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The median age at diagnosis of carcinoma of the prostate is 66 years. 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. 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. There is a large number of these clinically indolent tumors, estimated from autopsy series of men dying of causes unrelated to prostate cancer to be in the range of 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.[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. 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 2018:[A Snapshot of Prostate Cancer]
Figure 1. Anatomy of the male reproductive and urinary systems.
The issue of prostate cancer screening is controversial. In the United States, most prostate cancers are diagnosed as a result 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.)
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.
A number of rare tumors account for the remaining few percentages of cases. These include the following:
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. 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).
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.
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.
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. 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.
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. 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. Less frequently, a transperineal, ultrasound-guided approach can be used in patients who may be at increased risk of complications caused by using a transrectal approach.
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.[27,28] Therefore, men undergoing transrectal biopsy should be told to seek medical attention immediately if they experience fever after biopsy.
The survival of patients with prostate cancer is related to several factors, including the following:[29,30,31,32,33]
(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.[31,32,34,35,36,37,38,39] 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.[40,41] 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.
Use of nomograms as a prognostic tool
Several nomograms have been developed to predict outcomes either before radical prostatectomy [42,43,44,45] or after radical prostatectomy [46,47] 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.[48,49]
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.[50,51] 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.
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.
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.
Likewise, a retrospective analysis (SWOG-S9916 [NCT00004001]) showed that PSA declines of 20% to 40% (but not 50%) at 3 months and 30% or more at 2 months after initiation of chemotherapy for hormone-independent prostate cancer, and fulfilled several criteria of surrogacy for overall survival (OS).
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.
Follow-up after radical prostatectomy
After radical prostatectomy, a detectable PSA level identifies patients at elevated risk of local treatment failure or metastatic disease; however, a substantial proportion of patients with an elevated or rising PSA level after surgery remain clinically free of symptoms for extended periods. 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.
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.[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.[59,60] 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.[61,62]
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. 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.
Other PDQ summaries containing information related to prostate cancer include the following:
Note: The American Joint Committee on Cancer (AJCC) has published the 8th edition of the AJCC Cancer Staging Manual, which includes revisions to the staging for this disease. Implementation of the 8th edition began in January 2018. The PDQ Adult Treatment Editorial Board, which maintains this summary, is reviewing the revised staging and will make appropriate changes as needed.
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).
Tests used to determine stage include the following:
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. 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. 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.
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.
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. 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%, 13%, and 23% for Gleason scores of 5, 6, and 8, respectively.
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. Over the years, there has been a trend toward taking eight to ten or more biopsy samples at the same time. 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.
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.
Computed tomography (CT) scans
CT scans can detect grossly enlarged lymph nodes but poorly define intraprostatic features; therefore, it is not reliable for the staging of pelvic node disease when compared with surgical staging.
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.Figure 2. Staging of 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 8.
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). (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. (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.)
A radical prostatectomy is usually reserved for patients who:[20,21,22]
Prostatectomy can be performed by the perineal or retropubic approach. The perineal approach requires a separate incision for lymph node dissection. Laparoscopic lymphadenectomy is technically possible and accomplished with much less patient morbidity. For small, well-differentiated nodules, the incidence of positive pelvic nodes is less than 20%, and pelvic node dissection may be omitted. With larger, less-differentiated tumors, a pelvic lymph node dissection is more important. The value of pelvic node dissection (i.e., open surgical or laparoscopic) in these cases is not therapeutic but spares patients with positive nodes the morbidity of prostatectomy. Radical prostatectomy is not usually performed if frozen section evaluation of pelvic nodes reveals metastases; such patients should be considered for entry into existing clinical trials or receive radiation therapy to control local symptoms.
The role of preoperative (neoadjuvant) hormonal therapy is not established.[25,26]
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:
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%). 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.
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):
Complications of radical prostatectomy
Complications of radical prostatectomy include the following:
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:
Over the study period, these rates decreased by 30%, 8%, and 12%, respectively.
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:[39,40]
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).
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):
Differences are often reported between population-based surveys and case series from individual centers. Reasons could include the following:
Case series of men who have undergone radical prostatectomy have shown shortening of penile length (by an average of 1–2 cm).[49,50,51] 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. 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.
Inguinal hernia has been reported as a complication of radical prostatectomy.
Evidence (inguinal hernia after radical prostatectomy):
Although the observations of increased rates of inguinal hernia after radical prostatectomy are consistent, it is conceivable that men with prostate cancer who are being followed carefully by urologists could have higher detection rates of hernia as a result of frequent examinations or diagnostic imaging (i.e., detection bias). Men should be made aware of this potential complication of prostatectomy.
Radical prostatectomy may cause fecal incontinence, and the incidence may vary with surgical method.
Evidence (fecal incontinence after radical prostatectomy):
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.
Long-term results with radiation therapy are dependent on stage and are associated with dosimetry of the radiation.
(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.[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.
Evidence (conventional vs. hypofractionated EBRT):
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.[Level of evidence: 3iiiDiv]
Information about ongoing clinical trials is available from the NCI website.
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%).[78,79][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.[20,41,48,80,81,82] These conditions are generally reversible but may be chronic and rarely require surgical intervention.
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.
Radiation is also known to be carcinogenic.[83,84,85] 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.
Potency, in most cases, is preserved with radiation therapy in the short term but appears to diminish over time. Sildenafil citrate may be effective in the management of sexual dysfunction after radiation therapy in some men.
Evidence (reducing complications):
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.[88,89]
Evidence (3-dimensional conformal vs. conventional radiation therapy):
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.[90,91,92] 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.
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.
Evidence (complications of radical prostatectomy vs. radiation therapy):
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 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. It may also be associated with a small increase in respiratory disorders.
Benefits of bilateral orchiectomy include the following:
Disadvantages of bilateral orchiectomy include the following:[41,99]
Bilateral orchiectomy has also been associated with an elevated risk of coronary heart disease and myocardial infarction.[100,101,102,103]
(Refer to the PDQ summary on Hot Flashes and Night Sweats.)
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.[100,101,102,103,104]
Evidence (LH-RH agonists and cardiovascular disease):
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. Use of nonsteroidal antiandrogens as monotherapy decreased OS and increased the rate of clinical progression and treatment failure.[Level of evidence: 1iiA]
The pure antiandrogen, flutamide, may cause diarrhea, breast tenderness, and nausea. Case reports show fatal and nonfatal liver toxic effects.
Bicalutamide may cause nausea, breast tenderness, hot flashes, loss of libido, and impotence. (Refer to the PDQ summaries on Gastrointestinal Complications; Treatment-Related Nausea and Vomiting; 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.
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:[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.
The use of ADT may be associated with complaints of penile shortening, although the data are very limited. 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.
The use of ADT has also been associated with an increased risk of colorectal cancer.
Evidence (increased risk of colorectal cancer):
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
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.[Level of evidence: 3iiiC]; [Level of evidence: 3iii]; [115,116][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.
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.[115,116] Other major complications include urethral sloughing, urinary fistula or stricture, and bladder neck obstruction.
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.
Neoadjuvant hormonal therapy
The role of neoadjuvant hormonal therapy is not established.[25,26]
Bicalutamide has not been shown to improve OS in patients with localized or locally advanced prostate cancer.
Stage I prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
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.
In younger patients (aged 50–60 years) whose expected survival is long, treatment should be considered. 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.
Standard Treatment Options for Stage I Prostate Cancer
Standard treatment options for stage I prostate cancer include the following:
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):
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. Careful treatment planning is necessary to avoid morbidity.
Evidence (radical prostatectomy followed by radiation therapy):
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):
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. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.[23,24]
Evidence (EBRT with or without adjuvant hormonal therapy):
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]; [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 include the following:
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.
Stage II prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
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. 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):
Standard Treatment Options for Stage II Prostate Cancer
Standard treatment options for stage II prostate cancer include the following:
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).
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. Careful treatment planning is necessary to avoid morbidity.
Evidence (radical prostatectomy compared directly with watchful waiting/active surveillance/active monitoring and/or external-beam radiation therapy):
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. Adjuvant hormonal therapy should be considered for patients with bulky T2b to T2c tumors.
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.
3-dimensional (3D) conformal radiation therapy
EBRT designed to decrease exposure of normal tissues using methods such as CT-based 3-D conformal treatment planning is under clinical evaluation.
Interstitial implantation of radioisotopes (i.e., iodine I 125 [125I], palladium, and iridium), using a transperineal technique with either ultrasound or computed-tomography (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.[41,42]; [Level of evidence: 3iiiDiv]
Retropubic freehand implantation with 125I has been associated with an increased local failure and complication rate [44,45] and is now rarely done.
Treatment Options Under Clinical Evaluation for Stage II Prostate Cancer
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.[Level of evidence: 3iiiC]; [47,48][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.[47,48]
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.[49,50,51]
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 that compare its efficacy and toxicity with those of other forms of radiation therapy.
Other clinical trials
Other clinical trials, including trials of neoadjuvant hormonal therapy followed by radical prostatectomy, are ongoing.
Stage III prostate cancer is defined by the American Joint Committee on Cancer's TNM classification system:
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. 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 taken into account before deciding on a therapeutic plan. In a series of 372 patients treated with radiation therapy and followed for 20 years, 47% eventually died of prostate cancer, but 44% died of intercurrent illnesses without evidence of prostate cancer.
Standard Treatment Options for Stage III Prostate Cancer
Standard treatment options for stage III prostate cancer include the following:
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.
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):
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.[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, 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). 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):
Evidence (orchiectomy vs. LH-RH agonist):
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):