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Systematic Review: Comparative Effectiveness and Harms of Treatments for Clinically Localized Prostate Cancer FREE

Timothy J. Wilt, MD, MPH; Roderick MacDonald, MS; Indulis Rutks, BA; Tatyana A. Shamliyan, MD, MS; Brent C. Taylor, PhD; and Robert L. Kane, MD
[+] Article and Author Information

From the University of Minnesota School of Medicine, Center for Chronic Disease Outcomes Research, Veterans Affairs Medical Center, and Clinical Outcomes Research Center, School of Public Health, Health Policy and Management, University of Minnesota, Minneapolis, Minnesota.


Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank William Lawrence, MD, MS, Agency for Healthcare Research and Quality Task Order Officer, for his guidance on and patience with this project.

Financial Support: This project was prepared by the Minnesota Evidence-based Practice Center, Minneapolis, Minnesota, with funding from the Agency for Healthcare Research and Quality under contract no. 290-02-0009, U.S. Department of Health and Human Services.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Timothy J. Wilt, MD, MPH, University of Minnesota School of Medicine, Minneapolis Veterans Affairs Center for Chronic Disease Outcomes Research, 1 Veterans Drive (111-0), Minneapolis, MN 55417; e-mail, tim.wilt@med.va.gov.

Current Author Addresses: Drs. Wilt and Taylor, Mr. MacDonald, and Mr. Rutks: University of Minnesota School of Medicine, Minneapolis Veterans Affairs Center for Chronic Disease Outcomes Research, 1 Veterans Drive (111-0), Minneapolis, MN 55417.

Drs. Shamliyan and Kane: Clinical Outcomes Research Center, School of Public Health, Division of Health Policy and Management, University of Minnesota, MMC 729 Mayo (8729), 420 Delaware, Minneapolis, MN 55455.


Ann Intern Med. 2008;148(6):435-448. doi:10.7326/0003-4819-148-6-200803180-00209
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Background: The comparative effectiveness of localized prostate cancer treatments is largely unknown.

Purpose: To compare the effectiveness and harms of treatments for localized prostate cancer.

Data Sources: MEDLINE (through September 2007), the Cochrane Library (through Issue 3, 2007), and the Cochrane Review Group in Prostate Diseases and Urologic Malignancies registry (through November 2007).

Study Selection: Randomized, controlled trials (RCTs) published in any language and observational studies published in English that evaluated treatments and reported clinical or biochemical outcomes in localized prostate cancer.

Data Extraction: 2 researchers extracted information on study design, sample characteristics, interventions, and outcomes.

Data Synthesis: 18 RCTs and 473 observational studies met inclusion criteria. One RCT enrolled mostly men without prostate-specific antigen (PSA)–detected disease and reported that, compared with watchful waiting, radical prostatectomy reduced crude all-cause mortality (24% vs. 30%; P = 0.04) and prostate cancer–specific mortality (10% vs. 15%; P = 0.01) at 10 years. Effectiveness was limited to men younger than age 65 years but was not associated with Gleason score or baseline PSA level. An older, smaller trial found no significant overall survival differences between radical prostatectomy and watchful waiting (risk difference, 0% [95% CI, −19% to 18%]). Radical prostatectomy reduced disease recurrence at 5 years compared with external-beam radiation therapy in 1 small, older trial (14% vs. 39%; risk difference, 21%; P = 0.04). No external-beam radiation regimen was superior to another in reducing mortality. No randomized trials evaluated primary androgen deprivation. Androgen deprivation used adjuvant to radical prostatectomy did not improve biochemical progression compared with radical prostatectomy alone (risk difference, 0% [CI, −7% to 7%]). No randomized trial evaluated brachytherapy, cryotherapy, robotic radical prostatectomy, or photon-beam or intensity-modulated radiation therapy. Observational studies showed wide and overlapping effectiveness estimates within and between treatments. Adverse event definitions and severity varied widely. The Prostate Cancer Outcomes Study reported that urinary leakage (≥1 event/d) was more common with radical prostatectomy (35%) than with radiation therapy (12%) or androgen deprivation (11%). Bowel urgency occurred more often with radiation (3%) or androgen deprivation (3%) than with radical prostatectomy (1%). Erectile dysfunction occurred frequently after all treatments (radical prostatectomy, 58%; radiation therapy, 43%; androgen deprivation, 86%). A higher risk score incorporating histologic grade, PSA level, and tumor stage was associated with increased risk for disease progression or recurrence regardless of treatment.

Limitations: Only 3 randomized trials compared effectiveness between primary treatments. No trial enrolled patients with prostate cancer primarily detected with PSA testing.

Conclusion: Assessment of the comparative effectiveness and harms of localized prostate cancer treatments is difficult because of limitations in the evidence.

Editors' Notes
Context

  • Sorting through the proven benefits and harms of the multiple strategies available to treat clinically localized prostate cancer is difficult.

Contribution

  • This systematic review of 18 randomized trials and 473 observational studies found little high-quality evidence that established the superiority of one therapy over another. All treatments, including androgen deprivation, radical prostatectomy, and radiotherapy, caused urinary, bowel, or sexual dysfunction; the frequency, duration, and severity of these adverse events varied among treatments.

Implication

  • Available data insufficiently characterize the relative benefits of various treatments for clinically localized prostate cancer, and all therapies cause some harms.

—The Editors

In 2007, prostate cancer was diagnosed in an estimated 218 900 men in the United States, and approximately 27 050 men died of the disease. Approximately 90% of men have disease confined to the prostate gland (clinically localized disease). Prostate cancer incidence increased and disease-specific mortality rates decreased after introduction of the prostate-specific antigen (PSA) blood test and with greater use of early interventions (1).

Treatment goals are to prevent death and disability from prostate cancer while minimizing intervention-related complications. Common treatments include watchful waiting (expectant management or active surveillance), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy (EBRT) and interstitial radiation therapy (brachytherapy), and androgen deprivation. Patient treatment decisions incorporate physician recommendations; estimated likelihood of cancer progression without early intervention; and treatment-related convenience, costs, and potential for eradication and adverse effects (2). Little is known about how patient and tumor characteristics modify treatment outcomes.

This report summarizes evidence from a review prepared for the Agency for Healthcare Research and Quality (3). We determined the comparative short- and long-term benefits and harms of therapies for clinically localized prostate cancer and how patient and tumor characteristics affect the outcomes of these therapies, overall and differentially.

Data Sources and Selection of Randomized, Controlled Trials

We identified randomized, controlled trials (RCTs) published through mid-September 2007 by using the Cochrane Library (through Issue 3, 2007) and the Cochrane Review Group in Prostate Diseases and Urologic Malignancies specialized registry (through November 2007) (Appendix Figure 1). We included studies if they enrolled men with clinically localized disease (tumor stage T1 or T2) and randomly allocated them to any prostate cancer treatment, including usual care or watchful waiting. We included RCTs that enrolled men with advanced disease (tumor stage T3 or T4) if outcomes were reported separately for localized disease.

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Appendix Figure 1.
Study flow diagram.

AUA = American Urological Association; RCT = randomized, controlled trial; RP = radical prostatectomy.

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Data Sources and Selection of Observational Studies

Very few RCTs compared major treatment options, especially for PSA-detected prostate cancer (Appendix Figure 1). Therefore, we reanalyzed a database that primarily comprised nonrandomized reports that we had previously extracted under a separate contract with the American Urological Association (AUA) Prostate Cancer Clinical Guideline Panel (4). The AUA panel used PubMed to identify English-language articles published from 1991 through April 2004. We rejected articles if authors did not report or stratify outcomes for localized disease or reported on fewer than 50 patients.

Our review indicated that this database varied greatly in effectiveness estimates, outcome reporting, lack of controls or risk adjustment, and likelihood that it contained results from studies using identical or nearly identical samples. Our technical expert panel recommended against updating this search because the panel did not believe that additional data from nonrandomized studies would provide reliable evidence for assessing comparative effectiveness. We used results from the AUA database to evaluate and demonstrate the range of specific outcomes reported with each intervention in nonrandomized studies and to further assess harms.

We obtained additional data on harms and patient satisfaction from the Prostate Cancer Outcomes Study because it is a large, nationally representative prospective survey of men with localized prostate cancer (5). Investigators designed the Prostate Cancer Outcomes Study to assess the long-term health-related quality-of-life outcomes in a large, diverse population-based sample of men in whom prostate cancer was diagnosed in 1994 or 1995. Eligible men were treated in community-based settings and resided in 1 of 6 U.S. Surveillance, Epidemiology, and End Result geographic regions.

No RCT evaluated emerging technologies, and the AUA database contained little information on these therapies. Therefore, we used MEDLINE (between April 2004 and September 2007) and contact with Endocare (a manufacturer of cryotherapy devices) to identify and include English-language nonrandomized trials, reviews, and case series of cryotherapy, laparoscopic or robotic-assisted radical prostatectomy, high-intensity focused ultrasonography, proton-beam radiation, and intensity-modulated radiation therapy that reported patient outcomes regardless of size or duration.

Study Selection for Effect of Patient and Tumor Characteristics

We addressed the effect of patient and tumor characteristics on outcomes of therapies by reviewing RCTs for comparative effectiveness according to age, race, comorbid condition or PSA level, tumor stage, histologic grade, and tumor risk strata. We extracted any study from the AUA database or U.S. population–based studies that had outcomes stratified according to age or race, looking for comparative effectiveness between treatments according to these factors. We used U.S. population–based observational studies to evaluate the effect of tumor characteristics on the natural history and survival of men with prostate cancer treated with watchful waiting.

Data Extraction and Quality Assessment

Two researchers independently abstracted information on study, patient, tumor, and intervention characteristics and outcomes. Outcomes included all-cause and disease-specific mortality, biochemical and clinical progression, adverse events, and patient satisfaction. We assessed the study quality of RCTs on the basis of allocation concealment (6), intention-to-treat-analysis, length of follow-up, and dropouts or loss to follow-up. We rated the strength of the evidence as high (consistent results from ≥2 high-quality studies with long-term follow-up), medium (data from <2 high-quality studies or studies that did not have long-term follow-up), or low (inconsistent results, studies of low quality or from populations with little relevance to current patients or practice) (3). We considered evidence from nonrandomized trials, case series, and meta-analyses of these studies as low strength. We evaluated applicability of patient populations, clinical settings, and length of follow-up and adjustment for confounding.

Data Synthesis and Statistical Analysis

Only 3 trials of radical prostatectomy plus neoadjuvant androgen deprivation had data that permitted pooling. We analyzed overall mortality, disease-specific mortality, and biochemical progression or recurrence by using Cochrane Collaboration Review Manager software, version 4.2 (The Cochrane Collaboration, Oxford, United Kingdom) (7). A chi-square test with a P value less than 0.100 and I2 value greater than 50% indicated statistical heterogeneity (8). We calculated absolute risk differences, odds ratios, and 95% CIs by using random-effects models (9). We present outcomes individually according to study size and duration of follow-up.

Role of the Funding Source

This project was prepared by the Minnesota Evidence-based Practice Center, Minneapolis, Minnesota, with funding from the Agency for Healthcare Research and Quality. The funding source suggested the initial questions and provided copyright release for this manuscript but did not participate in the literature search, data analysis, or interpretation of the results.

Summary of Evidence on Treatment Effectiveness

The AUA panel search and our additional searches identified 14 045 potentially relevant articles. Eighteen RCTs and 473 observational studies met the inclusion criteria. No treatment option had consistent results from at least 2 high-quality RCTs with adequate follow-up and statistical power (Table 1). Only 3 RCTs (1012) compared effectiveness between major treatment categories (radical prostatectomy vs. radiation therapy or watchful waiting). None enrolled men with primarily PSA-detected disease. Many RCTs were inadequately powered to provide long-term survival outcomes. Most reported biochemical progression or recurrence as the main outcomes. No RCT evaluated cryotherapy, laparoscopic or robotic-assisted radical prostatectomy, primary androgen deprivation, high-intensity focused ultrasonography, proton-beam radiation, or intensity-modulated radiation therapy.

Table Jump PlaceholderTable 1.  Summary of Evidence on the Comparative Effectiveness and Harms of Therapies for Localized Prostate Cancer

Nonrandomized studies varied widely in treatment effectiveness and harms (Figures 1 and 2). The definitions of outcomes (for example, the criteria used to define biochemical progression) and their reporting varied considerably. Investigators rarely stratified outcomes according to patient and tumor characteristics. Many studies included patients with locally advanced disease but did not analyze outcomes on the basis of tumor stage.

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Figure 1.
Overall survival at time points, by treatment, from nonrandomized studies.

The symbol size is proportional to the number of patients: <50, 50–150, 150–300, or >300. Brachy = brachytherapy; C-EBRT = conformal external-beam radiation therapy, EBRT = external-beam radiation therapy; RP = radical prostatectomy; WW = watchful waiting.

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Figure 2.
Complications of brachytherapy, radical prostatectomy, external-beam radiation therapy, conformal external-beam radiation therapy, nerve-sparing radical prostatectomy, and watchful waiting from nonrandomized studies.

The symbol size is proportional to the number of patients: <50, 50–150, 150–300, or >300.

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Characteristics of Randomized Studies

We identified 18 RCTs (1027) and 1 pooled analysis of 3 trials (28) (14 595 patients in total) (Appendix Table 1). Fifteen RCTs evaluated variations of a particular treatment approach (for example, different doses, isotopes, or duration of radiation therapy or addition of androgen deprivation to radical prostatectomy or EBRT). Six trials (13, 15, 19, 22, 2627) included men with locally advanced prostate cancer, who comprised 24% of all patients in these trials. Seven studies (1011, 1618, 2425) reported mean age (65 years [2903 patients]). Only 3 trials (1617, 28) reported ethnicity; most participants were white. Three quarters of patients had stage T2 tumors (10, 1318, 21, 23). Nine studies (1011, 14, 1718, 2021, 23) reported Gleason score at randomization; 66% of patients had a score of 6 or less (low or moderate histologic grade), 24% had a score of 7, and 6% had a score of 8 to 10 (high histologic grade). One trial enrolled only men with a Gleason score of 6 or less (17). Six studies reported eligibility based on PSA levels ranging from less than 15 μg/L (25) to less than 40 or 50 μg/L (10, 14, 16, 18, 23). Most studies began enrollment before widespread PSA testing.

Table Jump PlaceholderAppendix Table 1.  Description and Quality of the Included Randomized Trials
Randomized Comparisons between Treatment Categories
Radical Prostatectomy versus Watchful Waiting

Two RCTs compared radical prostatectomy with watchful waiting (Tables 1 and 2 and Appendix Table 2). Nearly all cases of prostate cancer were detected by methods other than PSA testing (10). The Scandinavian Prostate Cancer Group Study No. 4 randomly assigned 695 men with a life expectancy greater than 10 years. Surgery reduced the incidence of all-cause deaths, disease-specific deaths, and distant metastases compared with watchful waiting, and the risk difference in all-cause mortality after 10 years was 5% [95% CI, −2.8% to 13.0%]. Compared with watchful waiting, radical prostatectomy reduced death from prostate cancer (10% vs. 15%; P = 0.01) and reduced distant metastases at 10 years (15.2% vs. 25.4%; absolute risk difference, 10.2% [CI, 3.1% to 17.2%]). An older study of 142 patients reported a median overall survival of 10.6 years for radical prostatectomy and 8 years for watchful waiting (11). These differences did not statistically differ (P > 0.05), even after longer follow-up. This study was underpowered to detect moderately large treatment differences.

Table Jump PlaceholderTable 2.  All-Cause Mortality in Randomized, Controlled Trials
Table Jump PlaceholderAppendix Table 2.  Biochemical/Clinical Progression or Recurrence in Randomized, Controlled Trials from the Era of Prostate-Specific Antigen Testing
Radical Prostatectomy versus EBRT

One small older trial (106 patients) indicated that radical prostatectomy was more effective in preventing progression, recurrence, or distant metastases compared with EBRT in men with clinical stage A2 or B (tumor stage T1 or T2) prostate cancer detected by methods other than PSA testing (12). Treatment failure after 5 years of follow-up, defined as an elevated acid phosphatase level at 2 consecutive follow-up visits or appearance of bony or parenchymal disease with or without concomitant acid phosphatase elevation, was 39% for EBRT compared with 14% for radical prostatectomy (risk difference, 25%; P = 0.04).

Randomized Comparisons within Treatment Categories
Radical Prostatectomy plus Neoadjuvant Androgen Deprivation

Three trials (1416) compared radical prostatectomy alone with radical prostatectomy plus neoadjuvant androgen deprivation (Table 1 and Appendix Table 2). One small RCT (213 patients) found no overall or disease-specific survival benefit with neoadjuvant androgen deprivation after 6 years (14). Pooled analysis of the 3 trials (673 patients) found that neoadjuvant androgen deprivation did not prevent PSA progression compared with radical prostatectomy alone (30% vs. 31%; risk difference, 0% [CI, −7% to 7%]) (1416).

EBRT

No EBRT regimen, whether conventional, high-dose conformal, dose fractionated, or hypofractionated, was superior to another in reducing overall or disease-specific mortality. Increasing the total amount of radiation or adding brachytherapy after EBRT did not decrease cancer recurrence compared with lower radiation doses. One trial found that the proportion of patients with biochemical or clinical progression at 5 years was borderline statistically significantly lower with conventional therapy (66 Gy in 33 fractions) than with hypofractionated therapy (52.5 Gy in 20 fractions) (risk difference, −6% [CI, −13% to 0%]) (18). Conventional-dose EBRT (64 Gy in 32 fractions) and hypofractionated EBRT (55 Gy in 20 fractions) resulted in similar rates of PSA relapse (20). High-dose EBRT was more effective than conventional-dose radiation therapy in terms of the proportion of men without biochemical failure at 5 years (21), and biochemical progression occurred in 20% and 39% of patients, respectively (risk difference, 19% [CI, 28% to 10%]). High-dose EBRT was more effective in both low-risk (PSA level <10 μg/L, tumors stage ≤T2a, or Gleason score ≤6) and high-risk disease. One small trial (62 patients with stage T2 disease) found that EBRT plus brachytherapy reduced biochemical or clinical progression compared with EBRT alone (26% vs. 56%; risk difference, −30% [CI, −54% to −7%]) (19).

EBRT plus Androgen Deprivation

External-beam radiation therapy plus androgen deprivation decreased overall and disease-specific mortality but increased adverse events compared with EBRT alone in high-risk patients defined by PSA levels (>10 μg/L) and Gleason histologic score (>6). Conformal EBRT plus 6 months of androgen deprivation reduced all-cause mortality, disease-specific mortality, and PSA failure in these men compared with conformal EBRT alone after a median follow-up of 4.5 years (23). In the combination therapy and EBRT groups, 12 versus 23 (12% vs. 22%) all-cause deaths occurred (difference, −10% [CI, −20% to 0%]), respectively, and 0 versus 6 (0% vs. 6%) disease-specific deaths occurred (difference, −6% [CI, −11% to −1%]). The proportion of men with PSA failure was 45% with EBRT plus androgen deprivation and 21% with EBRT alone (difference, 23% [CI, 36% to 11%]).

Six months of combination therapy with EBRT plus androgen deprivation reduced clinical failure, biochemical failure, or death from any cause compared with conformal EBRT alone in men with stage T2c but not T2b disease. However, disease-specific mortality did not differ in the overall group that included both patients with stage T2b disease and those with stage T2c disease (26). Eight months of EBRT plus androgen deprivation did not improve freedom from biochemical (PSA) failure compared with 3 months of EBRT plus androgen deprivation in low-risk men (PSA level <10 μg/L, tumor stage T1c to T2a, or Gleason score ≤6) (22).

Brachytherapy, with or without Adjuvant EBRT

One small trial (159 patients) compared 20-Gy with 44-Gy EBRT, both adjuvant to brachytherapy with a 103Pd implant, and found no differences in biochemical failure events (14% vs. 12%) and freedom from biochemical progression at 3 years (absolute risk difference, 3% [CI, −8% to 13%]) (25). Preliminary results from 1 small trial (126 patients) compared 125I with 103Pd brachytherapy and found similar biochemical control at 3 years (24).

Adjuvant Androgen Deprivation with Bicalutamide plus Radical Prostatectomy, EBRT, or Watchful Waiting

A pooled analysis of 3 RCTs (8113 patients) found that androgen deprivation with bicalutamide alone or in addition to radical prostatectomy or EBRT did not reduce mortality or cancer recurrence (28). The death rate at 5 years did not differ between the bicalutamide and placebo groups for men receiving either radical prostatectomy or EBRT: Approximately 10% of patients in both groups died (risk difference, 0% [CI, −2% to 2%]). Bicalutamide increased mortality compared with placebo among men randomly assigned to watchful waiting (25% vs. 20%; difference, 5% [CI, 1% to 9%]). Bicalutamide plus radical prostatectomy or EBRT did not reduce disease progression (confirmed by bone scan, computed tomography, ultrasonography, magnetic resonance imaging, or histologic evidence of distant metastases) or death from any cause without progression (risk difference, 0% [CI, −3% to 2%] for bicalutamide plus radical prostatectomy vs. placebo plus radical prostatectomy and −3% [CI, −8% to 2%] for bicalutamide plus EBRT vs. placebo plus EBRT).

Comparative Outcomes from Nonrandomized Reports

More than 80% of nonrandomized reports were case series, and only 6% were controlled trials (3). We could not accurately estimate the relative effectiveness of treatments beyond the information available from the few RCTs, for reasons described in the Data Sources and Selection of Observational Studies section. In addition, investigators infrequently reported overall and disease-specific mortality. Figure 1 shows wide variation across studies, with overlapping overall survival estimates within and between treatments at 5, 10, 15, and 20 years. Disease-specific mortality results also varied widely. Investigators frequently did not report standardized definitions of biochemical outcomes. Studies reported more than 200 definitions of biochemical disease–free survival, and ranges for this outcome were wide and overlapped at 5 and 10 years (3).

Emerging Therapies

Appendix Figures 2 and 3 show details of studies of emerging therapies.

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Appendix Figure 2.
Biochemical progression–free survival after cryotherapy or high-intensity focused ultrasonography among patients in nonrandomized clinical trials and case series.

*Combined with transurethral resection of the prostate.

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Appendix Figure 3.
Clinical outcomes after laparoscopic radical prostatectomy, robotic-assisted radical prostatectomy, or intensity-modulated radiation therapy.

PSA = prostate-specific antigen.

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The sample sizes of the 15 included studies on cryosurgery ranged from 54 to 1467 patients, with follow-up of 3 to 69 months (2943). Most reports included men with locally advanced disease. Investigators did not report overall or prostate cancer–specific survival. Biochemical progression–free survival for patients with stage T1 or T2 tumors was reported in 10 studies (1539 patients), with ranges of 29% to 100% (2938).

Laparoscopic and Robotic-Assisted Radical Prostatectomy

One RCT compared intraoperative and early postoperative outcomes for laparoscopic radical prostatectomy with those of retropubic radical prostatectomy (120 patients) but did not report longer-term effectiveness (44). One systematic review (45) and 2 narrative reviews (4647) estimated the effectiveness and adverse events of laparoscopic radical prostatectomy and robotic-assisted radical prostatectomy from 21 nonrandomized clinical trials and case series involving 2301 and 1757 patients, respectively. Most studies were done at centers outside the United States. Median follow-up was 8 months. Two studies with median follow-up of 30 and 67 months reported that overall survival was similar between laparoscopic and robotic-assisted radical prostatectomy (46). No differences existed between treatments in terms of PSA relapse; however, estimates were wide and ranged from 28% lower to 90% higher with laparoscopic radical prostatectomy (46, 48). Wound healing was better with laparoscopic radical prostatectomy than with open radical prostatectomy. Robotic-assisted radical prostatectomy and open radical prostatectomy had similar reintervention rates. Length of hospital stay was shorter after robotic-assisted prostatectomy than after open radical prostatectomy (median, 1.2 vs. 2.7 days) (47).

Intensity-Modulated Radiation Therapy

Case series reported similar rates of biochemical-free survival after intensity-modulated radiation therapy compared with conformal radiation therapy. The odds ratio of survival without relapse was 1.09 (CI, 0.96 to 1.24) at 66 months of follow-up after intensity-modulated radiation therapy versus conformal radiation therapy. The rate of distant metastases was 1% to 3% after intensity-modulated radiation therapy in a series of 561 patients (4951). A case series of 133 men (67% with localized disease) reported a 5-year biochemical relapse–free survival rate of 100% in low-risk men, 94% in intermediate-risk men, and 74% in high-risk men (52).

Proton-Beam Radiation Therapy

Several nonrandomized reports from 1 center of excellence provided clinical outcomes after combined proton-beam and photon radiation therapy (5357). Between 86% and 97% (54, 57) of men were free of disease at the end of follow-up, and 73% to 88% did not have biochemical failure (5356). Two percent to 8% had distant metastases (54, 57).

High-Intensity Focused Ultrasonography

High-intensity focused ultrasonography has been used for primary treatment of localized disease and salvage therapy for patients in whom radiation therapy has failed (58). Eight uncontrolled studies (963 patients) reported biochemical progression–free survival rates ranging from 66% to 87% (5964). Duration of follow-up was less than 2 years.

Evidence on Harms
Randomized Comparisons between Treatment Categories

In the Scandinavian Prostate Cancer Group Study No. 4, radical prostatectomy was associated with greater sexual and urinary dysfunction than watchful waiting (65). Radical prostatectomy increased the relative risk for sexual dysfunction compared with watchful waiting among men who responded to the questionnaire (relative risk, 1.2 to 18.0 for specific domains). Eighteen percent versus 2% reported moderate or severe leakage, and 29% versus 9% said that they had moderate or great distress. Twenty-seven percent of men who received radical prostatectomy and 18% of those who received watchful waiting (relative risk, 1.5 [CI, 1.0 to 2.3]) reported overall distress from all urinary symptoms. Watchful waiting was associated with worse bowel function. Six percent of men treated with watchful waiting and 3% treated with radical prostatectomy had distress from all bowel symptoms.

Randomized Comparisons within Treatment Categories

Eight months of neoadjuvant androgen deprivation before radical prostatectomy resulted in more adverse events, including hot flashes, than did 3 months of neoadjuvant androgen deprivation (17). The rate of acute combined gastrointestinal and genitourinary toxicity was lower with conventional EBRT (7%) than with hypofractionated EBRT (11%) (18). The rate of late toxicity was similar between groups. Conventional and hypofractionated EBRT resulted in similar adverse effects, with the exception of rectal bleeding at 2 years after therapy, which was more common with hypofractionated EBRT (42% vs. 27%; P < 0.05) (20). High-dose and conventional-dose regimens led to a similar frequency of acute severe gastrointestinal or genitourinary symptoms (2% vs. 1%) (21). Gynecomastia was more common with EBRT plus androgen deprivation compared with EBRT alone (18% vs 3%; P = 0.002) (23). More men treated with EBRT plus androgen deprivation who were potent at baseline became impotent after treatment compared with men treated with EBRT alone (26% vs. 21%; P = 0.02). The brachytherapy trial reported a similar frequency of radiation proctitis in men treated with 125I versus men treated with 103Pd (13% vs. 8%; P = 0.21) (66). In the bicalutamide trial, stage T3 and T4 tumors contaminated harms data (28).

Outcomes from Nonrandomized Reports

Investigators' definitions of adverse events and criteria to define event severity varied widely. We could not derive precise estimates of specific adverse events for each treatment. The AUA data contained 24 predefined complications, including bladder complications (7), bowel complications (3), erectile dysfunction (1), and deep venous thromboses (10). Authors infrequently used the same definition for a given complication; often did not report outcomes during identical follow-up periods; and varied in whether they reported on all participants or only those with or without dysfunction at baseline, and how they assessed outcome. For example, we found many definitions of incontinence (112 definitions); erectile dysfunction (79 definitions); and bladder (203 definitions), bowel (87 definitions), and other complications (336 definitions). Most definitions were used only once.

Data from the AUA database found that urinary dysfunction was more common in men treated with radical prostatectomy than in men treated with radiation therapy (Appendix Figure 3) (34). Sexual dysfunction was common after all treatments. Impotence rates ranged from less than 5% to approximately 60% in the few studies reporting on men undergoing nerve-sparing radical prostatectomy. Incontinence of any severity was the most frequently assessed bladder complication, although it was rarely reported. Investigators reported incontinence rates for brachytherapy (2% to 32%), radical prostatectomy (5% to 35%), and radiation therapy (2% to 6%). Urethral stricture and hematuria were more frequent with radiation therapy. Studies of patients undergoing radical prostatectomy rarely reported bowel complications of diarrhea, fecal incontinence, and rectal bleeding. When reported, these adverse effects occurred less frequently in men treated with radiation therapy or conformal radiation therapy (15% to 30%). Except for rectal injury, bowel complications persisted beyond 6 months of follow-up.

The Prostate Cancer Outcomes Study (5) results for treatment harms and patient satisfaction indicated that urinary leakage occurring daily or more often was more common in men undergoing radical prostatectomy (35%) than EBRT (12%) or androgen deprivation (11%) (Appendix Table 3). External-beam radiation therapy and androgen deprivation were associated with a higher frequency of bowel urgency (3% each) compared with radical prostatectomy (1%). Inability to attain an erection was higher in men undergoing active intervention, especially androgen deprivation (86%) or radical prostatectomy (58%), than in men receiving watchful waiting (33%). Patient satisfaction with all selected treatments was high. More than 90% would make the same treatment decision again, and most were delighted or pleased with their treatment decision. Satisfaction was higher in men who received early intervention than in those who received watchful waiting.

Table Jump PlaceholderAppendix Table 3.  Patient Characteristics and Response to Therapy at 24 Months of Follow-up in the Prostate Cancer Outcomes Study, by Treatment
Emerging Technologies

Cryosurgery adverse events were infrequently reported but included bladder outlet obstruction (3% to 21%) (3435, 3743), tissue sloughing (4% to 15%) (32, 3435, 3741, 43), and impotence (40% to 100%) (30, 32, 3435, 40, 4243). Laparoscopic radical prostatectomy and robotic-assisted radical prostatectomy generally resulted in less operative blood loss and transfusion requirements than open radical prostatectomy (44). Patients required 5-day urinary catheterization more often after laparoscopic radical prostatectomy than after open radical prostatectomy. Other intraoperative and early postoperative outcomes were similar between the 2 procedures. Total complications, continence rates, and positive surgical margins were similar for laparoscopic radical prostatectomy and open radical prostatectomy (46). Robotic-assisted radical prostatectomy was associated with lower total complication rates than laparoscopic radical prostatectomy but higher rates than open radical prostatectomy. Fewer than 1% of persons undergoing proton-beam radiation therapy had gastrointestinal and urinary toxicity (5355, 57). Absolute risk for impotence and treatment-related morbidity was similar across studies of high-intensity focused ultrasonography versus other treatments (5964, 6768).

Effect of Patient and Tumor Characteristics on Therapeutic Outcomes

Few high-quality data were available on the comparative effectiveness of treatments based on age and race or PSA levels, histologic score, and volume to identify low-, intermediate-, and high-risk tumors. No RCTs reported comparisons of treatment outcomes stratified by race or ethnicity, and most did not provide baseline racial characteristics of participants. Available data were largely from case series. Few studies reported direct comparisons, and adjustment for confounding factors was limited (69). Modest treatment differences that were reported in some nonrandomized reports were not consistently observed in well-powered studies. Little evidence indicated a differential effect of treatments based on age. Differences exist in the incidence and morbidity of prostate cancer according to patient age and in the treatments offered to men at different age ranges. Practice patterns in the United States show that radical prostatectomy is the most common treatment in younger men with localized prostate cancer. Only 1 RCT provided subgroup analysis by age (10). Ten-year disease-specific survival benefits of radical prostatectomy compared with watchful waiting differed according to age (interaction term for age, 0.03). Survival was limited to men younger than 65 years of age.

With regard to tumor characteristics, we focused on baseline PSA levels and Gleason histologic score. The natural history of PSA-detected tumors is unknown because few men remain untreated for a long period. One report assessed 20-year outcomes in the United States from a cohort of 767 men with localized prostate cancer detected before PSA testing and treated with watchful waiting (70). Histologic grade was associated with overall and prostate cancer–specific survival. Men with low-grade prostate cancer were at minimal risk for dying of prostate cancer (7% of those with a Gleason score of 2 to 4). Men with high-grade prostate cancer had a high probability of dying of the disease within 10 years of diagnosis regardless of their age at diagnosis (53% of those with a Gleason score of 8 to 10). Outcomes according to race were not provided. Estimates from ongoing screening trials suggest that PSA increases the lead time for detection by 5 to 15 years (71). Therefore, the 20-year outcomes of men with prostate cancer diagnosed by PSA testing will probably be better than those in historical cohorts comprising men with cancer detected by methods other than PSA screening.

Most RCTs did not exclude participants on the basis of PSA levels or tumor histology, and few provided comparative analysis according to these factors. Men with Gleason scores of 8 to 10 were more likely than men with Gleason scores of 2 to 6 to have evidence of PSA recurrence, regardless of whether treatment was radical prostatectomy alone or was combined with neoadjuvant androgen deprivation. One RCT reported that the 10-year disease-specific survival benefit of radical prostatectomy versus watchful waiting did not differ according to baseline PSA level or Gleason histologic score among men with tumors primarily detected by methods other than PSA testing (10). High-dose EBRT was more effective than conventional-dose therapy at controlling biochemical failure in both low-risk (PSA level <10 μg/L, tumor stage ≤T2a, or Gleason score ≤6) and higher-risk disease (25). When the higher-risk men were further divided into intermediate- and high-risk groups, the benefit of high-dose therapy remained for the intermediate-risk patients but not for the highest-risk patients. On the basis of limited nonrandomized data, disease-specific survival was similar for men with a baseline PSA level greater than 10 μg/L who were treated with radiation therapy compared with those treated with radical prostatectomy (3). Men with Gleason scores of 8 to 10 were more likely than men with Gleason scores of 2 to 6 to have biochemical recurrence, regardless of type of treatment (3, 69).

Little high-quality evidence is available to guide patients and their families and health care providers on the comparative effectiveness and harms of treatments for clinically localized prostate cancer, especially in men with PSA-detected disease. Because the quality of evidence on treatment effectiveness, necessity, and harm was limited, we could not accurately assess many clinically important outcomes. All treatments cause adverse events (primarily urinary, bowel, and sexual) that occur soon after therapy, although the frequency, duration, and severity vary among treatments.

Differences in development of metastatic disease and survival due to treatments are unlikely to occur for many years, especially among men with PSA-detected disease. In addition, treatment decision making may be based in part on differences in the importance that individuals assign to estimated effectiveness and convenience versus earlier and potentially persistent adverse events. Multidisciplinary health care teams and new educational materials are needed to assist patient decision making and match treatment selection with personal preferences. Key features include accuracy of information, balanced presentation of treatment options, and comprehensibility to the average patient.

The paucity of clinically important information from high-quality randomized trials remains the main barrier to well-informed decision making. Few existing trials assessed between-treatment rather than within-treatment category differences. Few randomized trials were adequately powered to assess overall or disease-specific survival or metastases. The 3 RCTs comparing surgery with watchful waiting or radiation therapy were old or were conducted before prostate cancer detection with PSA testing was available. Some studies used technical aspects of treatment that may not reflect current practice. Primary androgen deprivation, cryotherapy, brachytherapy, intensity-modulated radiation therapy, proton-beam radiation therapy, and laparoscopic and robotic-assisted radical prostatectomy have not been evaluated in randomized trials, despite their widespread use.

Few RCTs provided comparative analysis according to PSA levels or tumor stage. Observational studies also failed to adequately control for important confounding factors. Reporting and definitions of outcomes varied widely. Secondary analysis of 1 RCT comparing radical prostatectomy with watchful waiting indicated that improvement in disease-specific mortality at 10 years due to radical prostatectomy was limited to men younger than age 65 years but was not associated with baseline PSA level or Gleason score. Fewer than 5% of these men had prostate cancer detected by PSA testing.

Data from RCTs indicate that men with Gleason scores of 8 to 10 were more likely than men with Gleason scores of 2 to 6 to have evidence of biochemical recurrence, regardless of whether treatment was radical prostatectomy alone or was combined with androgen deprivation. High-dose EBRT was more effective than conventional-dose EBRT in controlling biochemical failure in both low-risk disease and higher-risk disease. No RCT provided outcomes according to race.

Clinically relevant outcomes include overall survival, disease-specific survival, metastatic disease–free survival, adverse events, quality of life, and costs. Standardized definitions of biochemical disease–free survival according to patient and tumor characteristics are needed. Previously initiated RCTs of brachytherapy versus radical prostatectomy for men with low-risk prostate cancer and EBRT versus radical prostatectomy or cryotherapy were closed because of poor recruitment. Two ongoing trials, one in the United States (72) and one in the United Kingdom (73), are evaluating radical prostatectomy or radical conformal radiation therapy treatments with watchful waiting or active monitoring with delayed intervention in men with mostly PSA-detected, clinically localized prostate cancer. Other studies in progress or development include cryotherapy versus EBRT and an RCT evaluating radical prostatectomy versus expectant management in men with “low-risk” prostate cancer with delayed intervention based on repeated PSA testing and prostate biopsy results. Successful completion of these studies is needed to provide accurate assessment of the comparative effectiveness and harms of therapies for localized prostate cancer.

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Figures

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Appendix Figure 1.
Study flow diagram.

AUA = American Urological Association; RCT = randomized, controlled trial; RP = radical prostatectomy.

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Figure 1.
Overall survival at time points, by treatment, from nonrandomized studies.

The symbol size is proportional to the number of patients: <50, 50–150, 150–300, or >300. Brachy = brachytherapy; C-EBRT = conformal external-beam radiation therapy, EBRT = external-beam radiation therapy; RP = radical prostatectomy; WW = watchful waiting.

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Figure 2.
Complications of brachytherapy, radical prostatectomy, external-beam radiation therapy, conformal external-beam radiation therapy, nerve-sparing radical prostatectomy, and watchful waiting from nonrandomized studies.

The symbol size is proportional to the number of patients: <50, 50–150, 150–300, or >300.

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Appendix Figure 2.
Biochemical progression–free survival after cryotherapy or high-intensity focused ultrasonography among patients in nonrandomized clinical trials and case series.

*Combined with transurethral resection of the prostate.

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Appendix Figure 3.
Clinical outcomes after laparoscopic radical prostatectomy, robotic-assisted radical prostatectomy, or intensity-modulated radiation therapy.

PSA = prostate-specific antigen.

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Tables

Table Jump PlaceholderTable 1.  Summary of Evidence on the Comparative Effectiveness and Harms of Therapies for Localized Prostate Cancer
Table Jump PlaceholderAppendix Table 1.  Description and Quality of the Included Randomized Trials
Table Jump PlaceholderTable 2.  All-Cause Mortality in Randomized, Controlled Trials
Table Jump PlaceholderAppendix Table 2.  Biochemical/Clinical Progression or Recurrence in Randomized, Controlled Trials from the Era of Prostate-Specific Antigen Testing
Table Jump PlaceholderAppendix Table 3.  Patient Characteristics and Response to Therapy at 24 Months of Follow-up in the Prostate Cancer Outcomes Study, by Treatment

References

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