Description of Condition

Prostate cancer is the most common nondermatologic cancer in men. In 2007 an estimated 218,890 men will be diagnosed with, and 27,050 deaths will be attributed to, prostate cancer in the United States. Approximately 90 percent of men have disease considered confined to the prostate gland (clinically localized disease). Prostate cancer incidence has increased coinciding with introduction of the PSA blood test. Disease-specific mortality rates have declined, and an estimated 1.8 million men living in the United States have a diagnosis of prostate cancer. ¹

Autopsy studies indicate that the prevalence of subclinical prostate cancer is high at all ages: 30 percent for men ages 30–39 years and more than 75 percent for men older than 85 years. ² Clinically-detected prostate cancer is primarily a disease of elderly men. ² Many prostate cancers have a relatively protracted course if left untreated. Due largely to widespread PSA testing, the lifetime risk of being detected with prostate cancer in the United States has nearly doubled to 20 percent. However, the risk of dying of prostate cancer has remained at approximately 3 percent. Therefore, many men die with, rather than from, prostate cancer. Considerable over detection and treatment may exist.

The primary goal of treatment is to target intervention to men most likely to need intervention in order to prevent prostate cancer death and disability while minimizing intervention-related complications. Common treatments include watchful waiting (expectant management), surgery to remove the prostate gland (radical prostatectomy), external beam radiotherapy, and interstitial radiotherapy (brachytherapy), freezing the prostate (cryotherapy), and androgen deprivation therapy (Table 1). Patient treatment decisions incorporate physician recommendations, estimated likelihood of cancer progression without treatment, as well as treatment-related convenience, costs, and potential for eradication and adverse effects. ³ Patient characteristics, including race/ethnicity, age, and comorbidities, have an important role in predicting mortality, the likelihood of urinary, bowel, and sexual dysfunction, and treatment selection. However, little is known about how these characteristics modify the effect of treatment.

Table 1

Treatment options for clinically localized prostate cancer.

Strategies for early detection of prostate cancer include the DRE and PSA blood testing. The DRE ⁴ has not been proven to improve morbidity or mortality. Sensitivity, specificity, and inter-examiner agreement with findings are poor. The DRE requires considerable experience to achieve the tactile sensitivity for detection of early tumors. More than half of subjects with DRE-detected cancer will have disease that has spread beyond the gland at diagnosis. ⁵

Prior to the advent of widespread PSA testing, most prostate cancers were detected based on abnormalities on the DRE or incidentally from tissue obtained at surgery for treatment of symptoms due to benign prostatic obstruction. Prostate cancer can cause signs or symptoms due to local (hematuria, urinary obstruction), regional (edema), or metastatic progression (bone pain). However, the vast majority of newly diagnosed prostate cancers in the United States are asymptomatic and detected by elevated levels or rates of changes of PSA tests. Estimates for the lead time associated with PSA-detected tumors range from 5–15 years. Many tumors detected by PSA testing are found serendipitously and may never cause signs or symptoms. The clinical significance, natural history, and comparative effectiveness of treatments, particularly in PSA-detected cancer, are not known.

In the United States, nearly three-quarters of men over age 50 have had at least one PSA test. PSA testing finds more cancers, shifts detection to tumors of lower stage, smaller volume, and at earlier time periods (stage, lead, and length shift) compared to DRE. Sensitivity and specificity of the PSA test vary with test thresholds of abnormality as well as factors such as family history, age, gland size, findings on DRE, and whether prior biopsies (negative) have been obtained.

The greatest factor leading to a diagnosis of prostate cancer is aggressive testing. The lifetime risk of prostate cancer diagnosis for men in their 50s in the United States was approximately 10 percent prior to widespread PSA testing. This nearly doubled to 19 percent during 2000-2002 with widespread PSA testing. With increasing regular and repeated PSA testing, lower PSA thresholds considered normal, and obtaining a greater numbers of core prostate specimens during biopsy, the lifetime risk of being diagnosed with prostate cancer is likely to exceed 20 percent. An individual's risk of both any prostate cancer and potentially aggressive cancers can be calculated using a risk assessment tool (http://www.compass.fhcrc.org/edrnnci/bin/calculator/main.asp) and may be useful for decisionmaking. ⁶

Increased detection of localized disease has resulted in more frequent utilization of interventions that are potentially effective but have adverse effects, thus complicating treatment decisionmaking. This may be particularly problematic in men with a life expectancy <10–15 years due to age or comorbid conditions. For example, among men >75 years, almost half have received PSA screening, including those in poor health. ⁷ The likelihood of detecting clinically insignificant disease in men over age 75, based on histopathologic criteria, has been estimated to be 56 percent. ⁸

Despite widespread testing, there is no conclusive evidence that screening improves morbidity or mortality. Prostate cancer screening is associated with AEs, including anxiety related to abnormal results, pain, infection, and bleeding due to diagnostic prostate biopsies, and detection/treatment of prostate cancers unlikely to cause health problems. ^{9 – 11} While prostate cancer mortality rates have been declining in several countries and some age groups, it is not clear if this is due to increased PSA testing.

Pretreatment assessment of whether prostate cancer is localized is determined by tumor stage based on clinical examination; primarily the DRE. Prostate cancer believed confined to the prostate gland (T1–T2, NxM0 or Stage 1–2) is considered “clinically localized,” forms the foundation for treatment decisionmaking, and is the focus of this report. T1 tumors include those with a normal DRE (typically detected by abnormalities of PSA tests but also diagnosed on histopathology from specimens obtained during surgical prostate resection for treatment of benign prostate conditions). T1a and T1b are defined as incidental histologic findings of less than and greater than 5 percent of tissue resected during transurethral resection of the prostate (TURP), respectively. T1c is noted as a nonpalpable tumor identified due to an elevated PSA. T2 stage is described as an abnormal DRE but no evidence of disease spread beyond the prostate. T2a involves a tumor in up to one-half of a lobe, T2b involves more than one-half but is limited to one lobe, and T2c is a tumor in both lobes. Additional tests, including x-rays, bone scans, computerized tomography (CT), or magnetic resonance imaging (MRI) are of limited use and not typically performed.

Because of limited sensitivity of pretreatment evaluations, some men with clinically localized disease may have disease that has spread outside of the gland (i.e., pathologically nonlocalized). The risk of pathologically nonlocalized disease is associated with several pretreatment classification factors. Classification includes measures of tumor volume/extent determined by tumor stage, number of biopsy cores with cancer, and extent of cancer in the involved core(s). The primary measure of aggressiveness is the Gleason histologic score. Gleason scores range from 2–10. Gleason 8–10 tumors are considered the most aggressive, Gleason 7 tumors somewhat less, and Gleason ≤6 tumors potentially indolent. ¹²

Pretreatment histology is determined based on a pathologist's examination of several small cores of prostate tissue. Typically, six cores are obtained during a prostate biopsy (sextant biopsy that includes both lobes of the prostate). However, the number has increased over time to 12, 24, and even “saturation techniques.” This has led to an increasing amount of prostate glands sampled with enhancement in the likelihood of detecting even small volume disease. In addition to the histologic score, the number of biopsy cores that contain prostate cancer and the percent within each core containing tumor is recorded. Risk stratification strategies have incorporated PSA level, biopsy Gleason score, and clinical tumor category because these appear to be associated with risk of PSA failure and prostate cancer-specific mortality. Readily available tables have been designed to help men and their doctors predict the definitive pathological stage (determined after surgery, when a pathologist examines the removed prostate for the presence of cancer) and are often used in treatment decisionmaking. ¹³ Because Gleason score, tumor volume, and PSA levels do not appear to be complete indicators of an individual tumor risk characteristic, efforts are underway to identify more reliable prognostic factors.

One risk classification currently recommended is:

• Low Risk: PSA ≤10 ng/ml, Gleason score ≤6, and clinical stage T1c or T2a
• Intermediate Risk: 10 <PSA ≤20 ng/ml, or Gleason score 7, or clinical stage T2b
• High Risk: PSA >20 ng/ml or Gleason score 8–10 or clinical stage T2c

The most common Gleason score is 6 or 7 disease. ^{14, 15} Most men diagnosed with prostate cancer have a PSA between 4 and 10 ng/ml; increasingly between 2.5 and 4.0 ng/ml. Therefore, the average man currently diagnosed with prostate cancer and facing uncertainty about the comparative risks, benefits, and outcomes of treatment decisions is between 60 and 70 years of age and has “low-risk” disease. However, changes in the application of the Gleason scoring has resulted in contemporary uropathologists assigning these grades more commonly than in the past when these tumors were more likely to receive a grade one or two scores lower. ^{14, 15} A resultant improved survival relative to historical controls assigned similar scores has been reported. As thresholds to define PSA abnormalities are lowered and a greater number of prostate cores obtained at biopsy, an individual diagnosed with prostate cancer in the future is likely to have a lower PSA level, smaller tumor volume, and better long-term natural tumor history.

Factors incorporated into the decision process include cancer eradication, adverse effects, physician recommendations, convenience, and costs. Patient characteristics, including age, race, family history, and comorbidities have an important role in predicting the mortality rate of a patient with localized prostate cancer and the likelihood of urinary, bowel, and sexual dysfunction. Little is known regarding how patient characteristics modify the effect of treatment.

Provider/hospital characteristics may affect number and type of detected tumors, patient characteristics, treatment selection, and outcomes. The effect of provider volumes on clinical outcomes in men with localized prostate cancer is not well established. Evidence suggests that provider characteristics, including higher volume, ¹⁶ affiliation with academic center, ^{17, 18} and profit status ^{18, 19} are associated with improved quality of care and better outcomes. The association can be partially explained by patient selection, aging and comorbidities, and differences in process of care. ²⁰ One study found substantial differences in published definitions of volume categories and its effects on surgical mortality and complications after urological cancer procedures. ²¹ Volume thresholds and patient distributions in low and high volume hospitals are defined for several cardiovascular and oncology operations, but not for prostate cancer. ²² The effect size of provider volumes on clinical outcomes in patients with localized prostate cancer is not well established. Because prostate cancer is the second most expensive cancer organ site for Medicare with approximately $8 billion annual expenditure, ²³ improved understanding of the role of provider/hospital characteristics is important.

Specialty and geographical location of providers influence diagnostic strategies and the management of localized prostate cancer. ^{24 – 26} Variability in the management of localized prostate cancer is often based on physician opinions and specialty. ^{25, 26} Diagnosis of localized disease is based primarily on screening of asymptomatic patients. Therefore, differences in screening practices lead to length bias in the stage of tumors detected and referral onward to more likely recommend intervention. Physician recommendations play an important role in patient decisions on treatment preferences. ²⁷ A systematic review of treatment choices for localized prostate cancer concluded that variations in treatment decisions are attributable to differences in physician recommendations more than on patient and tumor characteristics. ³ Recent studies showed that patient and physicians treatment preferences reflect perceived personal factors more than evidence-based recommendations. ^{3, 28}

Scope and Key Questions

This report was conducted for the Agency for Healthcare Research and Quality (AHRQ) under Section 1013 of the Medicare Modernization Act to address the following questions:

1.

What are the comparative risks, benefits, short- and long-term outcomes of the following therapies for clinically localized prostate cancer?

a.

Radical prostatectomy, including perineal and retropubic approaches, and open vs. laparoscopic vs. no lymphadenectomy

b.

External beam radiotherapy, including standard therapy, and therapies designed to decrease exposure to normal tissues such as 3D conformal radiation therapy and Intensity Modulated Radiation Therapy

c.

Interstitial brachytherapy

d.

Cryosurgery

e.

Expectant management (“watchful waiting”)

f.

Hormonal therapy as primary therapy, adjuvant or neoadjuvant to other therapies

2.

How do specific patient characteristics, e.g., age, race/ethnicity, presence or absence of comorbid illness, preferences (e.g., tradeoff of treatment-related adverse effects vs. potential for disease progression) affect the outcomes of these therapies, overall and differentially?

3.

How do provider/hospital characteristics affect outcomes overall and differentially (e.g., geographic region and volume)?

4.

How do tumor characteristics, e.g., Gleason score, tumor volume, screen vs. clinically detected tumors, and PSA levels, affect the outcomes of these therapies, overall and differentially?

5.

What are the gaps in our knowledge that would allow patients to better understand the comparative risks, benefits, and outcomes of these treatment options for clinically localized prostate cancer, including for those with and without screen-detected disease?