Background

Prostate cancer is the most common nondermatologic cancer in men.^1,2 American Cancer Society data show that in 2012, an estimated 241,740 men were expected to receive a diagnosis of prostate cancer and 28,170 were expected to die from the disease.¹ Approximately 90 percent of those who receive such a diagnosis have cancer confined to the prostate gland (clinically localized disease). Since 2004, the prostate cancer incidence rate has decreased by 2.7 percent annually among men 65 years of age or older and has remained steady among men younger than age 65.¹ The major risk factors for prostate cancer are advanced age, race and ethnicity (the highest incidence is in blacks), and family history.

Many cases of prostate cancer have a protracted course if left untreated. Mortality rates have been declining, and many men die with prostate cancer rather than from it.³ During its early stages, clinically localized prostate cancer is usually asymptomatic.⁴ However, as the cancer grows, it may cause urinary problems, such as blood in the urine, pain or a burning sensation during urination, a weak urine stream, inability to urinate, and frequent urination, especially at night. These presenting symptoms along with a physical examination, prostate-specific antigen (PSA) levels, and biopsy may be used to evaluate patients for the presence of prostate cancer.

The PSA test is used to measure blood levels of PSA, a protein produced by the prostate gland.⁴ Elevated PSA levels may indicate prostate cancer, but elevations are also seen in conditions such as benign prostatic hyperplasia and prostatitis. Conversely, some patients with prostate cancer do not have elevated PSA levels.⁵ Moreover, the cutpoint separating a “normal” PSA level from an abnormal level also remains a subject of debate. In recent years, more frequent use of PSA testing has intensified concern about overdiagnosis of prostate cancer—that is, detection of cancer that would have remained silent and caused the patient no illness throughout his lifetime.^2,4

In May 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against PSA-based screening for prostate cancer in healthy men of all ages, concluding that the harms of screening outweigh the benefits (Grade D recommendation).⁶ However, health care professionals and professional societies have continued to debate the merits of PSA-based screening. Potential benefits of regular PSA screening include early cancer detection and reduced mortality rates. Potential harms include anxiety related to abnormal results, pain, infection, bleeding due to diagnostic biopsies, and the morbidity of definitive treatment in men who may not need such treatment.^7-10

Landmark trials, including the European Randomized Study of Screening for Prostate Cancer (ERSPC), the Göteborg trial (from the Swedish center in the ERSPC trial), and the U.S.-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial have published findings on PSA screening's effect on prostate cancer mortality. Both the ERSPC and PLCO trials found little effect on mortality after PSA screening.¹¹ The Göteborg trial reported a 0.40 percent absolute cumulative risk reduction in prostate cancer mortality (from 0.90% in the control group to 0.50% in the screening group) and no difference in overall mortality in men aged 50–64 years over 14 years of screening.¹²

Citing these trials, USPSTF assessed the potential benefit of screening to be zero to one death from prostate cancer prevented for every 1,000 men aged 55–69 years screened by PSA testing every 1–4 years for 10 years. USPSTF also estimated that there would be 100–120 men with false-positive tests and 110 men with true-positive tests; complication rates from treatment would range from fewer than 1 death per 1,000 men screened to 29 cases of erectile dysfunction per 1,000 men screened.⁶ For these reasons, determining which men with clinically localized prostate cancer are most likely to benefit from interventions such as surgery and radiation could potentially improve the balance of benefits and harms, especially in those identified by screening.

Current practice is to use tumor grade as the primary prognostic variable in patients with clinically localized prostate cancer.² After biopsy confirms the presence of the cancer, pathologists report tumor grade in terms of the Gleason score, which ranges from 2 to 10.⁴ Gleason 8–10 tumors are considered the most aggressive, Gleason 7 tumors are considered somewhat less aggressive, and Gleason 6 or lower tumors are considered potentially indolent.¹³ However, the Gleason grade assigned based on a biopsy specimen may differ from the Gleason grade assigned based on a surgical specimen. Although the primary measure of tumor aggressiveness is the Gleason histologic score, efforts are under way to identify more reliable prognostic factors. PSA, PSA kinetics (rate of increase in PSA over time, or PSA velocity, and PSA doubling time), and digital rectal examination (DRE) are still very important when considering treatment options.

Staging is the process of assessing whether the cancer is confined to the prostate gland or has spread beyond it and, if so, to what extent it has spread.⁴ Staging of prostate cancer could be clinical (based on a DRE of the prostate gland, prostate biopsy, and laboratory tests) or pathological (based on surgery and examination of resected prostate tissue). The staging system currently used is the American Joint Committee on Cancer (AJCC) TNM classification.⁴ TNM classification is based on the extent of primary tumor (T stages), whether cancer has spread to the adjacent lymph nodes (N stages), and any metastasis (M stages).^4,14 These classifications are detailed in Table 1, Table 2, and Table 3.

Table 1

American Joint Committee on Cancer TNM classification: Tumor (T) stages.

Table 2

American Joint Committee on Cancer TNM classification: Lymph node (N) stages.

Table 3

American Joint Committee on Cancer TNM classification: Metastasis (M) stages.

Clinicians usually make pretreatment assessment of prostate cancer tumor stage based on DRE and in some cases, transrectal ultrasound of the prostate (TRUS) and/or magnetic resonance imaging (MRI). The accuracy of clinical staging is affected by tumor size and location as well as the skill of the examiner and the accuracy and interpretation of the imaging study, if performed. Several surgical studies have documented both under- and overstaging by clinical examination when compared with surgical findings. For example, although the Scandinavian Prostate Cancer Group 4 (SPCG-4) trial's eligibility criteria specified clinical stage T1 or T2 disease, nearly half the patients undergoing RP were found to have extracapsular extension (pT3) on resection.¹⁵

Unfortunately, additional assessments such as radiographs, bone scans, computed tomography, and MRI are of limited use, particularly for detecting small foci of cancer in lymph nodes. Several methods for improving detection via imaging are under study. For detecting cancer in the lymph nodes, an innovative technique called enhanced MRI may help.¹⁴ For identifying prostate cancer in other parts of the body, a new type of positron-emission tomography scan that uses the radioactive tracer carbon acetate as a replacement for fluorodeoxyglucose may be useful. It may also be used to define the effectiveness of the therapy.¹⁴

Determining tumor anatomy and extent when assigning clinical stage is inherently difficult, but clinical application of current staging criteria is also problematic. Staging errors have been documented in several studies, including one using the Cancer of the Prostate Strategic Urologic Research Endeavor database.¹⁶ This registry included men with prostate cancer from 40 academic and community-based urology practices. Reese et al. examined the clinical T stage reported by clinicians based on their individual interpretation of clinical staging criteria and compared that with the corrected clinical stage based on AJCC staging criteria. They found staging errors in 1,370 of 3,875 men (35.4%); the clinicians assigned a lower stage than was appropriate 55% of the time, and a higher stage 45% of the time.¹⁶

A number of risk classification schemes have been developed in an attempt to better predict the pathologic stage and the aggressiveness of prostate cancer. The TNM categories are combined with the Gleason histologic score and PSA-level results (stage grouping) to determine the overall stage, which is commonly reported in Roman figures (Stages I, IIA, IIB, III, and IV), with stage I being the least advanced and stage IV being the most advanced. In the absence of a Gleason histologic score, staging can still be based on the TNM classification. The criteria for Stages I, II and III are provided in Table 4.

Table 4

Anatomic and prognostic prostate cancer staging.

Another categorization, the D'Amico Classification System, also incorporates PSA levels, Gleason histologic score, and TNM stage. It stratifies tumors into low-, intermediate-, and high-risk in terms of their likelihood of progressing with no treatment or of recurring after early intervention.⁴

• Low risk (corresponding to stage I): a PSA level of 10 ng/mL or less, a Gleason score of 6 or less, and a clinical stage of T1c or T2a
• Intermediate risk (roughly corresponding to stage IIA): a PSA level of 10–20 ng/mL, a Gleason score of 7, or a clinical stage of T2b but not qualifying for high risk
• High risk (roughly corresponding to stage IIB): a PSA level of more than 20 ng/mL, a Gleason score of 8–10, or a clinical stage of T2c

The risk assessment scheme described above, although commonly used among men with clinically localized prostate cancer, has significant limitations in assessing patients in the intermediate- and high-risk groups. Another example of a risk assessment scheme that has been developed, validated across populations, and associated with both overall and cause-specific survival is the University of California, San Francisco, Cancer of the Prostate Risk Assessment (CAPRA) score. CAPRA can be used to predict disease recurrence and mortality after radical prostatectomy (RP).^17-20 These risk assessment tools may be improved in the future with the use of biomarkers (e.g., actinin alpha 1, derlin 1).

The term “clinically localized” prostate cancer has most often been used to describe tumors of stages I and II, and the term “locally advanced” has been used for tumors that have spread beyond the prostatic capsule (“extracapsular extension”) but not beyond the seminal vesicles.

However, the National Comprehensive Cancer Network (NCCN) issued a clinical practice guideline in 2013 in which it defined clinically localized prostate cancer as clinical stages T1–T3a, NX, M0; or stage I–IIIa.²¹ This shift reflects the impression that tumors with extracapsular extension (T3a) but without spread into the seminal vesicles (T3b) respond better to therapy. The NCCN guideline, which was based on opinions of individual experts, describes the various categories based on the recurrence risk:²¹

• Clinically localized
  • Very low recurrence risk: T1c, Gleason score 6 or less, PSA of less than 10 ng/mL, fewer than 3 prostate biopsy cores positive, 50% or less cancer in each core, and PSA density (PSA/prostate volume) of less than 0.15 ng/mL/g
  • Low recurrence risk: T1–T2a, Gleason score 2-6, and PSA of less than 10 ng/mL
  • Intermediate recurrence risk: T2b-T2c or PSA 10–20 ng/mL or Gleason score 7
  • High recurrence risk: T3a or Gleason score 8–10 or PSA of more than20 ng/mL
• Locally advanced
  • Very high recurrence risk: T3b–T4

The focus of this report is clinically localized prostate cancer (T1–T3a). Locally advanced (T3b–T4), metastatic, and recurrent prostate cancer are outside the scope of this report.

Therapies for Clinically Localized Prostate Cancer

The primary goal of treating clinically localized prostate cancer is to target the men most likely to need intervention to prevent disability or death while minimizing intervention-related complications. Treatment options that are frequently used include the following and are described in Table 5:

Table 5

Treatment options for clinically localized prostate cancer.

• RP, including laparoscopic or robotic-assisted prostatectomy (RALRP)
• External beam radiotherapy (EBRT), including conventional radiation, intensity modulated radiation therapy (IMRT), three-dimensional conformal radiation therapy (3D-CRT), stereotactic body radiation therapy, and proton beam radiation
• Interstitial brachytherapy (BT)
• Cryotherapy
• Observation or watchful waiting (WW) (these terms will be used interchangeably)
• Active surveillance (AS)
• Hormonal therapy (e.g., androgen deprivation therapy [ADT])
• High-intensity focused ultrasound (HIFU)

Choice of treatment options may be influenced by factors such as patient age and health at the time of the diagnosis, life expectancy, estimated likelihood of cancer progression without treatment, the surgeon's experience and preference, and treatment-related convenience, costs, and potential for eradication and adverse effects (e.g., incontinence, sexual dysfunction).⁴ Before choosing any intervention, an assessment of the overall health status of patients is important because it may influence response to therapy, severity of complications, and life expectancy.⁴

The treatment for men with clinically localized prostate cancer has been the subject of much debate. As discussed above, identifying those men most likely to benefit from aggressive therapy is challenging. Ideally, those with slowly progressing disease who are more likely to die of other causes would be spared unnecessary treatment, while men with aggressive, localized prostate cancer would be offered curative procedures.^3,10 One option under study for assessing disease progression is an approach called “active surveillance,” or AS, which typically includes monitoring of PSA levels and rate of increase, periodic DRE, and repeat prostate biopsies with curative intent.

The National Cancer Institute and the Centers for Disease Control and Prevention sponsored a National Institutes of Health (NIH) State-of-the Science Conference in December 2011 to better understand the risks and benefits of AS and other observational management strategies for PSA screening–detected, low-grade, localized prostate cancer.³ The panel concluded that AS should be offered to patients with low-risk prostate cancer.

The NIH panel used the term “watchful waiting”, or WW, to describe a palliative observational strategy—that is, waiting for symptoms to appear and then intervening to manage the symptoms. In the 2008 systematic review, “Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer,” these two approaches were considered together.²² In the literature, the distinction between AS (with curative intent) and other observational strategies (with palliative intent) has not always been clear; however, for this systematic review update, we attempted to separate the two using the definitions proposed at the 2011 NIH State-of-the-Science Conference.³

Findings From the Original Report

The 2008 systematic review on therapies for clinically localized prostate cancer, written by the University of Minnesota Evidence-based Practice Center (EPC), included 18 randomized controlled trials (RCTs) and 473 observational studies.²² None of these included studies enrolled patients with prostate cancer primarily identified by PSA testing. The main findings of the 2008 report include the following:

• No single therapy can be considered the preferred treatment for localized prostate cancer because of limitations in the body of evidence as well as the likely tradeoffs a patient must make between estimated treatment effectiveness, necessity, and adverse effects. All treatment options result in adverse effects (primarily urinary, bowel, and sexual), although the severity and frequency may vary across treatments.
• No RCT reported head-to-head comparisons of treatment outcomes stratified by race/ethnicity.
• The results from the analysis of national administrative databases and surveys suggested that provider and hospital characteristics, including RP procedure volume, physician specialty, and geographic region, affect outcomes. Patient outcomes varied in different locations and were associated with provider and hospital case volume, independent of patient and disease characteristics. Screening practices and treatment choices varied by physician specialty and across U.S. regions. Clinicians were more likely to recommend procedures they performed regardless of tumor grades and PSA levels.
• Few data exist on the comparative effectiveness of treatments based on stratification of risk into low, intermediate, and high categories using PSA levels, histologic score, and tumor volume.

Overall, the authors concluded that “assessment of the comparative effectiveness and harms of localized prostate cancer treatments is difficult because of limitations in the evidence.”²² For example, only a few RCTs directly compared the effectiveness between (rather than within) major treatment categories. Additionally, many of these RCTs were inadequately powered to provide long-term survival outcomes, with the majority reporting biochemical progression or recurrence as the primary outcomes. Finally, some RCTs were conducted before prostate cancer detection with PSA testing was available.

Remaining issues and future research needs that were outlined in the 2008 report included the following:²²

• RCTs should evaluate relative effectiveness and adverse events and stratify their findings based on patient (e.g., age, race, comorbidity) and tumor (e.g., level of PSA, stage, histologic grade) characteristics.
• Comparative trials on technologies that were considered to be “emerging” at the time the report was written—IMRT, proton beam radiation, cryotherapy, and robotic-assisted and laparoscopic prostatectomy—must provide long-term followup data.
• Head-to-head RCTs must be adequately powered to compare primary treatments for localized prostate cancer.
• Trials should standardize reporting of key clinically relevant outcomes and should structure the assessment of outcome measures such as quality of life (QOL) and health status.

Rationale for Update

A surveillance analysis conducted by the Southern California EPC in May 2012 determined the need for this update. In the analysis, investigators evaluated the Key Questions (KQs) from the 2008 systematic review and conducted a restricted literature search for new evidence.²³ The key finding of the analysis was that the Prostate Cancer Intervention Versus Observation Trial (PIVOT),^23-25 published after the 2008 report, makes the 2008 report's conclusions out-of-date. Specifically, the analysis suggested re-evaluating KQs 1, 2, and 4 as newly available evidence from the PIVOT trial and other recent studies may change the conclusions from those of the previous report.²³

Conceptual Framework

An analytic framework illustrating the connections between the population of interest (patients with clinically localized prostate cancer), the treatments, and the outcomes is shown in Figure 1 below. The population of interest enters the diagram at the left, undergo treatment (KQ 1), and outcomes (intermediate and patient-oriented clinical outcomes) are monitored and recorded. Intermediate outcomes such as biochemical progression require shorter followup for measurement than clinical outcomes such as all-cause or prostate cancer–specific mortality, which require years of followup to accumulate enough events for detection of differences between treatments. When enough outcome data are available, investigators often conduct statistical analyses to detect moderators of treatment effects (KQ 2–4).

Figure 1

Analytic framework. Abbreviations: 3D = three-dimensional; KQ = key question.