasound is operator dependent and does not assess lymph node size.

A prospective multi-institutional study of preoperative TRUS in men with clinically localized prostate cancer eligible for radical prostatectomy showed that TRUS was no better than digital rectal examination in predicting extracapsular tumor extension or seminal vesicle involvement.[ 11 ]

Computed tomography (CT) scans

CT scans can detect grossly enlarged lymph nodes but poorly define intraprostatic features;[ 12 ] therefore, it is not reliable for the staging of pelvic node disease when compared with surgical staging.[ 13 ]

Staging Systems

Historically, two systems have been in common use for the staging of prostate cancer.

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM classification.[ 15 ]

Table 1. Definition of Histologic Grade Groupa
Grade Group Gleason Score Gleason Pattern
aAdapted from AJCC: Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.
1 ≤6 ≤3+3
2 7 3+4
3 7 4+3
4 8 4+4, 3+5, or 5+3
5 9 or 10 4+5, 5+4, or 5+5
Table 2. Definitions of TNM Stage Ia
Stage TNM Description PSA Gleason Score; Gleason Pattern (Grade Group) Illustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis; cT = clinical T; PSA = prostate-specific antigen; pT = pathological T.
aAdapted from AJCC: Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.
The explanations for superscripts b through g are at the end of Table 5.
I cT1a–c, cT2a, N0, M0 cT1 = Clinically inapparent tumor that is not palpable. <10 Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).  
Two panel drawing of stage I prostate cancer; the top panel shows cancer in less than one-half of the right side of the prostate found by needle biopsy. The bottom panel shows cancer in less than one-half of the left side of the prostate found by digital rectal exam. In both panels, the PSA level is less than 10 and the Grade Group is 1. The bladder, rectum, and urethra are also shown.

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–cT1a = Tumor incidental histologic finding in ≤5% of tissue resected.
–cT1b = Tumor incidental histologic finding in >5% of tissue resected.
–cT1c = Tumor identified by needle biopsy found in one or both sides, but not palpable.
cT2 = Tumor is palpable and confined within prostate.
–cT2a = Tumor involves 1/2 of one side or less.
N0 = No positive regional nodes.
M0 = No distant metastasis.
pT2, N0, M0 pT2 = Organ confined. <10 Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).
N0 = No positive regional nodes.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stages IIA, IIB, and IICa
Stage TNM Description PSA Gleason Score; Gleason Pattern (Grade Group) Illustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis; cT = clinical T; PSA = prostate-specific antigen; pT = pathological T.
aAdapted from AJCC: Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.
The explanations for superscripts b through g are at the end of Table 5.
IIA cT1a–c, cT2a, pT2, N0, M0 See cT1a–c, cT2a descriptions in Table 2, Stage I. ≥10 <20 Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).  
Two-panel drawing of stage IIA prostate cancer; the top panel shows cancer in one-half or less of one side of the prostate. The PSA level is at least 10 but less than 20 and the Grade Group is 1. The bottom panel shows cancer in more than one-half of one side of the prostate. The PSA level is less than 20 and the Grade Group is 1. In both panels, the bladder, rectum, and urethra are also shown.

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pT2 = Organ confined.
cT2b–c, N0, M0 cT2 = Tumor is palpable and confined within prostate. <20 Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).
cT2b = Tumor involves >1/2 of one side but not both sides.
cT2c = Tumor involves both sides.
N0 = No positive regional nodes.
M0 = No distant metastasis.
IIB T1–2, N0, M0 T1 = Clinically inapparent tumor that is not palpable. <20 Gleason Score, 7; Gleason Pattern 3+4 (2).  
Stage IIB prostate cancer; drawing shows cancer in one side of the prostate. The PSA level is less than 20 and the Grade Group is 2. Also shown are the bladder, rectum, and urethra.

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–T1a = Tumor incidental histologic finding in ≤5% of tissue resected.
–T1b = Tumor incidental histologic finding in >5% of tissue resected.
–T1c = Tumor identified by needle biopsy found in one or both sides, but not palpable.
cT2 = Tumor is palpable and confined within prostate.
–cT2a = Tumor involves 1/2 of one side or less.
–cT2b = Tumor involves >1/2 of one side but not both sides.
–cT2c = Tumor involves both sides.
pT2 = Organ confined.
N0 = No positive regional nodes.
M0 = No distant metastasis.
IIC T1–2, N0, M0 See T1–2, N0, M0 descriptions above in Stage IIB. <20 Gleason Score, 7; Gleason Pattern, 4 + 3 (3).  
Stage IIC prostate cancer; drawing shows cancer in both sides of the prostate. The PSA level is less than 20 and the Grade Group is 3 or 4. Also shown are the bladder, rectum, and urethra.

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T1–2, N0, M0 See T1–2, N0, M0 descriptions above in Stage IIB. <20 Gleason Score, 8; Gleason Pattern, 4+4, 3+5, or 5+3 (4).
Table 4. Definitions of TNM Stages IIIA, IIIB, and IIICa
Stage TNM Description PSA Gleason Score; Gleason Pattern (Grade Group) Illustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis; cT = clinical T; PSA = prostate-specific antigen; pT = pathological T.
aAdapted from AJCC: Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.
The explanations for superscripts b through g are at the end of Table 5.
IIIA T1–2, N0, M0 See T1–2, N0, M0 descriptions in Table 3, Stage IIB. ≥20 Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).  
Stage IIIA prostate cancer; drawing shows cancer in one side of the prostate. The PSA level is at least 20 and the Grade Group is 1, 2, 3, or 4. Also shown are the bladder, rectum, and urethra.

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Gleason Score, 7; Gleason Pattern 3+4 (2).
Gleason Score, 7; Gleason Pattern, 4+3 (3).
Gleason Score, 8; Gleason Pattern, 4+4, 3+5, or 5+3 (4).
IIIB T3–4, N0, M0 cT3 = Extraprostatic tumor that is not fixed or does not invade adjacent structures. Any value Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).  
Stage IIIB prostate cancer; drawing shows cancer that has spread from the prostate to the seminal vesicles and to nearby tissue. The PSA can be any level and the Grade Group is 1, 2, 3, or 4. Also shown are the pelvic wall, bladder, and rectum.

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–cT3a = Extraprostatic extension (unilateral or bilateral). Gleason Score, 7; Gleason Pattern 3+4 (2).
–cT3b = Tumor invades seminal vesicle(s). Gleason Score, 7; Gleason Pattern, 4+3 (3).
pT3 = Extraprostatic extension. Gleason Score, 8; Gleason Pattern, 4+4, 3+5, or 5+3 (4).
–pT3a = Extraprostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck.
–pT3b = Tumor invades seminal vesicle(s).
cT4 or pT4= Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall.
N0 = No positive regional nodes.
M0 = No distant metastasis.
IIIC Any T, N0, M0 TX = Primary tumor cannot be assessed. Any value Gleason Score, 9 or 10; Gleason Pattern, 4+5, 5+4, or 5+5 (5).  
Stage IIIC prostate cancer; drawing shows cancer in one side of the prostate. The PSA can be any level and the Grade Group is 5. Also shown are the bladder, rectum, and urethra.

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T0 = No evidence of primary tumor.
T1 = Clinically inapparent tumor that is not palpable.
–T1a = Tumor incidental histologic finding in ≤5% of tissue resected.
–T1b = Tumor incidental histologic finding in >5% of tissue resected.
–T1c = Tumor identified by needle biopsy found in one or both sides, but not palpable.
cT2 = Tumor is palpable and confined within prostate.
–cT2a = Tumor involves 1/2 of one side or less.
–cT2b = Tumor involves >1/2 of one side but not both sides.
–cT2c = Tumor involves both sides.
–pT2 = Organ confined.
cT3 = Extraprostatic tumor that is not fixed or does not invade adjacent structures.
–cT3a = Extraprostatic extension (unilateral or bilateral).
–cT3b = Tumor invades seminal vesicle(s).
pT3 = Extraprostatic extension.
–pT3a = Extraprostatic extension (unilateral or bilateral) or microscopic invasion of bladder neck.
–pT3b = Tumor invades seminal vesicle(s).
cT4 or pT4 = Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles, and/or pelvic wall.
N0 = No positive regional nodes.
M0 = No distant metastasis.
Table 5. Definitions of TNM Stages IVA and IVBa
Stage TNM Description PSA Gleason Score; Gleason Pattern (Grade Group) Illustration
T = primary tumor; N = regional lymph nodes; M = distant metastasis; cT = clinical T; PSA = prostate-specific antigen; pT = pathological T.
aAdapted from AJCC: Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.
bWhen either PSA or Grade Group is not available, grouping should be determined by T category and/or either PSA or Grade Group as available.
cThere is no pathological T1 classification.
dPositive surgical margin should be indicated by an R1 descriptor, indicating residual microscopic disease.
eWhen more than one site of metastasis is present, the most advanced category is used. M1c is most advanced.
fPSA values are used to assign this category.
gRecently the Gleason system has been compressed into so-called Grade Groups.[ 16 ]
IVA Any T, N1, M0 Any T = See descriptions in Table 4, Stage IIIC. See Any PSA values in Table 4, Stage IIIC. Gleason Score, ≤6; Gleason Pattern, ≤3+3 (1).  
Stage IVA prostate cancer; drawing shows cancer in one side of the prostate and in nearby lymph nodes. The PSA can be any level and the Grade Group is 1 ,2, 3, 4, or 5. Also shown are the bladder, rectum, and urethra.

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Gleason Score, 7; Gleason Pattern 3+4 (2).
Gleason Score, 7; Gleason Pattern, 4+3 (3).
N1 = Metastases in regional node(s). Gleason Score, 8; Gleason Pattern, 4+4, 3+5, or 5+3 (4).
M0 = No distant metastasis. Gleason Score, 9 or 10; Gleason Pattern, 4+5, 5+4, or 5+5 (5).
IVB Any T, Any N, M1 Any T = See descriptions in Table 4, Stage IIIC. See Any PSA values Table 4, Stage IIIC. Any Gleason Score; Gleason Pattern (Grade Group) = See above in Stage IVA.  
Stage IVB prostate cancer; drawing shows other parts of the body where prostate cancer may spread, including the distant lymph nodes and bones. An inset shows cancer cells spreading from the prostate, through the blood and lymph system, to another part of the body where metastatic cancer has formed.

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NX = Regional nodes were not assessed.
N0 = No positive regional nodes.
N1 = Metastases in regional node(s).
M1 = Distant metastasis.
–M1a = Nonregional lymph node(s).
–M1b = Bone(s).
–M1c = Other site(s) with or without bone disease.
参考文献
  1. Zelefsky MJ, Eastham JA, Sartor AO: Cancer of the prostate. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1220-71.[PUBMED Abstract]
  2. Oesterling JE, Martin SK, Bergstralh EJ, et al.: The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer. JAMA 269 (1): 57-60, 1993.[PUBMED Abstract]
  3. Huncharek M, Muscat J: Serum prostate-specific antigen as a predictor of radiographic staging studies in newly diagnosed prostate cancer. Cancer Invest 13 (1): 31-5, 1995.[PUBMED Abstract]
  4. Schiebler ML, Yankaskas BC, Tempany C, et al.: MR imaging in adenocarcinoma of the prostate: interobserver variation and efficacy for determining stage C disease. AJR Am J Roentgenol 158 (3): 559-62; discussion 563-4, 1992.[PUBMED Abstract]
  5. Schuessler WW, Pharand D, Vancaillie TG: Laparoscopic standard pelvic node dissection for carcinoma of the prostate: is it accurate? J Urol 150 (3): 898-901, 1993.[PUBMED Abstract]
  6. Stone NN, Stock RG, Unger P: Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in men with localized carcinoma of the prostate. J Urol 154 (4): 1392-6, 1995.[PUBMED Abstract]
  7. Oesterling JE, Brendler CB, Epstein JI, et al.: Correlation of clinical stage, serum prostatic acid phosphatase and preoperative Gleason grade with final pathological stage in 275 patients with clinically localized adenocarcinoma of the prostate. J Urol 138 (1): 92-8, 1987.[PUBMED Abstract]
  8. Fournier GR, Narayan P: Re-evaluation of the need for pelvic lymphadenectomy in low grade prostate cancer. Br J Urol 72 (4): 484-8, 1993.[PUBMED Abstract]
  9. Daniels GF, McNeal JE, Stamey TA: Predictive value of contralateral biopsies in unilaterally palpable prostate cancer. J Urol 147 (3 Pt 2): 870-4, 1992.[PUBMED Abstract]
  10. Webb JA, Shanmuganathan K, McLean A: Complications of ultrasound-guided transperineal prostate biopsy. A prospective study. Br J Urol 72 (5 Pt 2): 775-7, 1993.[PUBMED Abstract]
  11. 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. J Urol 157 (3): 902-6, 1997.[PUBMED Abstract]
  12. Gerber GS, Goldberg R, Chodak GW: Local staging of prostate cancer by tumor volume, prostate-specific antigen, and transrectal ultrasound. Urology 40 (4): 311-6, 1992.[PUBMED Abstract]
  13. Hanks GE, Krall JM, Pilepich MV, et al.: Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification. Int J Radiat Oncol Biol Phys 23 (2): 293-8, 1992.[PUBMED Abstract]
  14. Jewett HJ: The present status of radical prostatectomy for stages A and B prostatic cancer. Urol Clin North Am 2 (1): 105-24, 1975.[PUBMED Abstract]
  15. Prostate. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 715–26.[PUBMED Abstract]
  16. Epstein JI, Egevad L, Amin MB, et al.: The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol 40 (2): 244-52, 2016.[PUBMED Abstract]
Treatment Option Overview for Prostate Cancer

Local treatment modalities are associated with prolonged disease-free survival (DFS) for many patients with localized prostate cancer but are rarely curative in patients with locally extensive tumors. Because of clinical understaging using current diagnostic techniques, even when the cancer appears clinically localized to the prostate gland, some patients develop disseminated tumors after local therapy with surgery or radiation.

Treatment options for each stage of prostate cancer are presented in Table 6.

Table 6. Treatment Options by Stage for Prostate Cancer
Stage ( Standard Treatment Options
EBRT = external-beam radiation therapy; LH-RH = luteinizing hormone-releasing hormone; TURP = transurethral resection of the prostate.
Stage I Prostate Cancer Watchful waiting or active surveillance/active monitoring
Radical prostatectomy
External-beam radiation therapy (EBRT)
Interstitial implantation of radioisotopes
Stage II Prostate Cancer Watchful waiting or active surveillance/active monitoring
Radical prostatectomy
EBRT with or without hormonal therapy
Interstitial implantation of radioisotopes
Stage III Prostate Cancer EBRT with or without hormonal therapy
Hormonal manipulations with or without radiation therapy
Radical prostatectomy with or without EBRT
Watchful waiting or active surveillance/active monitoring
Stage IV Prostate Cancer Hormonal manipulations
Bisphosphonates
EBRT with or without hormonal therapy
Palliative radiation therapy
Palliative surgery with transurethral resection of the prostate (TURP)
Watchful waiting or active surveillance/active monitoring
Recurrent Prostate Cancer Hormone therapy
Chemotherapy for hormone-resistant prostate cancer
Immunotherapy
Radiopharmaceutical therapy/alpha emitter radiation

Side effects of each of the treatment approaches are covered in the relevant sections below. Patient-reported adverse effects differ substantially across the options for management of clinically localized disease, with few direct comparisons, and include watchful waiting/active surveillance/active monitoring, radical prostatectomy, and radiation therapy. The differences in adverse effects can play an important role in patient choice among treatment options. Detailed comparisons of these effects have been reported in population-based cohort studies, albeit with relatively short follow-up times of 2 to 3 years.[ 1 ][ 2 ]

Watchful Waiting or Active Surveillance/Active Monitoring

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[ 3 ][ 4 ] Watch and wait, observation, expectant management, and active surveillance/active monitoring are terms indicating a strategy that does not employ immediate therapy with curative intent.

Watchful waiting and active surveillance/active monitoring are the most commonly used terms, and the literature does not always clearly distinguish them, making the interpretation of results difficult. The general concept of watchful waiting is patient follow-up with the application of palliative care as needed to alleviate symptoms of tumor progression. There is no planned attempt at curative therapy at any point in follow-up. For example, transurethral resection of the prostate (TURP) or hormonal therapy may be used to alleviate tumor-related urethral obstruction should there be local tumor growth; hormonal therapy or bone radiation might be used to alleviate pain from metastases. Radical prostatectomy has been compared with watchful waiting or active surveillance/active monitoring in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2).[ 5 ] (Refer to the Radical Prostatectomy section in the Treatment Option Overview for Prostate Cancer section of this summary for more information.)

In contrast, the strategy behind active surveillance/active monitoring is to defer therapy for clinically localized disease but regularly follow the patient and initiate local therapy with curative intent if there are any signs of local tumor progression.[ 6 ][ 7 ][ 8 ][ 9 ] The intention is to avoid the morbidity of therapy in men who have indolent or nonprogressive disease but preserve the ability to cure them should the tumor progress. Active surveillance/active monitoring often involves the following:

Patient selection, testing intervals, and specific tests, as well as criteria for intervention, are arbitrary and not established in controlled trials.

In the United States, as in other settings with widespread PSA screening, the results of conservative management of localized prostate cancer are particularly favorable. In the aggregate, men managed by watchful waiting or active surveillance/active monitoring (using various criteria, depending upon the study) have had very favorable prostate–cancer-specific mortalities ranging from about 1% to 10% (with the most favorable rates in more recent series).[ 10 ][ 11 ][ 12 ][ 13 ][ 14 ][ 15 ][ 16 ][ 17 ][ 18 ] Most men with screen-detected prostate cancer may, therefore, be candidates for active surveillance/active monitoring, with definitive therapy reserved for signs of tumor progression. This has been shown most clearly in the large Prostate Testing for Cancer Treatment (ProtecT [NCT02044172 and ISRCTN20141297]) randomized trial that compared active monitoring, radical prostatectomy, and radiation therapy.[ 19 ] (Refer to the Radical Prostatectomy section of this summary for information about comparisons of active surveillance and/or active monitoring with immediate therapies.)

(Refer to the Stage II Prostate Cancer Treatment section of this summary for more information.)

Radical Prostatectomy

A radical prostatectomy is usually reserved for patients who:[ 20 ][ 21 ][ 22 ]

Open 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.[ 23 ] Robot-assisted prostatectomy is an alternative to open prostatectomy and has become the most common technique in developed countries. In experienced hands, functional outcomes between open and robot-assisted prostatectomy appear to be very similar, at least in the short- to mid-term. In a randomized trial of 308 men suitable for prostatectomy, urinary, sexual, and bowel functional outcomes were similar between open retropubic and robotic surgeries at a median follow-up of 24 months.[ 24 ] The sample size and duration of follow-up were too small to detect meaningful differences in cancer outcomes.

For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted.[ 25 ] With larger, less-differentiated tumors, a pelvic lymph node dissection is more important. In these cases, the value of open surgical or laparoscopic pelvic node dissection is not therapeutic, but it spares patients with positive nodes the morbidity of prostatectomy. Radical prostatectomy is usually not performed if a frozen-section evaluation of pelvic nodes reveals metastases; these 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.[ 26 ][ 27 ]

After radical prostatectomy, pathologic evaluation stratifies tumor extent into the following classes:

Radical prostatectomy compared with other treatment options

In 1993, a structured literature review of 144 papers was done in an attempt to compare the three primary treatment strategies for clinically localized prostate cancer:[ 30 ]

  1. Radical prostatectomy.
  2. Definitive radiation therapy.
  3. Observation (watchful waiting or active surveillance/active monitoring).

The authors concluded that poor reporting and selection factors within all series precluded a valid comparison of efficacy for the three management strategies.

In a literature review of 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%).[ 31 ] Because it is highly unlikely that radiation therapy would worsen disease-specific survival, the most likely explanation is that selection factors affect choice of treatment. Such selection factors make comparisons of therapeutic strategies imprecise.[ 32 ]

Radical prostatectomy has been compared with watchful waiting or active surveillance/active monitoring in men with early-stage disease (i.e., clinical stages T1b, T1c, or T2) in randomized trials, with conflicting results. The difference in results may be the result of differences in how the men were diagnosed with prostate cancer.

Evidence (radical prostatectomy vs. watchful waiting or active surveillance/active monitoring):

  1. In a randomized clinical trial performed in Sweden in the pre-PSA screening era, 695 men with prostate cancer were randomly assigned to radical prostatectomy versus watchful waiting. Only about 5% of the men in the trial had been diagnosed by PSA screening. Therefore, the men had more extensive local disease than is typically the case in men diagnosed with prostate cancer in the United States.[ 33 ][ 34 ][ 35 ]
  2. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407) is a randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/mL) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy or watchful waiting.[ 5 ][ 36 ][ 37 ][Levels of evidence: 1iiA, 1iiB]
  3. In the ProtecT trial (NCT02044172 and ISRCTN20141297), 82,429 men were screened with PSA testing, and 2,664 were diagnosed with clinically localized prostate cancer, of whom 1,643 (median age 62 years, range 50–69 years) consented to a randomly assigned comparison of active monitoring, radical prostatectomy (nerve-sparing when possible), or external-beam 3-dimensional (3D) conformal radiation therapy (74 Gy in 37 fractions). The primary endpoint was prostate cancer–specific mortality.[ 19 ]
    1. With a median follow-up of 10 years, there were 17 deaths from prostate cancer, with no statistically significant differences among the three study arms (P = .48). The 10-year prostate cancer–specific survival rates were 98.8% in the active monitoring arm, 99.0% in the radical prostatectomy arm, and 99.6% in the radiation therapy arm.[ 19 ][Level of evidence: 1iiA]
    2. Likewise, all-cause mortality was nearly identical in all three study arms: 10.9 deaths in the active monitoring arm, 10.1 in the radical prostatectomy arm, and 10.3 in the radiation therapy arm per 1,000 person-years (P = .87).[ 19 ][Level of evidence: 1iiB]
    3. There were statistically significant differences in progression to metastatic disease among the treatment arms (active monitoring, 33/545; radical prostatectomy, 13/553; radiation therapy, 16/545) that began to emerge after 4 years, but these differences had not translated into any difference in mortality at the 10-year follow-up. Over the course of 10 years, 52% of the patients required active intervention.
    4. As expected, there were substantial differences in patient-reported outcomes among the three management approaches.[ 38 ][Level of evidence: 1iiC] A substudy of patient-reported outcomes up to 6 years after randomization included the following:

Complications of radical prostatectomy

Complications of radical prostatectomy include the following:

Functional outcomes of radical prostatectomy with respect to sexual, urinary, bowel function, and health-related quality of life (QOL), appear to be similar whether the procedure is open retropubic, laparoscopic, or robot-assisted radical prostatectomy.[ 59 ]

Morbidity and mortality associated with radical prostatectomy

An analysis of Medicare records on 101,604 radical prostatectomies performed from 1991 to 1994 showed the following:[ 39 ]

Over the study period, these rates decreased by 30%, 8%, and 12%, respectively.[ 39 ]

Prostatectomies done at hospitals where fewer of the procedures were performed than those done at hospitals where more were performed were associated with the following:[ 40 ][ 41 ]

Operative morbidity and mortality rates increase with age. Comorbidity, especially underlying cardiovascular disease and a history of stroke, accounts for a portion of the age-related increase in 30-day mortality.

In a cohort of all men with prostate cancer who underwent radical prostatectomy from 1990 to 1999 in Ontario, 75-year-old men with no comorbidities had a predicted 30-day mortality of 0.74%. Thirty-day surgical complication rates also depended more on comorbidity than age (i.e., about 5% vs. 40% for men with 0 vs. ≥4 underlying comorbid conditions, respectively).[ 41 ]

Urinary incontinence and impotence

Urinary incontinence and impotence are complications that can result from radical prostatectomy and have been studied in multiple studies.

Evidence (urinary incontinence and impotence after radical prostatectomy):

  1. A large case series of men undergoing the anatomic (nerve-sparing) technique of radical prostatectomy reported the following:[ 43 ]
  2. A national survey of Medicare patients who underwent radical prostatectomy in 1988 to 1990 reported more morbidity than in the case series reported above.[ 44 ]
  3. A population-based longitudinal cohort (Prostate Cancer Outcomes Study) of 901 men aged 55 to 74 years who had recently undergone radical prostatectomy for prostate cancer reported the following:[ 45 ]
  4. A cross-sectional survey of prostate cancer patients who were treated with radical prostatectomy, radiation therapy, or watchful waiting and active surveillance in a managed care setting showed substantial sexual and urinary dysfunction in the prostatectomy group.[ 46 ]
  5. Case series of 93, 459, and 89 men who had undergone radical prostatectomy by experienced surgeons showed rates of impotence as high as those in the national Medicare survey when men were carefully questioned about sexual potency, although the men in these case series were on average younger than those in the Medicare survey.[ 47 ][ 48 ][ 49 ] One of the case series used the same questionnaire as that used in the Medicare survey.[ 47 ] The urinary incontinence rate in that series was also similar to that in the Medicare survey.

Differences are often reported between population-based surveys and case series from individual centers. Reasons could include the following:

Penile shortening

Case series of men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[ 50 ][ 51 ][ 52 ] The functional consequence of the shortening is not well studied, but it is noticeable to some men.

In a registry of men with rising PSA after initial treatment of clinically localized prostate cancer, 19 of 510 men (3.7%) who had undergone radical prostatectomy complained of reduced penile size.[ 60 ] However, the data were based upon physician reporting of patients' complaints rather than direct patient questioning or before-and-after measurement of penile length. Also, the study sample was restricted to patients with known or suspected tumor recurrence, making generalization difficult.

Recovery of penile length to pre-operative measurements within 1 to 2 years has been reported in some, but not all, case series in which men were followed longitudinally.[ 61 ]

Inguinal hernia

Inguinal hernia has been reported as a complication of radical prostatectomy.

Evidence (inguinal hernia after radical prostatectomy):

  1. Retrospective cohort studies and case series have shown an increased incidence of inguinal hernia, ranging from 7% to 21%, in men undergoing radical prostatectomy, with rates peaking within 2 years of surgery.[ 53 ][ 54 ][ 55 ][ 56 ][ 57 ]
  2. Observational studies suggest that the rates are higher than in comparable men who have undergone prostate biopsy alone, transurethral resections, and simple open prostatectomy for benign disease;[ 53 ][ 54 ] or in men with prostate cancer who have undergone pelvic lymph node dissection alone or radiation therapy.[ 53 ][ 55 ][ 56 ]

Although the observations of increased rates of inguinal hernia after radical prostatectomy are consistent, it is conceivable that men with prostate cancer who are being followed carefully by urologists could have higher detection rates of hernia because of frequent examinations or diagnostic imaging (i.e., detection bias). Men should be made aware of this potential complication of prostatectomy.

Fecal incontinence

Radical prostatectomy may cause fecal incontinence, and the incidence may vary with surgical method.[ 58 ]

Evidence (fecal incontinence after radical prostatectomy):

  1. In a national survey sample of 907 men who had undergone radical prostatectomy at least 1 year before the survey, 32% of the men who had undergone perineal (nerve-sparing) radical prostatectomy and 17% of the men who had undergone a retropubic radical prostatectomy reported accidents of fecal leakage. Ten percent of the respondents reported moderate amounts of fecal leakage, and 4% of the respondents reported large amounts of fecal leakage. Fewer than 15% of men with fecal incontinence had reported it to a physician or health care provider.[ 58 ]

Radiation Therapy and Radiopharmaceutical Therapy

External-beam radiation therapy (EBRT)

Candidates for definitive radiation therapy must have a confirmed pathologic diagnosis of cancer that is clinically confined to the prostate and/or surrounding tissues (stage I, stage II, and stage III). Staging laparotomy and lymph node dissection are not required.

Radiation therapy may be a good option for patients who are considered poor medical candidates for radical prostatectomy. These patients can be treated with an acceptably low complication rate if care is given to the delivery technique.[ 62 ]

Long-term results with radiation therapy are dependent on stage and are associated with dosimetry of the radiation.

Evidence (EBRT):

  1. A retrospective review of 999 patients treated with megavoltage radiation therapy showed that cause-specific survival rates at 10 years varied substantially by T stage: T1 (79%), T2 (66%), T3 (55%), and T4 (22%).[ 63 ] An initial serum PSA level higher than 15 ng/mL is a predictor of probable failure with conventional radiation therapy.[ 64 ]
  2. Several randomized studies have demonstrated an improvement in freedom from biochemical (PSA based) recurrence with higher doses of radiation therapy (74–79 Gy) as compared with lower doses (64–70 Gy).[ 65 ][ 66 ][ 67 ][ 68 ][ 69 ][Level of evidence: 1iiDiii] None of the studies demonstrated a cause-specific survival benefit to higher doses.

(Refer to the Radical prostatectomy compared with other treatment options section of this summary for direct comparisons of radiation therapy with active surveillance/active monitoring and radical prostatectomy.)

Prophylactic radiation therapy to clinically or pathologically uninvolved pelvic lymph nodes does not appear to improve OS or prostate cancer-specific survival as was seen in the RTOG-7706 trial, for example.[ 70 ][Level of evidence: 1iiA]

Conventional versus hypofractionated EBRT

The more convenient schedules of hypofractionated radiation therapy (using fewer fractions at higher doses per fraction) appear to yield similar outcomes to conventional schedules of radiation, at least with respect to the intermediate outcomes of DFS and failure-free survival (low levels of evidence not known to translate into health outcomes), and early data on OS rates. However, hypofractionated radiation may incur more toxicity than standard doses, depending on the schedules used.[ 71 ]

Evidence (conventional vs. hypofractionated EBRT):

  1. In a small, randomized trial, primarily from one treatment center, conventional hypofractionation was not found to be superior to conventional fractionation.[ 72 ] In the trial, 303 assessable men were randomly assigned to receive IMRT for a total of 76 Gy in 38 fractions at 2.0 Gy per fraction (conventional IMRT [CIMRT]) versus IMRT for a total of 70.2 Gy in 26 fractions at 2.7 per fraction (hypofractionated IMRT [HIMRT]).
  2. In the much larger, multicenter Conventional or Hypofractionated High-Dose Intensity Modulated Radiotherapy in Prostate Cancer (CHHiP) trial [NCT00392535], 3,216 men with stages T1b–T3a, N0, M0 cancer and an estimated risk of seminal vesicle involvement of less than 30% were randomly assigned to receive either 74 Gy in 37 fractions (the conventional-fraction arm), 60 Gy in 20 fractions, or 57 Gy in 19 fractions (1:1:1 ratio).[ 73 ][ 74 ] The trial was designed as a noninferiority study.
  3. In another multicenter, randomized trial of Hypofractionated versus Conventionally Fractionated Radiotherapy for Patients with Prostate Cancer (HYPRO study [ISRCTN85138529]), conventional radiation therapy doses (78 Gy in 39 fractions over 8 weeks) were compared with hypofractionated radiation therapy doses (64.6 Gy in 19 fractions over 6.5 weeks) in a noninferiority design for hypofractionation in 820 men with intermediate- or high-risk prostate cancer (stages T1b–T4, NX–0, MX–0).[ 75 ][ 76 ] Median follow-up was 60 months.
  4. The RTOG reported a noninferiority trial of 1,115 men with low-risk prostate cancer (T1b–T2c) who were randomly assigned to receive hypofractionated radiation therapy (70 Gy in 28 fractions over 5.6 weeks) versus conventional radiation therapy doses (73.8 Gy in 41 fractions over 8.2 weeks).[ 78 ]
  5. In a multicenter trial (NCT00304759), 1,206 men with intermediate-risk prostate cancer (T1–2a Gleason score ≤6, PSA 10.1–20 ng/mL; T2b–2c Gleason ≤6, PSA ≤20 ng/mL; or T1–2 Gleason = 7, PSA ≤20 ng/mL) were randomly assigned in a noninferiority trial design to receive conventional radiation therapy (78 Gy in 39 fractions) versus hypofractionated radiation therapy (60 Gy over 20 fractions).[ 79 ]

Brachytherapy

Patients undergoing brachytherapy are often selected for favorable characteristics that include the following:

More information and further study are required to better define the effects of modern interstitial brachytherapy on disease control and QOL and to determine the contribution of favorable patient selection to outcomes.[ 80 ][Level of evidence: 3iiiDiv]

Information about ongoing clinical trials is available from the NCI website.

Radiopharmaceutical therapy

Alpha emitter radiation

Radium Ra 223 (223Ra) emits alpha particles (i.e., two protons and two neutrons bound together, identical to a helium nucleus) with a half-life of 11.4 days. It is administered intravenously and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of less than 100 mcM. 223Ra improved OS in patients with prostate cancer metastatic to bone. In a double-blind, randomized, controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more metastases, and no known visceral metastases were randomly assigned in a 2:1 ratio to 223Ra versus placebo. 223Ra statistically significantly improved OS (median 14.9 months vs. 11.3 months), rate of symptomatic skeletal events (33% vs. 38%), and spinal cord compression (4% vs. 7%).[ 81 ][ 82 ][Level of evidence: 1iA] With administration at a dose of 50kBq per kg body weight every 4 weeks for six injections, the side effects were similar to those of a placebo.

Complications of radiation therapy

Definitive EBRT can result in acute cystitis, proctitis, and enteritis.[ 20 ][ 42 ][ 49 ][ 83 ][ 84 ][ 85 ] These conditions are generally reversible but may be chronic and rarely require surgical intervention.[ 85 ]

A cross-sectional survey of prostate cancer patients who had been treated in a managed care setting by radical prostatectomy, radiation therapy, or watchful waiting and active surveillance showed substantial sexual and urinary dysfunction in the radiation therapy group.[ 46 ]

Radiation is also known to be carcinogenic.[ 86 ][ 87 ][ 88 ] EBRT for prostate cancer is associated with an increased risk of bladder and gastrointestinal cancer. Brachytherapy is associated with an increased risk of bladder cancer.

Reducing complications

Potency, in most cases, is preserved with radiation therapy in the short term but appears to diminish over time.[ 85 ] Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men.

Evidence (reducing complications):

  1. In a completed, randomized, placebo-controlled, crossover design study (RTOG-0215 [NCT00057759]) of 60 men who had undergone radiation therapy for clinically localized prostate cancer, and who reported erectile dysfunction that began after their radiation therapy, 55% reported successful intercourse after sildenafil versus 18% after placebo (P < .001).[ 89 ][Level of evidence: 1iC]
  2. A randomized trial (RTOG-0831 [NCT00931528]) of 121 men with intact erectile function compared daily preventive tadalafil (5 mg PO qd) with placebo for 24 weeks beginning at the start of either EBRT or brachytherapy.[ 90 ][Level of evidence: 1iC]

Morbidity may be reduced with the employment of sophisticated radiation therapy techniques—such as the use of linear accelerators—and careful simulation and treatment planning.[ 91 ][ 92 ]

Evidence (3D conformal vs. conventional radiation therapy):

  1. The side effects of similar doses of 3D conformal radiation therapy and conventional radiation therapy (total dose, 60–64 Gy) have been compared in a randomized nonblinded study.[ 92 ][Level of evidence: 1iiC]

Radiation therapy can be delivered after an extraperitoneal lymph node dissection without an increase in complications if careful attention is paid to radiation technique. The treatment field should not include the area that contained the dissected pelvic nodes. Previous TURP is associated with an increased risk of stricture above that seen with radiation therapy alone, but, if radiation therapy is delayed 4 to 6 weeks after the TURP, the risk of stricture is lower.[ 93 ][ 94 ][ 95 ] Pretreatment TURP to relieve obstructive symptoms has been associated with tumor dissemination; however, multivariable analysis in pathologically staged cases indicates that this may be due to a worse underlying prognosis of the cases that require TURP rather than the result of the procedure itself.[ 96 ]

Comparison of complications from radiation therapy and from radical prostatectomy

In general, radical prostatectomy is associated with a higher rate of urinary incontinence and early sexual impotence but a lower rate of stool incontinence and rectal injury. However, over time, the differences in sexual impotence diminish because the risk rises with time since radiation. Many side effects of definitive local therapy for prostate cancer persist well beyond a decade after therapy, and urinary problems in addition to sexual impotence may worsen with age.[ 97 ]

Evidence (complications of radical prostatectomy vs. radiation therapy):

  1. A population-based survey of Medicare recipients who had received radiation therapy as primary treatment for prostate cancer (similar in design to the survey of Medicare patients who underwent radical prostatectomy,[ 44 ] described above) has been reported, showing substantial differences in posttreatment morbidity profiles between surgery and radiation therapy.[ 98 ]
  2. A prospective, community-based cohort study of men aged 55 to 74 years treated with radical prostatectomy (n = 1,156) or EBRT (n = 435) attempted to compare the acute and chronic complications of the two treatment strategies after adjusting for baseline differences in patient characteristics and underlying health.[ 99 ]

Hormonal Therapy and Its Complications

Several different hormonal approaches are used in the management of various stages of prostate cancer.

These approaches include the following:

Abiraterone acetate

Abiraterone acetate has been shown to improve OS when added to ADT in men with advanced prostate cancer who have castration-sensitive disease. Abiraterone acetate is generally well-tolerated; however, it is associated with an increase in the mineralocorticoid effects of grade 3 or 4 hypertension and hypokalemia compared with ADT alone.[ 100 ] It may also be associated with a small increase in respiratory disorders.[ 101 ]

Bilateral orchiectomy

Benefits of bilateral orchiectomy include the following:[ 42 ]

Disadvantages of bilateral orchiectomy include the following:[ 42 ][ 102 ]

Bilateral orchiectomy has also been associated with an elevated risk of coronary heart disease and myocardial infarction.[ 103 ][ 104 ][ 105 ][ 106 ]

(Refer to the PDQ summary on Hot Flashes and Night Sweats.)

Estrogen therapy

Estrogens at a dose of 3 mg qd of diethylstilbestrol (DES) will achieve castrate levels of testosterone. Like orchiectomy, estrogens may cause loss of libido and impotence. Estrogens also cause gynecomastia, and prophylactic low-dose radiation therapy to the breasts is given to prevent this complication.

DES is no longer manufactured or marketed in the United States and is seldom used today because of the risk of serious side effects, including myocardial infarction, cerebrovascular accidents, and pulmonary embolism.

Luteinizing hormone-releasing hormone (LH-RH) agonist therapy

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

There is some evidence that LH-RH agonists are associated with increased risk of cardiovascular morbidity or mortality, although the results are conflicting.[ 103 ][ 104 ][ 105 ][ 106 ][ 107 ]

Evidence (LH-RH agonists and cardiovascular disease):

  1. In a population-based study within the Department of Veterans Affairs' system, LH-RH agonists were associated with an increased risk of diabetes as well as cardiovascular disease, including coronary heart disease, myocardial infarction, sudden death, and stroke.[ 103 ][ 104 ][ 105 ]
  2. A systematic evidence review and meta-analysis of eight trials (4,141 patients) of men with nonmetastatic prostate cancer who were randomly assigned to receive or not to receive LH-RH agonists found no difference in cardiovascular death rates (11.0% vs. 11.2%; RRdeath, 0.93; 95% CI, 0.79–1.10; P = .41).[ 108 ] Median follow-up in those studies was 7.6 to 13.2 years. No excess risk of LH-RH agonists was found regardless of treatment duration or patient age (median age of <70 years or ≥70 years).

Antiandrogen therapy

Antiandrogen agents used in the treatment of prostate cancer include flutamide and bicalutamide. A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[ 109 ] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[ 109 ][Level of evidence: 1iiA]

The pure antiandrogen, flutamide, may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.[ 110 ]

Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence.[ 111 ] (Refer to the PDQ summaries on Gastrointestinal Complications; Nausea and Vomiting Related to Cancer Treatment; and Hot Flashes and Night Sweats for more information.)

The steroidal antiandrogen, megestrol acetate, suppresses androgen production incompletely and is generally not used as initial therapy.

Additional studies that evaluate the effects of various hormone therapies on QOL are required.[ 112 ]

ADT

A national Medicare survey of men who had undergone radical prostatectomy for prostate cancer and either had or had not undergone androgen depletion (either medically or surgically induced) showed a decrease with androgen depletion in all seven health-related QOL measures, including the following:[ 113 ][Level of evidence: 3iC]

ADT can cause osteoporosis and bone fractures. In a population-based sample of 50,613 Medicare patients aged 66 years or older followed for a median of 5.1 years, men who had been treated with either a gonadotropin-releasing hormone (GnRH) or orchiectomy had a 19.4% bone fracture rate compared with 12.6% in men who had not received hormone deprivation therapy. The effect was similar in men whether or not they had metastatic bone disease.[ 114 ]

The use of ADT may be associated with complaints of penile shortening, although the data are very limited.[ 60 ] In a registry study of men with rising PSA after initial treatment of clinically localized prostate cancer treated with radiation therapy plus ADT, 6 of 225 men (2.7%) complained of reduced penile size. Of the 213 men treated with radiation therapy but no ADT, none complained of changes in penile size. However, the data were based upon physician reporting of patients' complaints rather than direct patient questioning or before-and-after measurement of penile length. Also, the study sample was restricted to patients with known or suspected tumor recurrence, making generalization difficult.

Placebo-controlled, randomized trials have shown that treatment of bone loss with bisphosphonates decreases the risk of bone fracture in men receiving ADT for prostate cancer (RR, 0.80 in a meta-analysis of 15 trials; 95% CI, 0.69–0.94). In the meta-analysis, zoledronate appeared to have the largest effect.[ 115 ]

The use of ADT has also been associated with an increased risk of colorectal cancer.

Evidence (increased risk of colorectal cancer):

  1. Using the Surveillance, Epidemiology, and End Results (SEER) Medicare database, investigators assessed the risk of subsequent colorectal cancer in 107,859 men aged 67 years and older after an initial diagnosis of prostate cancer.[ 116 ]

Antiadrenal therapy

Antiadrenal agents used in the treatment of prostate cancer include ketoconazole and aminoglutethimide. Long-term use of ketoconazole can result in impotence, pruritus, nail changes, and adrenal insufficiency. (Refer to the PDQ summary on Pruritus for more information.) Aminoglutethimide commonly causes sedation and skin rashes.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation for patients with prostate cancer include the following:

  1. Cryosurgery.
  2. Proton-beam therapy.
  3. Photodynamic therapy.
  4. Neoadjuvant hormonal therapy.
  5. Bicalutamide.

Cryosurgery

Cryosurgery, or cryotherapy, is under evaluation for the treatment of localized prostate cancer. It is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate with cryoprobes, followed by thawing.[ 117 ][Level of evidence: 3iiiC]; [Level of evidence: 3iii]; [ 118 ][ 119 ][Level of evidence: 3iiiDiv] There is limited evidence regarding its efficacy and safety compared with standard prostatectomy and radiation therapy, and the technique is evolving in an attempt to reduce local toxicity and normal tissue damage. The quality of evidence on efficacy is low, currently limited to case series of relatively small size, short follow-up, and surrogate outcomes of efficacy.[ 120 ]

Serious toxic effects associated with cryosurgery include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. Impotence is common, ranging from about 47% to 100%.

The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[ 118 ][ 119 ] Other major complications include urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.[ 120 ]

Proton-beam therapy

There is interest in the use of proton-beam therapy for the treatment of prostate cancer. Although the dose distribution of this form of charged-particle radiation could theoretically improve the therapeutic ratio of prostate radiation, allowing for an increase in dose to the tumor without a substantial increase in side effects, no randomized controlled trials have been reported that compare its efficacy and toxicity with those of other forms of radiation therapy.

Photodynamic therapy

Vascular-targeted photodynamic therapy using a photosensitizing agent has been tested in men with low-risk prostate cancer.[ 121 ]

Neoadjuvant hormonal therapy

The role of neoadjuvant hormonal therapy is not established.[ 26 ][ 27 ]

Bicalutamide

Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer.

Evidence (bicalutamide):

  1. The Early Prostate Cancer program is a large, randomized, placebo-controlled, international trial that compared bicalutamide (150 mg PO qd) plus standard care (radical prostatectomy, radiation therapy, or watchful waiting, depending on local custom) with standard care alone for men with nonmetastatic localized or locally advanced prostate cancer (T1–2, N0, and NX; T3–4, any N; or any T, N+). Less than 2% of the 8,113 men had known nodal disease.[ 122 ][Level of evidence: 1iA]

Information about ongoing clinical trials is available from the NCI website.

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  74. Dearnaley D, Syndikus I, Mossop H, et al.: Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 17 (8): 1047-60, 2016.[PUBMED Abstract]
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  85. Hamilton AS, Stanford JL, Gilliland FD, et al.: Health outcomes after external-beam radiation therapy for clinically localized prostate cancer: results from the Prostate Cancer Outcomes Study. J Clin Oncol 19 (9): 2517-26, 2001.[PUBMED Abstract]
  86. Nieder AM, Porter MP, Soloway MS: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180 (5): 2005-9; discussion 2009-10, 2008.[PUBMED Abstract]
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  88. Nam RK, Cheung P, Herschorn S, et al.: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol 15 (2): 223-31, 2014.[PUBMED Abstract]
  89. Incrocci L, Koper PC, Hop WC, et al.: Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study. Int J Radiat Oncol Biol Phys 51 (5): 1190-5, 2001.[PUBMED Abstract]
  90. Pisansky TM, Pugh SL, Greenberg RE, et al.: Tadalafil for prevention of erectile dysfunction after radiotherapy for prostate cancer: the Radiation Therapy Oncology Group [0831] randomized clinical trial. JAMA 311 (13): 1300-7, 2014.[PUBMED Abstract]
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  95. Green N, Treible D, Wallack H, et al.: Prostate cancer--the impact of irradiation on urinary outlet obstruction. Br J Urol 70 (3): 310-3, 1992.[PUBMED Abstract]
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  100. Fizazi K, Tran N, Fein L, et al.: Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 377 (4): 352-360, 2017.[PUBMED Abstract]
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Stage I Prostate Cancer Treatment

Overview

Stage I prostate cancer is defined by the American Joint Committee on Cancer's TNM (tumor, node, metastasis) classification system:[ 1 ]

The frequency of clinically silent, nonmetastatic prostate cancer that can be found at autopsy greatly increases with age and may be as high as 50% to 60% in men aged 90 years and older. Undoubtedly, the incidental discovery of these occult cancers at prostatic surgery performed for other reasons accounts for the similar survival of men with stage I prostate cancer, compared with the normal male population, adjusted for age.

Many stage I cancers are well differentiated and only focally involve the gland (T1a, N0, M0); most require no treatment other than careful follow-up.[ 2 ]

In younger patients (aged 50–60 years) whose expected survival is long, treatment should be considered.[ 3 ] Radical prostatectomy, external-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and watchful waiting and active surveillance/active monitoring yield apparently similar survival rates in noncontrolled, selected series. The decision to treat should be made in the context of the patient’s age, associated medical illnesses, and personal desires.[ 3 ]

Standard Treatment Options for Stage I Prostate Cancer

Standard treatment options for patients with stage I prostate cancer include the following:

  1. Watchful waiting or active surveillance/active monitoring.
  2. Radical prostatectomy.
  3. External-beam radiation therapy (EBRT).
  4. Interstitial implantation of radioisotopes.

Watchful waiting or active surveillance/active monitoring

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[ 4 ][ 5 ][ 6 ] Watch and wait, observation, expectant management, and active surveillance/active monitoring are terms indicating a strategy that does not employ immediate therapy with curative intent. (Refer to the Watchful Waiting or Active Surveillance/Active Monitoring section in the Treatment Option Overview for Prostate Cancer section of this summary for more information.)

Evidence (observation with delayed hormonal therapy):

  1. In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormonal therapy given at the time of symptomatic disease progression.

Radical prostatectomy

Radical prostatectomy, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency) is the most commonly applied therapy with curative intent.[ 7 ][ 8 ][ 9 ] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP).

Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Consideration may also be given to postoperative radiation therapy (PORT) for patients who are found to have seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[ 10 ][ 11 ][ 12 ] Because duration of follow-up in available studies is still relatively short, the value of PORT is yet to be determined; however, PORT does reduce local recurrence.[ 10 ] Careful treatment planning is necessary to avoid morbidity.

Evidence (radical prostatectomy followed by radiation therapy):

  1. In a randomized trial of 425 men with pathologic T3, N0, and M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[ 11 ][Level of evidence: 1iiA]
  2. Another randomized trial came to a different conclusion with respect to the effect of postoperative radiation therapy on OS.[ 13 ][Level of evidence: 1iiA] In the European Organization for Research and Treatment of Cancer (EORTC) trial (EORTC-22911 [NCT00002511]), 1,005 men aged 75 years and younger with clinical T0 to T3 prostate cancer were randomly assigned after prostatectomy to receive PORT (60 Gy) or observation, with subsequent therapy delayed until the occurrence of either biochemical or clinical relapse. The recommended treatment for local recurrence was radiation.

Radical prostatectomy has been compared with watchful waiting or active surveillance/active monitoring. (Refer to the Radical prostatectomy compared with other treatment options section in the Treatment Option Overview for Prostate Cancer section of this summary for more information about radical prostatectomy compared with watchful waiting or active surveillance/active monitoring.)

Evidence (radical prostatectomy compared with watchful waiting):

  1. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407 [NCT00007644]) is a randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/mL) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[ 14 ][ 15 ][ 16 ][Levels of evidence: 1iiA, 1iiB]

External-beam radiation therapy (EBRT)

EBRT is another treatment option used with curative intent.[ 17 ][ 18 ][ 19 ][ 20 ][ 21 ] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture.[ 22 ] Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.[ 23 ][ 24 ]

Evidence (EBRT with or without adjuvant hormonal therapy):

  1. Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[ 25 ][Level of evidence: 1iiA]
  2. RTOG-9413 (RTOG-9413 [NCT00769548]) trial.[ 26 ]; [ 27 ][Level of evidence: 1iiDiii]
  3. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of a luteinizing hormone-releasing hormone agonist plus long-term flutamide (250 mg PO tid) with or without EBRT.[ 24 ][Level of evidence: 1iiA]

Interstitial implantation of radioisotopes

Interstitial implantation of radioisotopes (i.e., iodine I 125 [125I], palladium, and iridium Ir 192) done through a transperineal technique with either ultrasound or computed-tomography guidance, is being used in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[ 28 ][ 29 ]; [ 30 ][Level of evidence: 3iiiDiv]

Factors for consideration in the use of interstitial implants include the following:

Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with 125I has been associated with an increased local failure and complication rate [ 31 ][ 32 ] and is now rarely done.

Treatment Options Under Clinical Evaluation for Stage I Prostate Cancer

Treatment options under clinical evaluation for patients with stage I prostate cancer include the following:

  1. High-intensity focused ultrasound therapy.[ 33 ][ 34 ][ 35 ][ 36 ]
  2. Photodynamic therapy.

Photodynamic therapy

Vascular-targeted photodynamic therapy using a photosensitizing agent has been tested in men with low-risk prostate cancer. In the CLIN1001 PCM301 (NCT01310894) randomized trial, 413 men with low-risk cancer (tumor stage T1–T2c, PSA ≤10 ng/mL, generally Gleason score 3 + 3) were randomly assigned in an open-label trial to receive either the photosensitizing agent, padeliporfin (4 mg/kg intravenously [IV] over 10 minutes, and optical fibers inserted into the target area of the prostate, then activated by 753 nm laser light at 150 mW/cm for 22 minutes 15 seconds), or active surveillance.[ 37 ] Median time to local disease progression was 28.3 months for patients receiving padeliporfin and 14.1 months for patients who were assigned to active surveillance (HR, 0.34; 95% CI, 0.24–0.46; P < .0001).[ 37 ][Level of evidence: 1iiDiii] However, the appropriate population for photodynamic therapy may be quite narrow, as it may overtreat men with very low-risk disease and undertreat men with higher-risk disease.[ 38 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  23. Seidenfeld J, Samson DJ, Aronson N, et al.: Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) (4): i-x, 1-246, I1-36, passim, 1999.[PUBMED Abstract]
  24. Widmark A, Klepp O, Solberg A, et al.: Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 373 (9660): 301-8, 2009.[PUBMED Abstract]
  25. Asbell SO, Martz KL, Shin KH, et al.: Impact of surgical staging in evaluating the radiotherapeutic outcome in RTOG #77-06, a phase III study for T1BN0M0 (A2) and T2N0M0 (B) prostate carcinoma. Int J Radiat Oncol Biol Phys 40 (4): 769-82, 1998.[PUBMED Abstract]
  26. Roach M, DeSilvio M, Lawton C, et al.: Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 21 (10): 1904-11, 2003.[PUBMED Abstract]
  27. Pollack A: A call for more with a desire for less: pelvic radiotherapy with androgen deprivation in the treatment of prostate cancer. J Clin Oncol 21 (10): 1899-901, 2003.[PUBMED Abstract]
  28. Wallner K, Roy J, Harrison L: Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 14 (2): 449-53, 1996.[PUBMED Abstract]
  29. D'Amico AV, Coleman CN: Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. J Clin Oncol 14 (1): 304-15, 1996.[PUBMED Abstract]
  30. Ragde H, Blasko JC, Grimm PD, et al.: Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 80 (3): 442-53, 1997.[PUBMED Abstract]
  31. Kuban DA, el-Mahdi AM, Schellhammer PF: I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 63 (12): 2415-20, 1989.[PUBMED Abstract]
  32. Fuks Z, Leibel SA, Wallner KE, et al.: The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 21 (3): 537-47, 1991.[PUBMED Abstract]
  33. Thüroff S, Chaussy C, Vallancien G, et al.: High-intensity focused ultrasound and localized prostate cancer: efficacy results from the European multicentric study. J Endourol 17 (8): 673-7, 2003.[PUBMED Abstract]
  34. Blana A, Murat FJ, Walter B, et al.: First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol 53 (6): 1194-201, 2008.[PUBMED Abstract]
  35. Ficarra V, Novara G: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1201-2, 2008.[PUBMED Abstract]
  36. Eastham JA: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1202-3, 2008.[PUBMED Abstract]
  37. Azzouzi AR, Vincendeau S, Barret E, et al.: Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol 18 (2): 181-191, 2017.[PUBMED Abstract]
  38. Freedland SJ: Low-risk prostate cancer: to treat or not to treat. Lancet Oncol 18 (2): 156-157, 2017.[PUBMED Abstract]
Stage II Prostate Cancer Treatment

Overview

Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM (tumor, node, metastasis) classification system:[ 1 ]

Stage IIA

Stage IIB

Stage IIC

Radical prostatectomy, external-beam radiation therapy (EBRT), and interstitial implantation of radioisotopes are each employed in the treatment of stage II prostate cancer with apparently similar therapeutic effects. Radical prostatectomy and radiation therapy yield apparently similar survival rates with as many as 10 years of follow-up. For well-selected patients, radical prostatectomy is associated with a 15-year survival comparable with an age-matched population without prostate cancer.[ 2 ] Unfortunately, randomized comparative trials of these treatment methods with prolonged follow-up are lacking.

Patients with a small, palpable cancer (T2a, N0, and M0) fare better than patients in whom the disease involves both sides of the gland (T2c, N0, and M0). Patients proven free of node metastases by pelvic lymphadenectomy fare better than patients in whom this staging procedure is not performed; however, this is the result of selection of patients who have a more favorable prognosis.

Side effects of the various forms of therapy—including impotence, incontinence, and bowel injury—should be considered in determining the type of treatment to employ.

Prostate-specific antigen (PSA) changes as markers of tumor progression

Often, changes in PSA are thought to be markers of tumor progression. Even though a tumor marker or characteristic may be consistently associated with a high risk of prostate cancer progression or death, it may be a very poor predictor of very limited utility in making therapeutic decisions.

Baseline PSA and rate of PSA change were associated with subsequent metastasis or prostate cancer death in a cohort of 267 men with clinically localized prostate cancer who were managed by watchful waiting or active surveillance in the control arm of a randomized trial comparing radical prostatectomy with watchful waiting.[ 3 ][ 4 ] Nevertheless, the accuracy of classifying men into groups whose cancer remained indolent versus those whose cancer progressed was poor at all examined cut points of PSA or PSA rate of change.

Bisphosphonates and risk of bone metastases

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases. Bisphosphonates are being studied as a strategy to decrease this risk.

Evidence (bisphosphonates and risk of bone metastases):

  1. A placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg qd) had no favorable impact on either time to symptomatic bone metastasis or survival.[ 5 ][Level of evidence: 1iA]

Standard Treatment Options for Stage II Prostate Cancer

Standard treatment options for patients with stage II prostate cancer include the following:

  1. Watchful waiting or active surveillance/active monitoring.
  2. Radical prostatectomy.
  3. External-beam radiation therapy (EBRT) with or without hormonal therapy.
  4. Interstitial implantation of radioisotopes.

Watchful waiting or active surveillance/active monitoring

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[ 6 ][ 7 ][ 8 ] Watch and wait, observation, expectant management, and active surveillance/active monitoring are terms indicating a strategy that does not employ immediate therapy with curative intent. (Refer to the Treatment Option Overview for Prostate Cancer section of this summary for more information).

Evidence (observation with delayed hormonal therapy):

  1. In a retrospective pooled analysis, 828 men with clinically localized prostate cancer were managed by initial conservative therapy with subsequent hormonal therapy given at the time of symptomatic disease progression.[ 6 ]

Radical prostatectomy

Radical prostatectomy, usually with pelvic lymphadenectomy (with or without the nerve-sparing technique designed to preserve potency) is the most commonly applied therapy with curative intent.[ 2 ][ 9 ][ 10 ] Radical prostatectomy may be difficult after a transurethral resection of the prostate (TURP).

Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Consideration may also be given to postoperative radiation therapy (PORT) for patients who are found to have seminal vesicle invasion by tumor at the time of prostatectomy or who have a detectable level of PSA more than 3 weeks after surgery.[ 11 ][ 12 ][ 13 ] Because the duration of follow-up in available studies is relatively short, the value of PORT is yet to be determined; however, PORT does reduce local recurrence.[ 11 ] Careful treatment planning is necessary to avoid morbidity.

Evidence (radical prostatectomy followed by radiation therapy):

  1. In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[ 12 ][Level of evidence: 1iiA]

Evidence (radical prostatectomy compared directly with watchful waiting/active surveillance/active monitoring and/or external-beam radiation therapy):

  1. In a randomized clinical trial performed in Sweden in the pre-PSA screening era, 695 men with prostate cancer were randomly assigned to radical prostatectomy versus watchful waiting. Only about 5% of the men in the trial had been diagnosed by PSA screening. Therefore, the men had more extensive local disease than is typically the case in men diagnosed with prostate cancer in the United States.[ 14 ][ 15 ][ 16 ]
  2. The Prostate Intervention Versus Observation Trial (PIVOT-1 or VA-CSP-407) is a randomized trial conducted in the PSA screening era that directly compared radical prostatectomy with watchful waiting. From November 1994 through January 2002, 731 men aged 75 years or younger with localized prostate cancer (stage T1–2, NX, M0, with a blood PSA <50 ng/mL) and a life expectancy of at least 10 years were randomly assigned to radical prostatectomy versus watchful waiting.[ 17 ][ 18 ][ 19 ][Levels of evidence: 1iiA, 1iiB]
  3. In the ProtecT trial (NCT02044172 and ISRCTN20141297), 82,429 men were screened with PSA testing, and 2,664 were diagnosed with clinically localized prostate cancer, of whom 1,643 (median age 62 years, range 50-69 years) consented to a randomly assigned comparison of active monitoring, radical prostatectomy (nerve-sparing when possible), or external-beam 3D conformal radiation (74 Gy in 37 fractions). The primary endpoint was prostate cancer-specific mortality.[ 20 ]
    1. With a median follow-up of 10 years, there were a total of 17 deaths from prostate cancer, with no statistically significant differences among the three study arms (P = .48). The 10-year prostate cancer–specific survival rates were 98.8% in the active monitoring arm, 99.0% in the radical prostatectomy arm, and 99.6% radiation therapy arms.[ 20 ][Level of evidence: 1iiA]
    2. Likewise, all-cause mortality was nearly identical in all three study arms: 10.9 deaths in the active monitoring arm, 10.1 in the radical prostatectomy arm, and 10.3 in the radiation therapy arm per 1,000 person-years (P = .87).[ 20 ][Level of evidence: 1iiA]
    3. There were statistically significant differences in progression to metastatic disease among the treatment arms (active monitoring, 33/545; radical prostatectomy, 13/553; radiation therapy, 16/545) that began to emerge after 4 years, but these differences had not translated into any difference in mortality by the 10-year follow-up. Over the course of 10 years, 52% of the patients required active intervention.
    4. As expected, there were substantial differences in patient-reported outcomes among the three management approaches.[ 21 ][Level of evidence: 1iiC] A substudy of patient-reported outcomes up to 6 years after randomization included the following:

External-beam radiation therapy (EBRT) with or without hormonal therapy

EBRT is another treatment option often used with curative intent.[ 22 ][ 23 ][ 24 ][ 25 ][ 26 ] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce the incidence of stricture.[ 27 ] Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.[ 28 ]

The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality). Most patients had more advanced disease, but patients with bulky T2b to T2c tumors were included in the studies that were re-evaluating the role of adjuvant hormonal therapy in patients with locally advanced disease.

Evidence (EBRT with or without adjuvant hormonal therapy):

  1. The Radiation Therapy Oncology Group's (RTOG) trial 7706 (RTOG-7706).[ 29 ][Level of evidence: 1iiA]
  2. RTOG-9413 (RTOG-9413 [NCT00769548]) trial.[ 30 ][ 31 ][Level of evidence: 1iiDiii]
  3. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of a luteinizing hormone-releasing hormone (LH-RH) agonist plus long-term flutamide (250 mg PO tid) with or without EBRT.[ 32 ][Level of evidence 1iiA]
  4. Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) with ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial, NCIC CTG PR.3/MRC UKPRO7 [NCT00002633], from the National Cancer Institute of Canada randomly assigned 1,205 patients with high-risk (PSA >40 ng/mL or PSA >20 ng/mL and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[ 33 ][ 34 ][Level of evidence; 1iiA]
  5. A meta-analysis of randomized clinical trial evidence comparing radiation therapy with radiation therapy plus prolonged androgen suppression has been published. The meta-analysis found a difference in 5-year OS in favor of radiation therapy plus continued androgen suppression (LH-RH agonist or orchiectomy) as compared with radiation therapy alone (HR, 0.631; 95% CI, 0.479–0.831).[ 28 ][Level of evidence: 1iiA]
  6. In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[ 36 ][Levels of evidence: 1iiA, 1iiB] In a multicenter trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions plus a total of either 18 or 36 months of goserelin acetate.
  7. A meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) to deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality for patients receiving early treatment (RR, 0.86; 95% CI, 0.82–0.91).[ 37 ][Level of evidence: 1iiA]
  8. Short-term neoadjuvant−androgen therapy administered before and during radiation therapy has shown benefit in at least some patients with clinically localized prostate cancer. In an open-label, randomized trial (RTOG-9408 [NCT00002597]), 1,979 men with nonmetastatic stage T1b–c, T2a, or T2b tumors and a PSA level of 20 ng/mL or less were randomly assigned to receive radiation therapy (66.6 Gy prostate dose in 1.8 Gy daily fractions) with or without 4 months of ADT (flutamide 250 mg PO tid plus either monthly goserelin 3.6 mg subcutaneously (SQ) or leuprolide 7.5 mg intramuscularly), beginning 2 months before radiation therapy. Median follow-up was about 9 years.[ 38 ][Level of evidence: 1iiA]
  9. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes).[ 39 ] In an open-label design, patients were randomly assigned to receive radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[ 39 ][Level of evidence: 1iiA]
  10. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant–androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[ 40 ][Levels of evidence: 1iiA and 1iiB]
  11. Addition of androgen suppression therapy to EBRT may benefit men who are at an elevated risk of disease recurrence and death from prostate cancer (RTOG-9202 [NCT00767286]).

3-dimensional (3D) conformal radiation therapy

EBRT designed to decrease exposure of normal tissues using methods such as computed tomography (CT)–based 3D conformal treatment planning is under clinical evaluation.[ 41 ]

Interstitial implantation of radioisotopes

Interstitial implantation of radioisotopes (i.e., iodine I 125 [125I], palladium, and iridium), using a transperineal technique with either ultrasound or CT guidance, is being done in patients with T1 or T2a tumors. Short-term results in these patients are similar to those for radical prostatectomy or EBRT.[ 42 ][ 43 ]; [ 44 ][Level of evidence: 3iiiDiv]

Factors for consideration in the use of interstitial implants include the following:

Long-term follow-up of these patients is necessary to assess treatment efficacy and side effects.

Retropubic freehand implantation with 125I has been associated with an increased local failure and complication rate [ 45 ][ 46 ] and is now rarely done.

Treatment Options Under Clinical Evaluation for Stage II Prostate Cancer

Treatment options under clinical evaluation for patients with stage II prostate cancer include the following:

  1. Ultrasound-guided percutaneous cryosurgery.
  2. High-intensity focused ultrasound.
  3. Proton-beam radiation therapy.
  4. Photodynamic therapy.
  5. Other clinical trials.

Ultrasound-guided percutaneous cryosurgery

Cryosurgery is a surgical technique that involves destruction of prostate cancer cells by intermittent freezing of the prostate with cryoprobes followed by thawing.[ 47 ][Level of evidence: 3iiiC]; [ 48 ][ 49 ][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include:

The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[ 48 ][ 49 ]

High-intensity focused ultrasound

High-intensity focused ultrasound has been reported in case series to produce good local disease control. However, it has not been directly compared with more standard therapies, and experience with it is more limited.[ 50 ][ 51 ][ 52 ]

Proton-beam radiation therapy

There is growing interest in the use of proton-beam radiation therapy for the treatment of prostate cancer. Although the dose distribution of this form of charged-particle radiation has the potential to improve the therapeutic ratio of prostate radiation, allowing for an increase in dose to the tumor without a substantial increase in side effects, no randomized controlled trials have been reported that compare its efficacy and toxicity with those of other forms of radiation therapy.

Photodynamic therapy

Vascular-targeted photodynamic therapy using a photosensitizing agent has been tested in men with low-risk prostate cancer. In the CLIN1001 PCM301 (NCT01310894) randomized trial, 413 men with low-risk cancer (tumor stage T1–T2c, PSA ≤10 ng/mL, generally Gleason score 3 + 3) were randomly assigned in an open-label trial to receive either the photosensitizing agent, padeliporfin (4 mg/kg IV over 10 minutes, and optical fibers inserted into the target area of the prostate, then activated by 753 nm laser light at 150 mW/cm for 22 minutes 15 seconds), or active surveillance.[ 53 ] Median time to local disease progression was 28.3 months for patients receiving padeliporfin and 14.1 months for patients who were under active surveillance (HR, 0.34; 95% CI, 0.24–0.46; P < .0001).[ 53 ][Level of evidence: 1iiDiii] However, the appropriate population for photodynamic therapy may be quite narrow, as it may overtreat men with very low-risk disease and undertreat men with higher-risk disease.[ 54 ]

Other clinical trials

Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy, are ongoing.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  45. Kuban DA, el-Mahdi AM, Schellhammer PF: I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 63 (12): 2415-20, 1989.[PUBMED Abstract]
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  47. Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999.[PUBMED Abstract]
  48. Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002.[PUBMED Abstract]
  49. Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002.[PUBMED Abstract]
  50. Blana A, Murat FJ, Walter B, et al.: First analysis of the long-term results with transrectal HIFU in patients with localised prostate cancer. Eur Urol 53 (6): 1194-201, 2008.[PUBMED Abstract]
  51. Ficarra V, Novara G: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1201-2, 2008.[PUBMED Abstract]
  52. Eastham JA: Editorial comment on: first analysis of the long-term results with transrectal HIFU in patients with localized prostate cancer. Eur Urol 53 (6): 1202-3, 2008.[PUBMED Abstract]
  53. Azzouzi AR, Vincendeau S, Barret E, et al.: Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol 18 (2): 181-191, 2017.[PUBMED Abstract]
  54. Freedland SJ: Low-risk prostate cancer: to treat or not to treat. Lancet Oncol 18 (2): 156-157, 2017.[PUBMED Abstract]
Stage III Prostate Cancer Treatment

Overview

Stage III prostate cancer is defined by the American Joint Committee on Cancer's TNM (tumor, node, metastasis) classification system:[ 1 ]

Stage IIIA

Stage IIIB

Stage IIIC

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

External-beam radiation therapy (EBRT), interstitial implantation of radioisotopes, and radical prostatectomy are used to treat stage III prostate cancer.[ 2 ] Prognosis is greatly affected by whether regional lymph nodes are evaluated and proven not to be involved.

EBRT using a linear accelerator is the most common treatment for patients with stage III prostate cancer, and large series support its success in achieving local disease control and disease-free survival (DFS).[ 3 ][ 4 ] The results of radical prostatectomy in stage III patients are greatly inferior compared with results in patients with stage II cancer. Interstitial implantation of radioisotopes is technically difficult in large tumors.

The patient’s symptoms related to cancer, age, and coexisting medical illnesses should be considered before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.[ 4 ]

Standard Treatment Options for Stage III Prostate Cancer

Standard treatment options for patients with stage III prostate cancer include the following:

  1. External-beam radiation therapy (EBRT) with or without hormonal therapy.
  2. Hormonal manipulations (with or without radiation therapy).
  3. Radical prostatectomy with or without EBRT.
  4. Watchful waiting or active surveillance/active monitoring.

External-beam radiation therapy (EBRT) with or without hormonal therapy

EBRT alone,[ 3 ][ 4 ][ 5 ][ 6 ][ 7 ] luteinizing hormone-releasing hormone (LH-RH) agonist, or orchiectomy, in addition to EBRT, should be considered.[ 8 ][ 9 ][ 10 ][ 11 ][ 12 ][ 13 ][ 14 ][ 15 ][ 16 ] Definitive radiation therapy should be delayed until 4 to 6 weeks after transurethral resection to reduce the incidence of stricture.[ 17 ]

Hormonal therapy should be considered in conjunction with radiation therapy especially in men who do not have underlying moderate or severe comorbidities.[ 8 ][ 9 ] Several studies have investigated its utility in patients with locally advanced disease.

Evidence (EBRT with or without hormonal therapy):

  1. Although patients in the Radiation Therapy Oncology Group (RTOG) RTOG-9413 (NCT00769548) trial showed a 15% estimated risk of lymph node involvement and received whole-pelvic radiation therapy compared with prostate-only radiation therapy, overall survival (OS) and PSA failure rates were not significantly different.[ 18 ]; [ 19 ][Level of evidence: 1iiDiii]
  2. In a randomized trial, 875 men with locally advanced nonmetastatic prostate cancer (T1b–T2 moderately or poorly differentiated tumors; T3 tumors of any grade) were randomly assigned to receive 3 months of an LH-RH agonist plus long-term flutamide (250 mg PO tid) with or without EBRT. Nineteen percent of the men had tumor stage T2, and 78% of the men had stage T3.[ 20 ][Level of evidence; 1iiA]
  3. Another trial compared androgen deprivation therapy (ADT: an LH-RH agonist or orchiectomy) to ADT plus radiation therapy (65–69 Gy to the prostate by 4-field box technique, including 45 Gy to the whole pelvis, seminal vesicles, and external/internal iliac nodes unless the lymph nodes were known to be histologically negative). This trial (NCIC CTG PR.3/MRC UKPRO7 [NCT00002633]) from the National Cancer Institute of Canada, randomly assigned 1,205 patients with high-risk (PSA >40 ng/mL or PSA >20 ng/mL and Gleason score ≥8), T2 (12%–13% of the patients), T3 (83% of the patients), and T4 (4%–5% of the patients) with clinical or pathologically staged N0, M0 disease.[ 21 ][ 22 ][Level of evidence: 1iiA]
  4. The RTOG performed a prospective randomized trial (RTOG-8531) in patients with T3, N0, or any T, N1, M0 disease who received prostatic and pelvic radiation therapy and then were randomly assigned to receive immediate adjuvant goserelin or observation with administration of goserelin at time of relapse. In patients assigned to receive adjuvant goserelin, the drug was started during the last week of the radiation therapy course and was continued indefinitely or until signs of progression.[ 24 ][Level of evidence: 1iiA]
  5. A similar trial was performed by the European Organization for Research and Treatment of Cancer (EORTC). Patients with T1, T2 (World Health Organization grade 3), N0–NX or T3, T4, N0 disease were randomly assigned to receive either pelvic/prostate radiation therapy or identical radiation therapy and adjuvant goserelin (with cyproterone acetate for 1 month) starting with radiation therapy and continuing for 3 years. The 401 patients available for analysis were followed for a median of 9.1 years.[ 10 ][ 25 ][Levels of evidence: 1iiA, 1iiDii]
  6. The role of adjuvant hormonal therapy in patients with locally advanced disease has been analyzed by the Agency for Health Care Policy and Research (AHCPR; now the Agency for Healthcare Research and Quality). Randomized clinical trial evidence comparing radiation therapy with radiation therapy with prolonged androgen suppression (with an LH-RH agonist or orchiectomy) was evaluated in a meta-analysis. Most patients had more advanced disease, but patients with bulky T2b tumors were included in the study.[ 11 ][Level of evidence: 1iiA]
  7. Additionally, the RTOG did a study (RTOG-8610) in patients with bulky local disease (T2b, T2c, T3, or T4), with or without nodal involvement below the common iliac chain: 456 men were randomly assigned to receive either radiation therapy alone or radiation therapy with androgen ablation, which was started 8 weeks before radiation therapy and continued for 16 weeks. This trial assessed only short-term hormonal therapy, not long-term therapy, as the studies analyzed by the AHCPR did.[ 12 ][ 28 ]
  8. A subset analysis of the RTOG-8610 trial and the RTOG-8531 trial that involved 575 patients with T3, N0, M0 disease indicated that long-term hormones compared with short-term hormones resulted in improved biochemical DFS and cause-specific survival.[ 29 ]
  9. This finding was confirmed by RTOG-9202 (NCT00767286), which reported that radiation therapy plus 28 months of androgen deprivation resulted in longer 10-year disease-specific survival (23% vs. 13%; P < .0001) but not OS (53.9% vs. 51.6%; P = .36).[ 13 ]
  10. In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[ 30 ][Levels of evidence: 1iiA, 1iiB] In the trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions alone plus a total of either 18 or 36 months of goserelin acetate.
  11. Likewise, a meta-analysis of seven randomized controlled trials comparing early hormonal treatment (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated by prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality for patients receiving early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[ 31 ][Level of evidence: 1iiA]
  12. The duration of neoadjuvant hormonal therapy has been tested in a randomized trial (TROG 96.01 [ACTRN12607000237482]) involving 818 men with locally advanced (T2b, T2c, T3, and T4) nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional lymph nodes). In an open-label design, patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg subcutaneously each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[ 14 ][Level of evidence: 1iiA]
  13. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant–androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[ 32 ][Levels of evidence: 1iiA and 1iiB]

Hormonal manipulations (with or without radiation therapy)

Hormonal manipulations (orchiectomy or LH-RH agonists) may be used in the treatment of stage III prostate cancer.[ 33 ][Level of evidence: 1iiA]

Some data suggest that the efficacy of orchiectomy or LH-RH agonists may be enhanced by the addition of abiraterone acetate in men with locally advanced tumors. In the randomized, open-label, STAMPEDE trial (NCT00268476) trial, 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).[ 34 ] Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of the study participants.

Antiandrogen monotherapy has also been evaluated in men with locally advanced prostate cancer as an alternative to castration.

Evidence (nonsteroidal antiandrogen monotherapy vs. surgical or medical castration):

  1. A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[ 35 ] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[ 35 ][Level of evidence: 1iiA]

Evidence (orchiectomy vs. LH-RH agonist):

  1. In a randomized equivalence study involving 480 men with locally advanced (T3 and T4) disease, those who were treated with castration had a median OS of 70 months, whereas those treated with bicalutamide (150 mg qd) had a median OS of 63.5 months (HR,1.05; 95% CI, 0.81–1.36); these results failed to meet the prespecified criteria for equivalence.[ 36 ][Level of evidence: 1iiA]

Immediate versus deferred hormonal therapy

In patients who are not candidates for or who are unwilling to undergo radical prostatectomy or radiation therapy, immediate hormonal therapy has been compared with deferred treatment (i.e., watchful waiting or active surveillance/active monitoring with hormonal therapy at progression).

Evidence (immediate vs. deferred hormonal therapy):

  1. A randomized trial looked at immediate hormonal treatment (orchiectomy or LH-RH agonist) versus deferred treatment in men with locally advanced or asymptomatic metastatic prostate cancer.[ 33 ][Level of evidence: 1iiA]
  2. In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to receive bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[ 38 ][Level of evidence: 1iiA]
  3. In the EORTC-30891trial (NCT01819285), 985 patients newly diagnosed with prostate cancer, stage T0–4, N0–2, M0, and a median age of 73 years were randomly assigned to receive androgen deprivation, either immediately or on symptomatic disease progression. The study was designed to demonstrate the noninferiority of deferred treatment as compared with immediate treatment in relation to OS.[ 39 ][Level of evidence: 1iiA]

Continuous versus intermittent hormonal therapy

When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is usually given continuously until there is disease progression. Some investigators have proposed intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow tumor repopulation by hormone-sensitive cells. Theoretically, this strategy might provide tumor hormone responsiveness for a longer period. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.[ 40 ]

Evidence (continuous vs. intermittent hormonal therapy):

  1. A systematic review of 15 randomized trials that compared continuous androgen deprivation versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate–cancer-specific survival, reported in five of the trials (HR,1.02; 95% CI, 0.87–1.19); or progression-free survival, reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[ 41 ][Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

Radical prostatectomy with or without EBRT

Radical prostatectomy may be used with or without EBRT (in highly selected patients).[ 42 ] Because about 40% to 50% of men with clinically organ-confined disease are found to have pathologic extension beyond the prostate capsule or surgical margins, the role of postprostatectomy adjuvant radiation therapy has been studied.

Evidence (radical prostatectomy with or without EBRT):

  1. In a randomized trial of 425 men with pathologic T3, N0, M0 disease, postsurgical EBRT (60–64 Gy to the prostatic fossa over 30–32 fractions) was compared with observation.[ 43 ][ 44 ]

Watchful waiting or active surveillance/active monitoring

Careful observation without further immediate treatment may be used in the treatment of stage III prostate cancer.[ 48 ][ 49 ]

Asymptomatic patients of advanced age or with concomitant illness may warrant consideration of careful observation without immediate active treatment.[ 50 ][ 51 ][ 52 ] Watch and wait, observation, expectant management, and active surveillance/active monitoring are terms indicating a strategy that does not employ immediate therapy with curative intent. (Refer to the Treatment Option Overview for Prostate Cancer section of this summary for more information.)

Treatment of Symptoms

Because many stage III patients have urinary symptoms, control of symptoms is an important consideration in treatment. The following modalities may be used to improve local control of disease and subsequent symptoms:

  1. Radiation therapy.[ 3 ][ 4 ][ 5 ][ 6 ] EBRT designed to decrease exposure of normal tissues using methods such as computed tomography–based 3-dimensional conformal radiation therapy treatment planning is under clinical evaluation.
  2. Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:

    A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[ 53 ][Level of evidence: 1iiA]

  3. Palliative surgery (TURP).
  4. Interstitial implantation combined with EBRT is being used in selected T3 patients, but little information is available.[ 54 ]
  5. Alternative forms of radiation therapy are being employed in clinical trials. A randomized trial from the RTOG reported improved local control and survival with mixed-beam (neutron/photon) radiation therapy compared with standard photon radiation therapy.[ 55 ] A subsequent randomized study from the same group compared fast-neutron radiation therapy with standard photon radiation therapy. Local-regional control was improved with neutron treatment, but no difference in OS was seen, although follow-up was shorter in this trial. Fewer complications were seen with the use of a multileaf collimator.[ 56 ] Proton-beam radiation therapy is also under investigation.[ 57 ]
  6. Ultrasound-guided percutaneous cryosurgery is under clinical evaluation. Cryosurgery is a surgical technique under development that involves destruction of prostate cancer cells by intermittent freezing of the prostate with cryoprobes, followed by thawing.[ 58 ][Level of evidence: 3iiiC]; [ 59 ]; [ 60 ][Level of evidence: 3iiiDiv] Cryosurgery is less well established than standard prostatectomy, and long-term outcomes are not as well established as with prostatectomy or radiation therapy. Serious toxic effects include bladder outlet injury, urinary incontinence, sexual impotence, and rectal injury. The technique of cryosurgery is under development. Impotence is common. The frequency of other side effects and the probability of cancer control at 5 years' follow-up have varied among reporting centers, and series are small compared with surgery and radiation therapy.[ 59 ][ 60 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  53. Seidenfeld J, Samson DJ, Hasselblad V, et al.: Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132 (7): 566-77, 2000.[PUBMED Abstract]
  54. Blasko JC, Grimm PD, Ragde H: Brachytherapy and Organ Preservation in the Management of Carcinoma of the Prostate. Semin Radiat Oncol 3 (4): 240-249, 1993.[PUBMED Abstract]
  55. Laramore GE, Krall JM, Thomas FJ, et al.: Fast neutron radiotherapy for locally advanced prostate cancer. Final report of Radiation Therapy Oncology Group randomized clinical trial. Am J Clin Oncol 16 (2): 164-7, 1993.[PUBMED Abstract]
  56. Russell KJ, Caplan RJ, Laramore GE, et al.: Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys 28 (1): 47-54, 1994.[PUBMED Abstract]
  57. Shipley WU, Verhey LJ, Munzenrider JE, et al.: Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 32 (1): 3-12, 1995.[PUBMED Abstract]
  58. Robinson JW, Saliken JC, Donnelly BJ, et al.: Quality-of-life outcomes for men treated with cryosurgery for localized prostate carcinoma. Cancer 86 (9): 1793-801, 1999.[PUBMED Abstract]
  59. Donnelly BJ, Saliken JC, Ernst DS, et al.: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 60 (4): 645-9, 2002.[PUBMED Abstract]
  60. Aus G, Pileblad E, Hugosson J: Cryosurgical ablation of the prostate: 5-year follow-up of a prospective study. Eur Urol 42 (2): 133-8, 2002.[PUBMED Abstract]
Stage IV Prostate Cancer Treatment

Overview

Stage IV prostate cancer is defined by the American Joint Committee on Cancer's TNM (tumor, node, metastasis) classification system:[ 1 ]

Stage IVA

Stage IVB

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

Treatment selection depends on the following factors:

The most common symptoms originate from the urinary tract or from bone metastases. Palliation of symptoms from the urinary tract with transurethral resection of the prostate (TURP) or radiation therapy and palliation of symptoms from bone metastases with radiation therapy or hormonal therapy are an important part of the management of these patients. Bisphosphonates may also be used for the management of bone metastases.[ 2 ]

Standard Treatment Options for Stage IV Prostate Cancer

Standard treatment options for patients with stage IV prostate cancer include the following:

  1. Hormonal manipulations.
  2. Hormonal manipulations with chemotherapy.
  3. Bisphosphonates.
  4. External-beam radiation therapy (EBRT) with or without hormonal therapy.
  5. Palliative radiation therapy.
  6. Palliative surgery with TURP.
  7. Watchful waiting or active surveillance/active monitoring.

Hormonal manipulations

Hormonal treatment is the mainstay of therapy for metastatic prostate cancer. Cure is rarely, if ever, possible, but striking subjective or objective responses to treatment occur in most patients. The cornerstone of hormonal therapy for prostate cancer is medical or surgical castration to stop the production of testosterone by the testes. This is commonly referred to as androgen deprivation therapy (ADT) and can be achieved with bilateral orchiectomy or with administration of gonadotropin-releasing hormone (GnRH) agonists or antagonists. The most effective purely hormonal approach employs a combination of ADT and one of the following agents:

Randomized controlled trials have reported that combination therapy with any one of these drugs plus ADT results in longer overall survival than does ADT alone.

  1. In the randomized, double-blind LATITUDE (NCT01715285) trial, 1,199 men with high-risk metastatic castration-sensitive prostate cancer were given ADT plus either abiraterone acetate (1,000 mg PO qd) and prednisone (5 mg PO qd) or ADT plus abiraterone-prednisone placebos.[ 3 ] High-risk disease was defined as having at least two of the following three factors: Gleason score of 8 or higher, three or more bone lesions, or measurable visceral metastases.
  2. In the randomized, open-label STAMPEDE trial (NCT00268476), 1,917 men (about 95% newly diagnosed; about 50% had metastatic disease and about 50% had locally advanced or node-positive disease) were treated with ADT alone or ADT plus abiraterone acetate (1,000 mg PO qd) and prednisolone (5 mg PO qd).[ 5 ] Local radiation therapy was mandated after 6 to 9 months for men with node-negative nonmetastatic disease and optional for those with node-positive nonmetastatic disease. Hormone therapy was curtailed at 2 years or until progression. Radiation therapy was planned in about 40% of study participants.
  3. In the randomized, controlled, double-blind phase III TITAN trial (NCT02489318), 1,052 men with metastatic, castration-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus either apalutamide (240 mg PO qd) or placebo.[ 6 ]
  4. In the randomized, controlled, open-label phase III ENZAMET trial (NCT02446405), 1,125 men with castrate-sensitive prostate cancer were randomly assigned to receive ADT alone or ADT plus enzalutamide (160 mg PO qd).[ 7 ]
    1. Three-year OS was 80% in the combined-therapy arm compared to 72% in the ADT monotherapy arm (HR, 0.67; 95% CI, 0.52−0.86).
    2. PSA PFS (HR, 0.39, P < .001) and clinical PFS (HR = 0.40, P < .001) were also longer in the combined-therapy arm.
    3. Serious adverse events were reported in 42% of patients in the enzalutamide arm compared to 34% in the monotherapy arm.

Hormonal manipulations effectively used as initial therapy for prostate cancer include the following:[ 8 ]

In some series, pretreatment levels of PSA are inversely correlated with progression-free duration in patients with metastatic prostate cancer who receive hormonal therapy. After hormonal therapy is initiated, a PSA reduction to beneath a detectable level provides information regarding the duration of progression-free status; however, decreases in PSA of less than 80% may not be very predictive.[ 15 ]

Orchiectomy and estrogens yield similar results, and selection of one or the other depends on patient preference and the morbidity of expected side effects. Estrogens are associated with the development or exacerbation of cardiovascular disease, especially in high doses. DES at a dose of 1 mg qd is not associated with cardiovascular complications as frequent as those found at higher doses; however, the use of DES has decreased because of cardiovascular toxic effects.

The psychological implications of orchiectomy are objectionable to many patients, and many will choose an alternative therapy if effective.[ 16 ] Combined orchiectomy and estrogens are not indicated to be superior to either treatment administered alone.[ 17 ]

A large proportion of men experience hot flushes after bilateral orchiectomy or treatment with LH-RH agonists. These hot flashes can persist for years.[ 18 ] Varying levels of success in the management of these symptoms have been reported with DES, clonidine, cyproterone acetate, or medroxyprogesterone acetate.

After tumor progression on one form of hormonal manipulation, an objective tumor response to any other form is uncommon.[ 19 ] Some studies, however, suggest that withdrawal of flutamide (with or without aminoglutethimide administration) is associated with a decline in PSA and that one may need to monitor for this response before initiating new therapy.[ 20 ][ 21 ][ 22 ] Low-dose prednisone may palliate symptoms in about 33% of cases.[ 23 ] Newer hormonal approaches, such as inhibition of androgen receptors, have been shown to improve OS and quality of life (QOL) after tumor progression despite ADT. (Refer to the Recurrent Prostate Cancer section of this summary for more information.)

Immediate versus deferred hormonal therapy

Some patients may be asymptomatic and careful observation without further immediate therapy may be appropriate.

Evidence (immediate vs. deferred hormonal therapy):

  1. A meta-analysis of seven randomized controlled trials comparing early (adjuvant or neoadjuvant) with deferred hormonal treatment (LH-RH agonists and/or antiandrogens) in patients with locally advanced prostate cancer, whether treated with prostatectomy, radiation therapy, or watchful waiting or active surveillance/active monitoring, showed improved overall mortality with early treatment (relative risk, 0.86; 95% CI, 0.82–0.91).[ 24 ][Level of evidence: 1iiA]
  2. In a small, randomized trial of 98 men who underwent radical prostatectomy plus pelvic lymphadenectomy and were found to have nodal metastases (stage T1–2, N1, M0), immediate continuous hormonal therapy with the LH-RH agonist goserelin or with orchiectomy was compared with deferred therapy until documentation of disease progression.[ 25 ][Level of evidence: 1iA]; [ 26 ]
  3. Another trial (RTOG-8531) with twice as many randomly assigned patients showed no difference in OS with early versus late hormonal manipulation.[ 28 ]
  4. Immediate hormonal therapy with goserelin or orchiectomy has also been compared with deferred hormonal therapy for clinical disease progression in a randomized trial (EORTC-30846) of men with regional lymph node involvement but no clinical evidence of metastases (any T, N+, M0). None of the 234 men had a prostatectomy or prostatic radiation therapy.[ 29 ][Level of evidence; 1iiA]
  5. Immediate hormonal treatment (e.g., orchiectomy or LH-RH agonist) versus deferred treatment (e.g., watchful waiting with hormonal therapy at progression) was examined in a randomized study in men with locally advanced or asymptomatic metastatic prostate cancer.[ 30 ][Level of evidence: 1iiA]
  6. In another trial, 197 men with stage III or stage IV prostate cancer were randomly assigned to have a bilateral orchiectomy at diagnosis or at the time of symptomatic progression (or at the time of new metastases that were deemed likely to cause symptoms).[ 31 ][Level of evidence: 1iiA]

Luteinizing hormone-releasing hormone (LH-RH) agonists or antiandrogens

Approaches using LH-RH agonists or antiandrogens in patients with stage IV prostate cancer have produced response rates similar to other hormonal treatments.[ 9 ][ 32 ]

Evidence (LH-RH agonists or antiandrogens):

  1. In a randomized trial, the LH-RH agonist leuprolide (1 mg subcutaneously [SQ] qd) was found to be as effective as DES (3 mg PO qd) in any T, any N, M1 patients, but caused less gynecomastia, nausea and vomiting, and thromboembolisms.[ 10 ]
  2. In other randomized studies, the depot LH-RH agonist goserelin was found to be as effective as orchiectomy [ 11 ][ 33 ][ 34 ] or DES at a dose of 3 mg qd.[ 32 ] A depot preparation of leuprolide, which is therapeutically equivalent to daily leuprolide, is available as a monthly or 3-monthly depot.
  3. A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[ 35 ] Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[ 35 ][Level of evidence: 1iiA]
  4. A small randomized study comparing 1 mg DES PO tid with 250 mg of flutamide tid in patients with metastatic prostate cancer showed similar response rates with both regimens but superior survival with DES. More cardiovascular and/or thromboembolic toxic effects of borderline statistical significance were associated with DES treatment.[ 36 ][Level of evidence: 1iA] A variety of combinations of hormonal therapy have been tested.

Maximal androgen blockade (MAB)

On the basis that the adrenal glands continue to produce androgens after surgical or medical castration, case series studies were performed in which antiandrogen therapy was added to castration. Promising results from the case series led to widespread use of the strategy, known as MAB or total androgen blockade. Subsequent randomized controlled trials, however, cast doubt on the efficacy of adding an antiandrogen to castration.

Evidence (MAB):

  1. In a large, randomized, controlled trial comparing treatment with bilateral orchiectomy plus either the antiandrogen flutamide or placebo, no difference in OS was reported.[ 37 ][Level of evidence: 1iA]
  2. A meta-analysis of 27 randomized trials of 8,275 patients comparing conventional surgical or medical castration with MAB—castration plus prolonged use of an antiandrogen such as flutamide, cyproterone acetate, or nilutamide—did not show a statistically significant improvement in survival associated with MAB.[ 14 ][Level of evidence: 1iA]

    When trials of androgen suppression versus androgen suppression plus either nilutamide or flutamide were examined in a subset analysis, the absolute survival rate at 5 years was better for the combined-therapy group (2.9% better, 95% CI, 0.3–5.5); however, when trials of androgen suppression versus androgen suppression plus cyproterone acetate were examined, the absolute survival trend at 5 years was worse for the combined-therapy group (2.8% worse, 95% CI, -7.6 to +2.0).[ 14 ]

  3. The Agency for Health Care Policy and Research (now the Agency for Healthcare Research and Quality) has performed a systematic review of the available randomized, clinical trial evidence of single hormonal therapies and total androgen blockade performed by its Technology Evaluation Center, an evidence-based Practice Center of the Blue Cross and Blue Shield Association. A meta-analysis of randomized trials comparing various hormonal monotherapies in men with stage III or stage IV prostate cancer (predominantly stage IV) came to the following conclusions:[ 39 ][Level of evidence: 1iiA]

    Total androgen blockade was of no greater benefit than single hormonal therapy and with less patient tolerance. Also, the evidence was judged insufficient to determine whether men newly diagnosed with asymptomatic metastatic disease should have immediate androgen suppression therapy or should have therapy deferred until they have clinical signs or symptoms of progression.[ 40 ]

Continuous versus intermittent hormonal therapy

When used as the primary therapy for patients with stage III or stage IV prostate cancer, androgen suppression with hormonal therapy is often given continuously until there is disease progression. Another option is intermittent androgen suppression as a strategy to attain maximal tumor cytoreduction followed by a period without therapy to allow treatment-free periods. It was proposed that this strategy might provide tumor hormone responsiveness for a longer period. An animal model suggested that intermittent androgen deprivation (IAD) could prolong the duration of androgen dependence of hormone-sensitive tumors.[ 41 ] However, randomized controlled trials in humans have failed to support the hypothesis that IAD would delay the development of castration-resistant disease. If there are benefits from IAD, they appear to be in the realm of physical and sexual functioning.

Evidence (continuous vs. intermittent hormonal therapy):

  1. A systematic review of 15 randomized trials that compared continuous androgen deprivation therapy versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate cancer-specific survival, reported in five of the trials (HR,1.02; 95% CI, 0.87–1.19); or PFS, reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HRdeath, 1.15).[ 42 ][Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

Hormonal manipulations with chemotherapy

The addition of chemotherapy has been shown in randomized trials to improve OS compared with ADT alone, with efficacy that appears to be comparable with hormonal therapy, which includes ADT plus abiraterone acetate. However, the two approaches have not been directly compared in a randomized study.

The addition of docetaxel has been tested in combination with long-term hormone therapy in the first-line management of metastatic prostate cancer and has been shown to improve results more than hormone therapy alone. A systematic evidence review and meta-analysis of randomized trials in hormone-sensitive metastatic prostate cancer summarizes these data.[ 43 ]

Evidence (hormonal manipulations with chemotherapy):

  1. In the analysis of three randomized trials (3,206 men), the HRdeath associated with the addition of docetaxel to standard of care was 0.77 (95% CI, 0.68–0.87; P < .0001), representing an absolute improvement of 9% in 4-year survival (95% CI, 5–14).[ 43 ][Level of evidence: 1iiA]
  2. In the CHAARTED trial (NCT00309985), 790 patients with metastatic, hormone-sensitive disease were randomly assigned to receive ADT with or without docetaxel (75 mg/m2 intravenously [IV] every 3 weeks for 6 cycles).[ 44 ][ 45 ] Previous adjuvant ADT was permissible if it lasted 12 months or less and progression had occurred within 12 months of completion. Patients were prospectively stratified as having a high- versus low-volume disease, with high volume defined as presence of visceral metastases or at least four bone lesions, with at least one lying outside the vertebral column or pelvis. About 65% of patients had high-volume disease by this definition.

Bisphosphonates

In addition to hormonal therapy, adjuvant treatment with bisphosphonates has been tested.[ 47 ]

Evidence (bisphosphonates):

  1. In MRC-PR05, 311 men with bone metastases who were starting or responding to standard hormonal therapy were randomly assigned to oral sodium clodronate (2,080 mg qd) or a matching placebo for up to 3 years.[ 47 ][Level of evidence: 1iA]
  2. A parallel study (MRC-PR04) in men with locally advanced but nonmetastatic disease showed no benefit associated with clodronate.
  3. CALGB-90202 [NCT00079001] was a randomized controlled trial that compared zoledronic acid (4 mg IV every 4 weeks) with placebo in 645 men with androgen deprivation-sensitive prostate cancer that was metastatic to bone. Patients who progressed on hormone-therapy resistance received open-label, zoledronic acid.[ 48 ][Level of evidence: 1iDiii]
  4. In another negative randomized trial (STAMPEDE [NCT00268476]), 1,245 men with locally advanced (M0) or metastatic (M1) prostate cancer, who were initiating long-term hormonal therapy, were randomly assigned to one of three arms (ratio of 2:1:1): standard of care, celecoxib (400 mg bid for 1 year), and celecoxib plus zoledronic acid (4 mg IV for six 3-week cycles, then 4-week cycles for 2 years).[ 49 ]

Bisphosphonates and decreasing risk of bone metastases

Patients with locally advanced nonmetastatic disease (T2–T4, N0–N1, and M0) are at risk for developing bone metastases, and bisphosphonates are being studied as a strategy to decrease this risk. However, a placebo-controlled randomized trial (MRC-PR04) of a 5-year regimen of the first-generation bisphosphonate clodronate in high oral doses (2,080 mg qd) had no favorable impact on either time to symptomatic bone metastasis or survival.[ 50 ][Level of evidence: 1iA]

External-beam radiation therapy (EBRT) with or without hormonal therapy

EBRT may be used for attempted cure in highly selected stage M0 patients.[ 51 ][ 52 ] Definitive radiation therapy should be delayed 4 to 6 weeks after TURP to reduce incidence of stricture.[ 53 ]

Hormonal therapy should be considered in addition to EBRT.[ 40 ][ 54 ]

Evidence (radiation therapy with or without hormonal therapy):

  1. The Blue Cross and Blue Shield Association Technology Evaluation Center, an evidence-based practice center of the Agency for Healthcare Research and Quality (AHRQ), performed a systematic review of the available randomized clinical trial evidence comparing radiation therapy with radiation therapy and prolonged androgen suppression.[ 40 ][Level of evidence: 1iiA] Some patients with bulky T2b tumors were included in the studied groups.
  2. In a randomized, prospective clinical trial, 18 months of androgen suppression with an LH-RH agonist appears to have provided results that were similar to 36 months with respect to OS and disease-specific survival.[ 55 ][Levels of evidence: 1iiA, 1iiB] In the trial, 630 men with stage II to stage IVA cancer (clinical stage T3–T4, or PSA >20 ng/ml, or Gleason score >7) received 70 Gy of radiation in 35 fractions alone plus a total of either 18 or 36 months of goserelin acetate.
  3. The optimal duration of neoadjuvant hormonal therapy has been studied. In a randomized trial (TROG 96.01 [ACTRN12607000237482]) of 818 men with locally advanced (T2b, T2c, T3, and T4), nonmetastatic cancer treated with radiation therapy (i.e., 66 Gy in 2 Gy daily fractions to the prostate and seminal vesicles but not including regional nodes). Patients were randomly assigned to radiation therapy alone, 3 months of neoadjuvant androgen deprivation therapy (NADT) (goserelin 3.6 mg SQ each month plus flutamide 250 mg PO tid) for 2 months before and during radiation, or 6 months of NADT for 5 months before and during radiation.[ 54 ][Level of evidence: 1iiA]
  4. The duration of neoadjuvant hormonal therapy was tested in another trial (RTOG-9910 [NCT00005044]) of 1,489 eligible men with intermediate-risk prostate cancer (T1b–4, Gleason score 2–6, and PSA >10 but ≤100 ng/mL; T1b–4, Gleason score 7, and PSA <20; or T1b–1c, Gleason score 8–10, and PSA <20) and no evidence of metastases. The men were randomly assigned to receive short-course neoadjuvant–androgen suppression (an LH-RH agonist plus bicalutamide or flutamide for 8 weeks before and 8 weeks during radiation therapy) or long-course neoadjuvant-androgen suppression (28 weeks before and 8 weeks during radiation therapy). Both groups received 70.2 Gy radiation in 39 daily fractions to the prostate and 46.8 Gy to the iliac lymph nodes.[ 56 ][Levels of evidence: 1iiA and 1iiB]

Palliative radiation therapy

A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) as was evidenced in the RTOG-9714 (NCT00003162) trial.[ 57 ]; [ 58 ][Level of evidence: 1iiC] (Refer to the PDQ summary on Cancer Pain for more information.)

Palliative surgery with transurethral resection of the prostate (TURP)

Transurethral resection of the prostate may be useful in relieving urinary obstruction as part of palliative care in advanced prostate cancer.

Watchful waiting or active surveillance/active monitoring

Careful observation without further immediate treatment (in selected asymptomatic patients).[ 59 ]

Treatment Options Under Clinical Evaluation for Stage IV Prostate Cancer

Treatment options under clinical evaluation for patients with stage IV prostate cancer include the following:

  1. Radical prostatectomy with immediate orchiectomy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  40. Seidenfeld J, Samson DJ, Aronson N, et al.: Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) (4): i-x, 1-246, I1-36, passim, 1999.[PUBMED Abstract]
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  42. Magnan S, Zarychanski R, Pilote L, et al.: Intermittent vs Continuous Androgen Deprivation Therapy for Prostate Cancer: A Systematic Review and Meta-analysis. JAMA Oncol 1 (9): 1261-9, 2015.[PUBMED Abstract]
  43. Vale CL, Burdett S, Rydzewska LH, et al.: Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol 17 (2): 243-56, 2016.[PUBMED Abstract]
  44. Sweeney CJ, Chen YH, Carducci M, et al.: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med 373 (8): 737-46, 2015.[PUBMED Abstract]
  45. Kyriakopoulos CE, Chen YH, Carducci MA, et al.: Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol 36 (11): 1080-1087, 2018.[PUBMED Abstract]
  46. Morgans AK, Chen YH, Sweeney CJ, et al.: Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer. J Clin Oncol 36 (11): 1088-1095, 2018.[PUBMED Abstract]
  47. Dearnaley DP, Mason MD, Parmar MK, et al.: Adjuvant therapy with oral sodium clodronate in locally advanced and metastatic prostate cancer: long-term overall survival results from the MRC PR04 and PR05 randomised controlled trials. Lancet Oncol 10 (9): 872-6, 2009.[PUBMED Abstract]
  48. Smith MR, Halabi S, Ryan CJ, et al.: Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 32 (11): 1143-50, 2014.[PUBMED Abstract]
  49. Mason MD, Clarke NW, James ND, et al.: Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial. J Clin Oncol 35 (14): 1530-1541, 2017.[PUBMED Abstract]
  50. Mason MD, Sydes MR, Glaholm J, et al.: Oral sodium clodronate for nonmetastatic prostate cancer--results of a randomized double-blind placebo-controlled trial: Medical Research Council PR04 (ISRCTN61384873). J Natl Cancer Inst 99 (10): 765-76, 2007.[PUBMED Abstract]
  51. Bagshaw MA: External radiation therapy of carcinoma of the prostate. Cancer 45 (7 Suppl): 1912-21, 1980.[PUBMED Abstract]
  52. Ploysongsang S, Aron BS, Shehata WM, et al.: Comparison of whole pelvis versus small-field radiation therapy for carcinoma of prostate. Urology 27 (1): 10-6, 1986.[PUBMED Abstract]
  53. Seymore CH, el-Mahdi AM, Schellhammer PF: The effect of prior transurethral resection of the prostate on post radiation urethral strictures and bladder neck contractures. Int J Radiat Oncol Biol Phys 12 (9): 1597-600, 1986.[PUBMED Abstract]
  54. Denham JW, Steigler A, Lamb DS, et al.: Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial. Lancet Oncol 12 (5): 451-9, 2011.[PUBMED Abstract]
  55. Nabid A, Carrier N, Martin AG, et al.: Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol 74 (4): 432-441, 2018.[PUBMED Abstract]
  56. Pisansky TM, Hunt D, Gomella LG, et al.: Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910. J Clin Oncol 33 (4): 332-9, 2015.[PUBMED Abstract]
  57. Kaasa S, Brenne E, Lund JA, et al.: Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol 79 (3): 278-84, 2006.[PUBMED Abstract]
  58. Chow E, Harris K, Fan G, et al.: Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol 25 (11): 1423-36, 2007.[PUBMED Abstract]
  59. Stattin P, Holmberg E, Johansson JE, et al.: Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study. J Natl Cancer Inst 102 (13): 950-8, 2010.[PUBMED Abstract]
  60. Zincke H: Extended experience with surgical treatment of stage D1 adenocarcinoma of prostate. Significant influences of immediate adjuvant hormonal treatment (orchiectomy) on outcome. Urology 33 (5 Suppl): 27-36, 1989.[PUBMED Abstract]
Recurrent or Hormone-Resistant Prostate Cancer Treatment

Overview

In recurrent or hormone-resistant prostate cancer, the selection of further treatment depends on many factors, including the following:

Definitive radiation therapy can be given to patients with disease that fails only locally after prostatectomy.[ 1 ][ 2 ][ 3 ][ 4 ] A randomized trial (RTOG-9601 [NCT00002874]) has shown improved overall survival (OS) and prostate–cancer-specific survival with the addition of high-dose bicalutamide to radiation therapy compared with radiation therapy alone in men with locally recurrent prostate cancer after radical prostatectomy.[ 5 ]

Some patients with a local recurrence after definitive radiation therapy can be salvaged with prostatectomy;[ 6 ] however, only about 10% of patients treated initially with radiation therapy will have local relapse only. In these patients, prolonged disease control is often possible with hormonal therapy, with median cancer-specific survival of 6 years after local failure.[ 7 ]

Cryosurgical ablation of recurrence after radiation therapy is associated frequently with a high complication rate. This technique is still undergoing clinical evaluation.[ 8 ]

Hormonal therapy is used to manage most relapsing patients with disseminated disease who initially received locoregional therapy with surgery or radiation therapy. (Refer to the Standard Treatment Options for Stage IV Prostate Cancer section of this summary for more information.)

Immediate Versus Deferred Hormonal Therapy

Refer to the Treatment Option Overview for Prostate Cancer section for information on the use of immediate hormonal therapy (bicalutamide or luteinizing hormone-releasing hormone [LH-RH] agonists) plus radiation in the setting of locally recurrent prostate cancer after radical prostatectomy.

PSA is often used to monitor patients after initial therapy with curative intent, and elevated or rising PSA is a common trigger for additional therapy even in asymptomatic men. Despite how common the situation is, it is not clear whether additional treatments given because of rising PSA in asymptomatic men with prostate cancer increase OS. The quality of evidence is limited.

  1. After radical prostatectomy, detectable PSA levels identify patients at elevated risk of local treatment failure or metastatic disease;[ 9 ] however, a substantial proportion of patients with elevated or rising PSA levels after initial therapy with curative intent may remain clinically free of symptoms for extended periods.[ 10 ] In a retrospective analysis of nearly 2,000 men who had undergone radical prostatectomy with curative intent and who were followed for a mean of 5.3 years, 315 men (15%) demonstrated an abnormal PSA of 0.2 ng/mL or higher, which is evidence of biochemical recurrence.[ 11 ]
  2. After radiation therapy with curative intent, persistently elevated or rising PSA may be a prognostic factor for clinical disease recurrence. However, reported case series have used a variety of definitions of PSA failure. Criteria have been developed by the American Society for Therapeutic Radiology and Oncology Consensus Panel.[ 12 ][ 13 ] The implication of the various definitions of PSA failure for OS is not known, and as in the surgical series, many biochemical relapses (rising PSA alone) may not be clinically manifested in patients treated with radiation therapy.[ 14 ][ 15 ]
  3. A randomized trial (PMCC-VCOG-PR-0103 [NCT00110162]) of androgen deprivation therapy (ADT) in men who received curative therapy but have a rising PSA, provides some evidence of improved OS associated with immediate versus delayed therapy.[ 16 ] The study had important shortcomings.
    1. Two groups of men were randomly assigned to open-label, immediate-versus-delayed (at least 2-year delay) ADT:

      Planned accrual was 750 patients, but because of slow accrual, the trial closed at 293 patients.

    2. In groups 1 and 2 combined, with a median follow-up of 5 years, the 5-year OS rate was 86.4% in the delayed ADT study arm versus 91.2% in the immediate ADT study arm (log rank, P = .047).[ 16 ][Level of evidence: 1iiA] After full adjustment for baseline characteristics, the HR for OS was 0.54 (95% CI, 0.27–1.06; P = .074).
    3. For group 1 only (those with PSA relapse after curative therapy, N = 261), the estimated 5-year survival rate was 78.2% versus 84.3% with delayed-versus-immediate ADT (log rank, P = .10; fully adjusted HR, = 0.59; 95% CI, 0.26–1.30, P = .19).
    4. Toxicity was greater in the immediate ADT study arm compared with delayed therapy. Serious (grade 4) adverse events were reported in 42% of patients in the immediate ADT study arm versus 31% of patients in the delayed therapy arm. Quality of life (QOL) fell by 6.1% (considered a small but clinically important drop) with immediate ADT versus 3% with delayed ADT (considered a trivial drop); but this was not a statistically significant difference (P = .14).[ 16 ] Sexual activity was lower and hormone-related symptoms (hot flashes and sore or enlarged nipples) were clinically and statistically significantly worse in the immediate ADT arm compared with the delayed therapy arm.[ 17 ]

Hormonal Therapy for Recurring Disease

Continuous versus intermittent hormonal therapy

Most men who are treated for recurrence after initial local therapy are asymptomatic, and the recurrence is detected by a rising PSA. It is possible that intermittent androgen deprivation (IAD) therapy can be used as an alternative to continuous androgen deprivation therapy (continuous ADT, or CAD) to improve QOL and decrease the amount of time during which the patient experiences the side effects of hormonal therapy, without decreasing the survival rate.

  1. This important clinical question was addressed in a noninferiority-designed, randomized, controlled trial with 1,386 men who had rising PSA levels (>3 ng/mL, with serum testosterone >5 nmol/L) more than 1 year after primary or salvage radiation therapy for localized prostate cancer.[ 18 ][Levels of evidence: 1iiA, 1iiB, 1iiC]
  2. A systematic review of 15 randomized trials that compared CAD versus IAD therapy for patients with advanced or recurrent prostate cancer found no significant difference in OS, which was reported in eight of the trials (HR, 1.02; 95% CI, 0.93–1.11); prostate–cancer-specific survival, reported in five of the trials (HR, 1.02; 95% CI, 0.87–1.19); or progression-free survival (PFS), reported in four of the trials (HR, 0.94; 95% CI, 0.84–1.05). The meta-analysis fulfilled prespecified criteria for noninferiority of OS (upper bound of 1.15 for the HR of 1.15).[ 19 ][Level of evidence: 1iiA] However, of the 15 trials, all but one had an unclear or high risk of bias according to prespecified criteria.

Nonsteroidal antiandrogen monotherapy versus surgical or medical castration

A systematic evidence review compared nonsteroidal antiandrogen monotherapy with surgical or medical castration from 11 randomized trials in 3,060 men with locally advanced, metastatic, or recurrent disease after local therapy.[ 20 ] The use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[ 20 ][Level of evidence: 1iiA]

Hormonal approaches

As noted above, studies have shown that chemotherapy with docetaxel or cabazitaxel and immunotherapy with sipuleucel-T can prolong OS in patients with hormone-resistant metastatic prostate cancer. Nevertheless, hormonal therapy has also been shown to improve survival even in men who have progressed after other forms of hormonal therapy as well as chemotherapy. Some forms of hormonal therapy are effective in the management of metastatic hormone–refractory prostate cancer.

Because there are no head-to-head comparisons, there are no trials to help decide which of these agents should be used first or in what sequence they should be used.

Even among patients with metastatic hormone-refractory prostate cancer, some heterogeneity is found in prognosis and in retained hormone sensitivity. In such patients who have symptomatic bone disease, several factors are associated with worsened prognosis: poor performance status, elevated alkaline phosphatase, abnormal serum creatinine, and short (<1 year) previous response to hormonal therapy.[ 21 ] 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.[ 22 ]

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 ranged from 2 to 4 months.[ 23 ] Survival rates are similar whether ketoconazole plus hydrocortisone is initiated at the same time as antiandrogen (e.g., flutamide, bicalutamide, or nilutamide) withdrawal or when PSA has risen after an initial trial of antiandrogen withdrawal, as seen in the CLB-9583 trial (NCT00002760), for example.[ 24 ][Level of evidence: 1iiA] There are conflicting data on whether PSA changes in men undergoing chemotherapy are predictive of survival.[ 22 ][ 25 ]

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 (ECOG) showed that a superior survival resulted when patients were maintained on primary androgen deprivation;[ 9 ] however, another study from SWOG (formerly the Southwest Oncology Group) did not show an advantage to continued androgen blockade.[ 26 ]

Evidence (hormonal approaches for progressive disease with no previous chemotherapy):

  1. Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17). Abiraterone has mineralocorticoid effects, producing an increased incidence of fluid retention and edema, hypokalemia, hypertension, and cardiac dysfunction. In addition, abiraterone is associated with hepatotoxicity.[ 27 ] However, compared with other therapies, abiraterone toxicities are mild. In a double-blinded placebo-controlled trial, 1,088 men with progressing hormone refractory disease (serum testosterone <50 ng per deciliter on previous antiandrogen therapy), no previous chemotherapy, and ECOG performance status (PS) 0 to 1 were given prednisone (5 mg PO bid) plus either abiraterone acetate (1,000 mg PO qd) or placebo.[ 28 ][ 29 ][Level of evidence: 1iA] The coprimary endpoints were radiologic PFS and OS. Four sequential analyses were planned.
  2. Enzalutamide, an androgen-receptor signaling inhibitor, has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT. In the PREVAIL (NCT01212991) study, 1,717 asymptomatic or mildly symptomatic men with recurrent metastatic prostate cancer despite ADT were randomly assigned to receive enzalutamide (160 mg PO qd) versus placebo.[ 31 ][ 32 ][ 33 ][Levels of evidence: 1iA, 1iC]
  3. Enzalutamide has also been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[ 34 ]
  4. Continuing enzalutamide in patients who were switched to abiraterone because of progression, and who had castration-resistant metastatic prostate cancer and a rising PSA while receiving enzalutamide, did not appear to improve the rate of PFS or of clinical progression, a strategy that was tested in the randomized PLATO trial (NCT01995513).[ 35 ][Level of evidence: 1iDiii]
  5. Apalutamide, a competitive inhibitor of the androgen receptor, has been tested in the setting of clinically nonmetastatic, hormone-resistant prostate cancer (defined as PSA doubling time ≤10 months while undergoing hormonal therapy).[ 36 ]

Evidence (hormonal approaches for progressive disease with previous chemotherapy):

  1. Men with metastatic prostate cancer who had biochemical or clinical progression after treatment with docetaxel (N = 1,195) were randomly assigned in a 2:1 ratio to receive either abiraterone acetate (1,000 mg) (n = 797) or placebo (n = 398) by mouth every day (COU-AA-301 [NCT00638690]). Both groups received prednisone (5 mg PO bid).[ 38 ][Level of evidence; 1iA]
  2. Enzalutamide has also been shown to increase survival in patients with progressive prostate cancer who previously received ADT as well as docetaxel. In a double-blind, placebo-controlled trial, 1,129 men were randomly assigned in a 2:1 ratio to receive enzalutamide (160 mg PO qd) versus placebo.[ 40 ][ 41 ][ 42 ][ 43 ][Levels of evidence: 1iA, 1iC]

Prevention of bone metastases

Painful bone metastases can be a major problem for patients with prostate cancer. Many strategies have been studied for palliation, including the following:[ 44 ][ 45 ][ 46 ][ 47 ][ 48 ]

(Refer to the PDQ summary on Cancer Pain for more information.)

Evidence (palliation for bone metastases using radiation therapy):

  1. EBRT for palliation of bone pain can be very useful. A single fraction of 8 Gy has been shown to have similar benefits on bone pain relief and QOL as multiple fractions (3 Gy × 10) was seen in the RTOG-9714 trial (NCT00003162), for example.[ 49 ][ 50 ][Level of evidence: 1iiC]

Evidence (palliation for bone metastases using strontium chloride):

The use of radioisotopes such as 89Sr has been shown to be effective as palliative treatment of some patients with osteoblastic metastases. As a single agent, 89Sr has been reported to decrease bone pain in 80% of patients treated.[ 51 ]

  1. A multicenter randomized trial of a single IV dose of 89Sr (150 MBq: 4 mCi) versus palliative EBRT was done in men with painful bone metastases from prostate cancer despite hormone treatment.[ 52 ][Level of evidence: 1iiA]; [ 53 ]

Evidence (palliation or prevention of bone metastases using denosumab):

  1. A placebo-controlled randomized trial (NCT00321620) compared denosumab with zoledronic acid for the prevention of skeletal events (pathologic fractures, spinal cord compression, or the need for palliative bone radiation or surgery) in men with hormonal therapy-resistant prostate cancer with at least one bone metastasis.[ 44 ]
  2. A randomized, placebo-controlled trial included 1,432 men with castration-resistant prostate cancer with no evidence of any metastases who were given denosumab (120 mg administered subcutaneously every 4 weeks) to prevent the first evidence of bone metastasis (whether symptomatic or not).[ 54 ][Level of Evidence: 1iDiii]

Treatment Options for Recurrent Prostate Cancer

Treatment options for patients with recurrent prostate cancer include the following:

Chemotherapy for hormone-resistant prostate cancer

Evidence (chemotherapy for hormone-resistant prostate cancer):

  1. A randomized trial showed improved pain control in patients with hormone-resistant prostate cancer treated with mitoxantrone plus prednisone compared with those treated with prednisone alone.[ 55 ] Differences in OS or measured global QOL between the two treatments were not statistically significant.
  2. Docetaxel has been shown to improve OS compared with mitoxantrone. In a randomized trial involving patients with hormone-refractory prostate cancer, docetaxel (75 mg/m2 every 3 weeks) and docetaxel (30 mg/m2 weekly for 5 out of every 6 weeks) were compared with mitoxantrone (12 mg/m2 every 3 weeks). All patients received oral prednisone (5 mg bid). Patients in the docetaxel arms also received high-dose dexamethasone pretreatment for each docetaxel administration (8 mg given at 12 hours, 3 hours, and 1 hour before the 3-week regimen; 8 mg given at 1 hour before the 5 out-of-every-6 weeks' regimen).[ 56 ]
  3. In another randomized trial involving patients with hormone-refractory prostate cancer, a 3-week regimen of estramustine (280 mg PO tid for days 1 to 5, plus daily warfarin and 325 mg aspirin to prevent vascular thrombosis), and docetaxel (60 mg/m2 IV on day 2, preceded by dexamethasone [20 mg × 3 starting the night before]) was compared with mitoxantrone (12 mg/m2 IV every 3 weeks) plus prednisone (5 mg qd).[ 58 ][Level of evidence: 1iiA]
  4. A 2-weekly regimen of docetaxel has been compared with a 3-weekly regimen. OS appeared to be better in the 2-week regimen, and hematologic toxicity was less.[ 60 ][Level of evidence: 1iiA]
  5. In patients with metastatic hormone/castrate-refractory prostate cancer (mCRPC) and no previous chemotherapy, cabazitaxel and docetaxel appeared to provide similar results with respect to OS.[ 61 ]
  6. In patients with mCRPC whose disease progressed during or after treatment with docetaxel, cabazitaxel was shown to improve survival compared with mitoxantrone in a randomized trial (NCT00417079).[ 62 ] In this trial, 755 such men were treated with prednisone (10 mg PO qd) and randomly assigned to receive either cabazitaxel (25 mg/m2 IV) or mitoxantrone (12 mg/m2 IV) every 3 weeks.[ 62 ][Level of evidence; 1iiA]
  7. In a noninferiority-design randomized trial comparing cabazitaxel (20 mg/m2 IV every 3 weeks) with cabazitaxel (25 mg/m2 IV every 3 weeks) in a similar population of 1,200 men with mCRPC who had received previous docetaxel, the lower dose of cabazitaxel fulfilled noninferiority criteria with respect to OS (HRdeath, 1.024; CI, upper bound at 1.184), but with less toxicity.[ 63 ][Level of evidence; 1iiA]

Other chemotherapy regimens reported to produce subjective improvement in symptoms and reduction in PSA level include the following:[ 64 ][Level of evidence: 3iiiDiii]; [ 65 ]

A study suggests that patients whose tumors exhibit neuroendocrine differentiation are more responsive to chemotherapy.[ 66 ]

Immunotherapy

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

Side effects are generally consistent with cytokine release and include chills, fever, headache, myalgia, sweating, and influenza-like symptoms, usually within the first 24 hours of infusion. No increase in autoimmune disorders or secondary malignancies has been noted.[ 67 ]

Evidence (immunotherapy):

  1. In the largest trial (Immunotherapy for Prostate Adenocarcinoma Treatment: IMPACT trial [NCT00065442]), 512 patients with hormone-refractory metastatic disease were randomly assigned in a 2:1 ratio to receive sipuleucel-T (n = 341) versus placebo (n = 171) by IV in a 60-minute infusion every 2 weeks for a total of 3 doses.[ 68 ] Patients with visceral metastases, pathologic bone fractures, or ECOG performance status worse than 0–1 were excluded from the study. At documented disease progression, patients in the placebo group could receive, at the physician’s discretion, infusions manufactured with the same specifications as sipuleucel-T but using cells that had been cryopreserved at the time that the placebo was prepared (63.7% of the placebo patients received these transfusions). Time to disease progression and time to development of disease-related pain were the initial primary endpoints, but the primary endpoint was changed before unblinding based upon survival differences in two previous trials of similar design (described below).[ 68 ][Level of evidence: 1iA]
  2. The same investigators previously performed two smaller trials (D9901 and D9902A [NCT00005947]) of nearly identical design to the IMPACT trial.[ 70 ][ 71 ]

Low-dose prednisone may palliate symptoms in some patients.[ 72 ]

Evidence (low-dose prednisone for palliation):

  1. A randomized comparison of prednisone (5 mg qid) with flutamide (250 mg tid) was conducted in patients with disease progression after androgen ablative therapy (castration or LH-RH agonist).[ 73 ]

Ongoing clinical trials continue to explore the value of chemotherapy for these patients.[ 10 ][ 11 ][ 12 ][ 13 ][ 55 ][ 64 ][ 65 ][ 66 ]

Radiopharmaceutical Therapy

Alpha emitter radiation

Radium Ra 223 (223Ra) emits alpha particles (i.e., two protons and two neutrons bound together, identical to a helium nucleus) with a half-life of 11.4 days. It is administered by IV and selectively taken up by newly formed bone stroma. The high-energy alpha particles have a short range of <100 mcM. 223Ra improved OS in patients with prostate cancer metastatic to the bone.

Evidence (alpha emitter radiation):

  1. In a placebo-controlled trial, 921 men with symptomatic castration-resistant prostate cancer, two or more bone metastases, and no known visceral metastases, were randomly assigned in a 2:1 ratio to receive 223Ra at a dose of 50kBq per kg body weight every 4 weeks for six injections versus placebo. All study participants had already received docetaxel, were not healthy enough to receive it, or declined it.[ 74 ][ 75 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  52. Oosterhof GO, Roberts JT, de Reijke TM, et al.: Strontium(89) chloride versus palliative local field radiotherapy in patients with hormonal escaped prostate cancer: a phase III study of the European Organisation for Research and Treatment of Cancer, Genitourinary Group. Eur Urol 44 (5): 519-26, 2003.[PUBMED Abstract]
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  56. Tannock IF, de Wit R, Berry WR, et al.: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351 (15): 1502-12, 2004.[PUBMED Abstract]
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Key References for Prostate Cancer

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of prostate cancer treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for prostate cancer. Listed after each reference are the sections within this summary where the reference is cited.

Changes to This Summary (07/22/2020)

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

Editorial changes were made to this summary.

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

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

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

Board members review recently published articles each month to determine whether an article should:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Prostate Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389471]

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